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Yilmazer-Hanke, D. M. and J. Hanke (1999). "Progression of Alzheimer-related neuritic plaque pathology in the entorhinal region, perirhinal cortex and hippocampal formation." Dement Geriatr Cogn Disord 10(2): 70-6.
Extracellular deposits of the beta-amyloid protein and intraneuronal neurofibrillary changes are hallmarks of Alzheimer's disease. Neurofibrillary changes in the cell body of neurons are the neurofibrillary tangles, while beta-amyloid deposits containing dystrophic neurites with neurofibrillary changes are called neuritic plaques. beta-Amyloid deposits and neurofibrillary tangles display a sequential accumulation in the cerebral cortex. In the present study, the topographical distribution of beta-amyloid deposits and neuritic plaques in the entorhinal region, perirhinal cortex and hippocampal formation was investigated in relationship to the amyloid and neurofibrillary staging proposed by Braak. The number of subregions displaying beta-amyloid deposits and neuritic plaques continuously increases in correlation with the amyloid stage (for beta-amyloid deposits r = 0.90, p < 0.0001, for neuritic plaques r = 0.74, p < 0.0001) and neurofibrillary stage (for beta-amyloid deposits r = 0.53, p < 0.0001, for neuritic plaques r = 0.68, p < 0. 0001). Parallel to the advancement in the neurofibrillary stage, early and late predilection sites of beta-amyloid deposits and neuritic plaques can be distinguished. The early predilection sites correspond to projection areas of regions which exhibit incipient neurofibrillary tangles. Furthermore, neuritic plaques only occur in the presence of neurofibrillary tangles in the areas investigated. The findings indicate that neuritic plaques gradually develop in the projection areas of tangle-bearing neurons.

Yang, Y., K. Beyreuther, et al. (1999). "Spatial analysis of the neuronal density of aminergic brainstem nuclei in primary neurodegenerative and vascular dementia: a comparative immunocytochemical and quantitative study using a graph method." Anal Cell Pathol 19(3-4): 125-38.
A graph method was employed to analyse spatial neuronal patterns of pontine nuclei with ascending aminergic projections to the forebrain (nucleus centralis superior (NCS), raphes dorsalis (NRD) and locus coeruleus (LC)), in Alzheimer disease (AD), Huntington disease (HD), and vascular (VD) as well as "mixed-type" (VA) dementia, compared with non-demented controls (CO) and a small sample of brains from schizophrenics ("dementia praecox" (DP)). The quantitative evaluations by the "minimal spanning tree (MST)" were complemented by rough neurofibrillary tangle (NFT) counts and by semiquantitative immunohistochemical assessment of amyloid deposition, neuritic plaque formation, and cellular gliosis. The AD cases showed a significant decline of neuronal density in all nuclei examined, as compared with controls and DP. Neuronal loss was not significant in VD, while the mixed cases with both vascular and Alzheimer-type pathology exhibited pronounced changes of neuronal density. Amyloid deposition occurred almost exclusively in AD and VA, as a rule, being of moderate degree, except for two presenile AD cases where it was marked. NFT were significantly increased in all nuclei in AD and in the VA cases, while they only occasionally appeared beyond age 55 in HD, DP and CO. The four HD cases showed in the NCS and NRD neuronal loss as severe as in AD. This neuronal loss implicates impairment of serotoninergic and noradrenergic neuromodulation as one basic mechanism promoting dementia in AD, VA and perhaps in HD.

Yan, R., M. J. Bienkowski, et al. (1999). "Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity." Nature 402(6761): 533-7.
Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified proteases, referred to as beta- and gamma-secretases, generates the amyloid beta-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid beta-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by beta-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the beta-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid beta-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.

Yamada, T., Y. Tsujioka, et al. (1999). "Immunohistochemistry and in situ hybridization of T-cell acute lymphoblastic leukemia-associated antigen 1 in human brain tissues." Dement Geriatr Cogn Disord 10(2): 59-63.
One of the proteins belonging to the transmembrane 4 superfamily, T-cell acute lymphoblastic leukemia-associated antigen 1 (TALLA1), behaves like a potential tumor-associated antigen. Furthermore, its mRNA is expressed in normal brain. We examined here the histochemical localization of the protein and its mRNA in human brain tissues. Both nonneurological and Alzheimer disease (AD) brains showed astroglial staining for the TALLA1 molecule. In AD brain tissues, globular dystrophic neurites were positively stained. In damaged white matter showing leukoaraiosis by CT scan there was varicose axonal staining with the anti-TALLA1 antibody. In situ hybridization histochemistry using a RNA probe demonstrated neuronal expression of the mRNA. These results suggest that TALLA1, like amyloid precursor protein or chromogranin A, is produced in neurons and transported by axonal flow.

Wolf, D. S., M. Gearing, et al. (1999). "Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study." Alzheimer Dis Assoc Disord 13(4): 226-31.
Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Wilson, C. A., R. W. Doms, et al. (1999). "Intracellular APP processing and A beta production in Alzheimer disease." J Neuropathol Exp Neurol 58(8): 787-94.
Senile plaques composed of A beta peptides are a histopathological hallmark of Alzheimer disease (AD). A role for A beta in the etiology of AD has been argued from analysis of mutations associated with a subset of early-onset familial AD (FAD). Expression of autosomal dominant mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) in affected patients, cultured cells, or transgenic mice leads to increased production of total A beta or increased production of A beta ending at residue 42 (A beta42). Since A beta42 is the more amyloidogenic and toxic species in vitro and is the major component of amyloid senile plaques in vivo, overproduction of this peptide may play a crucial role in the pathogenesis of AD. Thus, an understanding of the production of A beta within the cell in normal and pathological conditions is critical to understanding early events in AD. Studies in cell culture have established that processing of APP to form A beta can occur at multiple locations within the cell and leads to the production of 2 pools of A beta: a secreted pool composed predominantly of A beta40 and a nonsecreted, intracellular pool composed preferentially of more amyloidogenic A beta42. The purpose of this review is to provide a summary of our current understanding of APP processing in the generation of the secreted and intracellular pools of A beta and to propose a model linking the intracellular pool to the formation of extracellular plaques and neuronal pathology in AD.

Wevers, A., L. Monteggia, et al. (1999). "Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein." Eur J Neurosci 11(7): 2551-65.
Impairment of cholinergic transmission and decreased numbers of nicotinic binding sites are well-known features accompanying the cognitive dysfunction seen in Alzheimer's disease (AD). In order to elucidate the underlying cause of this cholinoceptive dysfunction, the expression of two pharmacologically different nicotinic acetylcholine receptor (nAChR) subunits (alpha4, alpha7) was studied in the cerebral cortex of Alzheimer patients as compared to controls. Patch-clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of alpha4- and alpha7-containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of alpha4 and alpha7 mRNA-expressing neurons were similar, whereas at the protein level a decrease in the density of alpha4- and alpha7-expressing neurons of approximately 30% was observed in Alzheimer patients. The histotopographical correlation of nAChR expression with accompanying pathological changes, e.g. accumulation of hyperphosphorylated-tau (HP-tau) protein and beta-amyloid showed that neurons in the vicinity of beta-amyloid plaques bore both nAChR transcripts. Neurons heavily labelled for HP-tau, however, expressed little or no alpha4 and alpha7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholinoceptive deficit in AD. Further investigations need to elucidate whether interactions of HP-tau with nAChR mRNA, or alterations in the quality of alpha4 and alpha7 transcripts give rise to decreased protein expression at the level of individual neurons.

Wang, J., D. W. Dickson, et al. (1999). "The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging." Exp Neurol 158(2): 328-37.
The abundance and solubility of Abeta peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Abeta1-40 and Abeta1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of Abeta1-40 and Abeta1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Abeta1-40 or Abeta1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble Abeta1-40 and Abeta1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Abeta1-40 were increased 20-fold while the average levels of insoluble Abeta1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Abeta1-40 and Abeta1-42 were the largest fractions of total Abeta in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain Abeta1-40 and Abeta1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Abeta1-40 plays mechanistic roles in the onset and/or progression of AD.

Veerhuis, R., I. Janssen, et al. (1999). "Cytokines associated with amyloid plaques in Alzheimer's disease brain stimulate human glial and neuronal cell cultures to secrete early complement proteins, but not C1-inhibitor." Exp Neurol 160(1): 289-99.
Complement activation products C1q, C4c/d, and C3c/d in amyloid plaques in Alzheimer's disease probably result from direct binding and activation of C1 by amyloid beta peptides. RT-PCR and in situ hybridization studies have shown that several complement factors are produced in the brain parenchyma. In the present study, cytokines that can be detected in amyloid plaques (i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha) were found to differentially stimulate the expression of C1 subcomponents, C1-Inhibitor (C1-Inh), C4, and C3, by astrocyte and microglial cell cultures derived from postmortem adult, human brain specimens and by neuroblastoma cell lines in culture. C1r and C1s were secreted at low levels by astrocytes and neuroblastoma cell lines. Exposure of cells to IL-1 alpha, IL-1 beta, TNF-alpha and to a far lesser extent IL-6, markedly upregulated C1r, C1s, and C3 production. C4 synthesis increased in response to interferon (IFN)-gamma and IL-6, whereas that of C1-Inh could be stimulated only by IFN-gamma. Thus, C1-Inh production is refractory to stimulation by plaque-associated cytokines, whereas these cytokines do stimulate C1r, C1s, and also C4 and C3 secretion by astrocytes and neuronal cells in culture. In contrast to the amyloid plaque associated cytokines IL-1 beta, IL-1 alpha, and TNF-alpha, the amyloid peptide A beta 1-42 itself did not stimulate C1r and C1s synthesis by astrocytes, microglial cells, or neuroblastoma cell lines. Microglial cells were the only cell type that constitutively expressed C1q. The ability of C1q to reassociate with newly formed C1r and C1s upon activation of C1 and subsequent inactivation by C1-Inh, may enable ongoing complement activation at sites of amyloid deposition, especially when C1-Inh is consumed and not replaced.

Urbanc, B., L. Cruz, et al. (1999). "Dynamics of plaque formation in Alzheimer's disease." Biophys J 76(3): 1330-4.
Plaques that form in the brains of Alzheimer patients are made of deposits of the amyloid-beta peptide. We analyze the time evolution of amyloid-beta deposition in immunostained brain slices from transgenic mice. We find that amyloid-beta deposits appear in clusters whose characteristic size increases from 14 microm in 8-month-old mice to 22 microm in 12-month-old mice. We show that the clustering has implications for the biological growth of amyloid-beta by presenting a growth model that accounts for the experimentally observed structure of individual deposits and predicts the formation of clusters of deposits and their time evolution.

Tseng, B. P., W. P. Esler, et al. (1999). "Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer's disease amyloid plaques in human brain preparations." Biochemistry 38(32): 10424-31.
Senile plaques composed of the peptide Abeta contribute to the pathogenesis of Alzheimer's disease (AD), and mechanisms underlying their formation and growth may be exploitable as therapeutic targets. To examine the process of amyloid plaque growth in human brain, we have utilized size exclusion chromatography (SEC), translational diffusion measured by NMR, and in vitro models of Abeta amyloid growth to identify the oligomerization state of Abeta that is competent to add onto an existing amyloid deposit. SEC of radiolabeled and unlabeled Abeta over a concentration range of 10(-)(10)-10(-)(4) M demonstrated that the freshly dissolved peptide eluted as a single low molecular weight species, consistent with monomer or dimer. This low molecular weight Abeta species isolated by SEC was competent to deposit onto preexisting amyloid in preparations of AD cortex, with first-order kinetic dependence on soluble Abeta concentration, establishing that solution-phase oligomerization is not rate limiting. Translational diffusion measurements of the low molecular weight Abeta fraction demonstrate that the form of the peptide active in plaque deposition is a monomer. In deliberately aged (>6 weeks) Abeta solutions, a high molecular weight (>100 000 M(r)) species was detectable in the SEC column void. In contrast to the active monomer, assembled Abeta isolated from the column showed little or no focal association with AD tissue. These studies establish that, at least in vitro, Abeta exists as a monomer at physiological concentrations and that deposition of monomers, rather than of oligomeric Abeta assemblies, mediates the growth of existing amyloid in human brain preparations.

Tolnay, M., M. Calhoun, et al. (1999). "Low amyloid (Abeta) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease." Neuropathol Appl Neurobiol 25(4): 295-305.
Argyrophilic grain disease constitutes one cause of late-onset dementia. Its classification among dementia disorders is still unclear because most of the reported argyrophilic grain disease cases are associated with neurofibrillary lesions (e.g. neurofibrillary tangles) which are also typical of Alzheimer's disease. In the present study we determine whether argyrophilic grain disease is associated with the senile plaques of Alzheimer's disease. The distribution and density of senile plaques was systematically investigated in 11 demented argyrophilic grain disease cases using Abeta immunohistochemistry and stereological techniques, and the results were compared with 11 Alzheimer's disease cases. All subjects with argyrophilic grain disease exhibited neurofibrillary changes corresponding to Braak stages I-III. Three of the 11 argyrophilic grain disease cases (27%) were completely devoid of Abeta deposits. In argyrophilic grain disease cases with senile plaques, the average total plaque-load was significantly lower (1%) than in Alzheimer's disease (3.1%) (P<0. 005). The regional distribution of the senile plaques and the proportion of diffuse vs. primitive or mature plaques in argyrophilic grain disease resembled values of senile plaques reported in non-demented elderly subjects, and was significantly different from Alzheimer's disease. Similarly the immunocytochemical profile of the Abeta deposition in argyrophilic grain disease resembled that of non-demented elderly subjects rather than that of subjects with Alzheimer's disease. As all argyrophilic grain disease cases under investigation were demented, including those devoid of senile plaques, the present study further supports the thesis that dementia in argyrophilic grain disease correlates more with the density and distribution of argyrophilic grains than with associated lesions of the Alzheimer-type.

Thal, D. R., W. Hartig, et al. (1999). "Diffuse plaques in the molecular layer show intracellular A beta(8-17)-immunoreactive deposits in subpial astrocytes." Clin Neuropathol 18(5): 226-31.
The presence of A beta protein- (A beta) containing astrocytes in diffuse plaques of the cortical layers II-VI has recently been demonstrated with antibodies directed against A beta(17-23) and C-terminal epitopes, of A beta. We here confirm and extend this finding by use of immunocytochemical double-labeling and preembedding immune-electron microscopy. Diffuse subpial plaques are associated with both anti-A beta(8-17) and anti-A beta(17-23)-positive granules in astrocytes. The ultrastructural nature of these intracellular deposits has been demonstrated to be lysosomal and the deposits have a lipofuscin-like appearance. These data point to a role of subpial astrocytes in the degradation of A beta by lysosomal processing.

Takahashi, M., Y. Tsujioka, et al. (1999). "Glycosylation of microtubule-associated protein tau in Alzheimer's disease brain." Acta Neuropathol (Berl) 97(6): 635-41.
In the neurofibrillary pathology of Alzheimer's disease (AD), neurofibrillary tangles (NFTs) contain paired helical filaments (PHFs) as their major fibrous component. Abnormally hyperphosphorylated, microtubule-associated protein tau is the major protein subunit of PHFs. A recent in vitro study showed that PHF tangles from AD brains are highly glycosylated, whereas no glycan is detected in normal tau. Deglycosylation of PHF tangles converts them into bundles of straight filaments and restores their accessibility to microtubules. We showed that PHF tangles from AD brain tissue were associated with specific glycan molecules by double immunostaining with peroxidase and alkaline phosphatase labeling. Intracellular tangles and dystrophic neurites in a neuritic plaque with abnormally hyperphosphorylated tau, detected with the monoclonal antibodies AT-8 and anti-tau-2, were also positive with lectin Galanthus nivalis agglutinin (GNA) which recognizes both the N- and O-glycosidically linked saccharides. Colocalization was not seen in the extracellular tangles and amyloid deposition, suggesting that the glycosylation of tau might be associated with the early phase of insoluble NFT formation. Thus, although abnormal phosphorylation might promote aggregation of tau and inhibition of the assembly of microtubules, glycosylation mediated by a GNA-positive glycan appears to be responsible for the formation of the PHF structures in vivo.

Suva, D., I. Favre, et al. (1999). "Primary motor cortex involvement in Alzheimer disease." J Neuropathol Exp Neurol 58(11): 1125-34.
In Alzheimer disease (AD) the involvement of entorhinal cortex, hippocampus, and associative cortical areas is well established. Regarding the involvement of the primary motor cortex the reported data are contradictory. In order to determine whether the primary motor cortex is involved in AD, the brains of 29 autopsy cases were studied, including, 17 cases with severe cortical AD-type changes with definite diagnoses of AD, 7 age-matched cases with discrete to moderate cortical AD-type changes, and 5 control cases without any AD-type cortical changes. Morphometric analysis of the cortical surface occupied by senile plaques (SPs) on beta-amyloid-immunostained sections and quantitative analysis of neurofibrillary tangles (NFTs) on Gallyas-stained sections was performed in 5 different cortical areas including the primary motor cortex. The percentage of cortical surface occupied by SPs was similar in all cortical areas, without significant difference and corresponded to 16.7% in entorhinal cortex, 21.3% in frontal associative, 16% in parietal associative, and 15.8% in primary motor cortex. The number of NFTs in the entorhinal cortex was significantly higher (41 per 0.4 mm2), compared with those in other cortical areas (20.5 in frontal, 17.9 in parietal and 11.5 in the primary motor cortex). Our findings indicate that the primary motor cortex is significantly involved in AD and suggest the appearance of motor dysfunction in late and terminal stages of the disease.

Sturchler-Pierrat, C. and B. Sommer (1999). "Transgenic animals in Alzheimer's disease research." Rev Neurosci 10(1): 15-24.
Alzheimer's disease (AD) is a neurodegenerative disorder of the brain accounting for about 50-70% of the typical late onset cases of dementia. The pathological and diagnostic hallmarks of the disease are principally the presence of extracellular deposits called neuritic amyloid plaques and the intracellular aggregation of neurofibrillary tangles. In addition selective neuronal cell loss accompanied by cerebrovascular amyloidosis is detectable. In the case of familial AD, defects in at least three different genes (APP, PS1, PS2) leading to indistinguishable pathology are now well defined. There is as yet no real treatment for AD. Therefore the availability of an easily manipulable animal model is crucial for the development of new drugs, which could slow down or, even better, stop the progression of the disease. The development and originality of such experimental models that could greatly facilitate the investigation of the aetiology and pathogenesis of AD are described and discussed in this review. They are based mainly on the attempt to reproduce the neurofibrillary tangles or the amyloid deposits and plaque formation.

Strunecka, A. and J. Patocka (1999). "[Reassessment of the role of aluminum in the development of Alzheimer's disease]." Cesk Fysiol 48(1): 9-15.
The pathophysiology of Alzheimer's disease (AD) is related to the alterations in neurotransmission, beta-amyloid production, plaque formation and cytoskeletal abnormalities. The question of aluminium relevance to the etiology of AD cannot yet be adequately answered. Aluminium is currently regarded as the putative risk factor for the disease. Our paper shows that some of pathologic changes are not raised by aluminium alone, but by the aluminofluoride complexes. These complexes may act as the initial signal stimulating impairment of homeostasis, degeneration and death of the cells. By influencing energy metabolism these complexes can accelerate the aging and impair the functions of the nervous system. In respect to the etiology of AD, the long term action of aluminofluoride complexes may represent a serious and powerful risk factor for the development of AD.

Stege, G. J., K. Renkawek, et al. (1999). "The molecular chaperone alphaB-crystallin enhances amyloid beta neurotoxicity." Biochem Biophys Res Commun 262(1): 152-6.
Amyloid beta (Abeta) is a 40- to 42-residue peptide that is implicated in the pathogenesis of Alzheimer's Disease (AD). As a result of conformational changes, Abeta assembles into neurotoxic fibrils deposited as 'plaques' in the diseased brain. In AD brains, the small heat shock proteins (sHsps) alphaB-crystallin and Hsp27 occur at increased levels and colocalize with these plaques. In vitro, sHsps act as molecular chaperones that recognize unfolding peptides and prevent their aggregation. The presence of sHsps in AD brains may thus reflect an attempt to prevent amyloid fibril formation and toxicity. Here we report that alphaB-crystallin does indeed prevent in vitro fibril formation of Abeta(1-40). However, rather than protecting cultured neurons against Abeta(1-40) toxicity, alphaB-crystallin actually increases the toxic effect. This indicates that the interaction of alphaB-crystallin with conformationally altering Abeta(1-40) may keep the latter in a nonfibrillar, yet highly toxic form.

Stege, G. J. and G. J. Bosman (1999). "The biochemistry of Alzheimer's disease." Drugs Aging 14(6): 437-46.
In the course of the biochemical efforts devoted to elucidation of the cause(s) and mechanism(s) of neurodegeneration in Alzheimer's disease (AD), much attention has been given to the processes by which amyloid is generated from amyloid precursor protein, notwithstanding the finding that mutations in 2 other proteins, presenilin 1 and 2, are associated with early-onset, familial AD in the majority of patients. In addition, the reason why the apolipoprotein E epsilon4 allele is over-represented in patients with the sporadic form of AD is unknown. Furthermore, the degree of dementia is clearly associated more with the degree of neurofibrillary pathology than with the amyloid plaque burden. In general, amyloid formation may very well be at the end of a pathophysiological cascade, set in motion by many different triggers. This cascade could involve excessive apoptosis, followed by necrosis and inflammation. In this process, microglia as well as astrocytes are involved. Disturbance of I or more critical signal transduction processes, especially at the level of the plasma membrane, may be an important trigger. The pathogenesis of AD is complicated, but further identification of the processes of neurodegeneration will also lead to identification of the factors that make specific neurons vulnerable and, hopefully, point the way to a means to prevent neuronal degeneration at an early stage.

Stalder, M., A. Phinney, et al. (1999). "Association of microglia with amyloid plaques in brains of APP23 transgenic mice." Am J Pathol 154(6): 1673-84.
Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between beta-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (betaPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived betaPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived betaPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.

St George-Hyslop, P. H. and D. A. Westaway (1999). "Alzheimer's disease. Antibody clears senile plaques." Nature 400(6740): 116-7.

Soto, C. (1999). "Plaque busters: strategies to inhibit amyloid formation in Alzheimer's disease." Mol Med Today 5(8): 343-50.
Alzheimer's disease is a devastating degenerative disorder of the brain for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, recent research suggests that deposition of cerebral amyloid plaques is central to the disease process. Therefore, an attractive therapeutic strategy for Alzheimer's disease is to prevent, reduce or reverse amyloid deposition in the brain. Several small chemical compounds, synthetic peptides and natural proteins have been described that inhibit amyloid formation or amyloid neurotoxicity in vitro. The effect of these and other compounds now needs to be tested in vivo and the ability of amyloid inhibitors to halt the progression of Alzheimer's disease in humans needs to be evaluated.

Smith, D. H., X. H. Chen, et al. (1999). "Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig." J Neuropathol Exp Neurol 58(9): 982-92.
Brain trauma in humans increases the risk for developing Alzheimer disease (AD) and may induce the acute formation of AD-like plaques containing amyloid beta (A beta). To further explore the potential link between brain trauma and neurodegeneration, we conducted neuropathological studies using a pig model of diffuse brain injury. Brain injury was induced in anesthetized animals via nonimpact head rotational acceleration of 110 degrees over 20 ms in the coronal plane (n = 15 injured, n = 3 noninjured). At 1, 3, 7, and 10 days post-trauma, control and injured animals were euthanized and immunohistochemical analysis was performed on brain sections using antibodies specific for A beta, beta-amyloid precursor protein (betaPP), tau, and neurofilament (NF) proteins. In addition to diffuse axonal pathology, we detected accumulation of A beta and tau that colocalized with immunoreactive betaPP and NF in damaged axons throughout the white matter in all injured animals at 3-10 days post-trauma. In a subset of brain injured animals, diffuse A beta-containing plaque-like profiles were found in both the gray and white matter, and accumulations of tau and NF rich inclusions were observed in neuronal perikarya. These results show that this pig model of diffuse brain injury is characterized by accumulations of proteins that also form pathological aggregates in AD and related neurodegenerative diseases.

Shao, H., S. Jao, et al. (1999). "Solution structures of micelle-bound amyloid beta-(1-40) and beta-(1-42) peptides of Alzheimer's disease." J Mol Biol 285(2): 755-73.
The amyloid beta-peptide is the major protein constituent of neuritic plaques in Alzheimer's disease. The beta-peptide varies slightly in length and exists in two predominant forms: (1) the shorter, 40 residue beta-(1-40), found mainly in cerebrovascular amyloid; and (2) the longer, 42 residue beta-(1-42), which is the major component in amyloid plaque core deposits. We report here that the sodium dodecyl sulphate (SDS) micelle, a membrane-mimicking system for biophysical studies, prevents aggregation of the beta-(1-40) and the beta-(1-42) into the neurotoxic amyloid-like, beta-pleated sheet structure, and instead encourages folding into predominantly alpha-helical structures at pH 7.2. Analysis of the nuclear Overhauser enhancement (NOE) and the alphaH NMR chemical shift data revealed no significant structural differences between the beta-(1-40) and the beta-(1-42). The NMR-derived, three-dimensional structure of the beta-(1-42) consists of an extended chain (Asp1-Gly9), two alpha-helices (Tyr10-Val24 and Lys28-Ala42), and a looped region (Gly25-Ser26-Asn27). The most stable alpha-helical regions reside at Gln15-Val24 and Lys28-Val36. The majority of the amide (NH) temperature coefficients were less than 5, indicative of predominately strong NH backbone bonding. The lack of a persistent region with consistently low NH coefficients, together with the rapid NH exchange rates in deuterated water and spin-labeled studies, suggests that the beta-peptide is located at the lipid-water interface of the micelle and does not become inbedded within the hydrophobic interior. This result has implications for the circulation of membrane-bound beta-peptide in biological fluids, and may also facilitate the design of amyloid inhibitors to prevent an alpha-helix-->beta-sheet conversion in Alzheimer's disease.

Selznick, L. A., D. M. Holtzman, et al. (1999). "In situ immunodetection of neuronal caspase-3 activation in Alzheimer disease." J Neuropathol Exp Neurol 58(9): 1020-6.
The mechanism by which cells die in Alzheimer disease (AD) is unknown. Several investigators speculate that much of the cell loss may be due to apoptosis, a highly regulated form of programmed cell death. Caspase-3 is a critical effector of neuronal apoptosis and may be inappropriately activated in AD. To address this possibility, we examined cortical and hippocampal brain sections from AD patients, as well as 2 animal models of AD, for in situ evidence of caspase-3 activation. We report here that senile plaques and neurofibrillary tangles in the AD brain are not associated with caspase-3 activation. Furthermore, amyloid beta (A beta) deposition in the APPsw transgenic mouse model of AD does not result in caspase-3 activation despite the ability of A beta to induce caspase-3 activation and neuronal apoptosis in vitro. AD brain sections do, however, exhibit caspase-3 activation in hippocampal neurons undergoing granulovacuolar degeneration. Our data suggests that caspase-3 does not have a significant role in the widespread neuronal cell death that occurs in AD, but may contribute to the specific loss of hippocampal neurons involved in learning and memory.

Schmidt, M. L., T. C. Saido, et al. (1999). "Spatial relationship of AMY protein deposits and different species of Abeta peptides in amyloid plaques of the Alzheimer disease brain." J Neuropathol Exp Neurol 58(12): 1227-33.
To further define the spatial relationship of "AMY" plaques detected by antibodies to an unidentified 100 kD AMY protein and amyloid plaques in Alzheimer disease (AD) brains, double immunofluorescence studies were performed with an anti-AMY antibody and a panel of antibodies to different species of Abeta peptides. We report substantial colocalization of AMY immunoreactive plaques with amyloid plaques labeled by antibodies to species of Abeta starting at position 3 with a pyroglutamate modified glutamic acid, however AMY immunoreactive deposits colocalized to a lesser degree with amyloid plaques labeled by antibodies to other variants of the Abeta peptide. Moreover, different immunohistochemical parameters influenced the extent to which colocalization of AMY deposits and Abeta immunoreactive plaques was demonstrable. We conclude that deposits of distinct species of Abeta peptides differentially colocalize with one another and with AMY plaques in the AD brain.

Schenk, D., R. Barbour, et al. (1999). "Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse." Nature 400(6740): 173-7.
Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.

Sadowski, M., H. M. Wisniewski, et al. (1999). "Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology." Acta Neuropathol (Berl) 97(2): 156-64.
In Alzheimer's disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus--a key structure of the memory system. People with Down's syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60-74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 +/- 914,000 (mean +/- standard deviation) to 932,000 +/- 504,000. The presence of 2,488,000 +/- 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 +/- 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of beta-amyloid to neuronal loss in the entorhinal cortex is unsubstantial.

Sabo, S. L., L. M. Lanier, et al. (1999). "Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein." J Biol Chem 274(12): 7952-7.
The principal component of Alzheimer's amyloid plaques, Abeta, derives from proteolytic processing of the Alzheimer's amyloid protein precursor (APP). FE65 is a brain-enriched protein that binds to APP. Although several laboratories have characterized the APP-FE65 interaction in vitro, the possible relevance of this interaction to Alzheimer's disease has remained unclear. We demonstrate here that APP and FE65 co-localize in the endoplasmic reticulum/Golgi and possibly in endosomes. Moreover, FE65 increases translocation of APP to the cell surface, as well as both alphaAPPs and Abeta secretion. The dramatic (4-fold) FE65-dependent increase in Abeta secretion suggests that agents which inhibit the interaction of FE65 with APP might reduce Abeta secretion in the brain and therefore be useful for preventing or slowing amyloid plaque formation.

Royston, M. C., J. E. McKenzie, et al. (1999). "Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition." Neuropathol Appl Neurobiol 25(5): 387-93.
S100beta is an astrocyte-derived uritotrophic' cytokine which has been implicated in the pathogenesis of Alzheimer's disease. S100beta overexpression by plaque-associated astrocytes correlates with growth of abnormal (strophic') neurites in beta-amyloid plaques, one of the major neuropathological hallmarks of Alzheimer's disease. As the characteristic neuropathological changes of Alzheimer's disease are virtually universal in middle-aged Down's syndrome patients, studies of Down's syndrome patients provide a unique opportunity to investigate the pathophysiological processes underlying the development of Alzheimer-type neuropathological changes. Computerized morphometric analysis was used to quantify astrocyte activation and astrocytic expression of S100beta, and to correlate these with beta-amyloid deposition, in a clinically well-characterized cohort of Down's syndrome subjects, aged 13-65 years. There were significant positive correlations between S100beta expression and patient age, and between S100beta expression and cerebral cortical beta-amyloid deposition. Moreover, the numbers of activated (enlarged) astrocytes overexpressing S100beta showed a significant correlation with the numeric density of beta-amyloid plaques, from the youngest to the oldest ages and within age ranges where pathology is most florid, while no such relationship was found between the numbers of small, non-activated S100beta-immunoreactive cells and numerical density of beta-amyloid plaques. These correlations, together with established functions of S100beta, are consistent with the idea that S100beta overexpression promotes beta-amyloid plaque formation and progression in Down's syndrome.

Roher, A. E. and Y. M. Kuo (1999). "Isolation of amyloid deposits from brain." Methods Enzymol 309: 58-67.

Reynolds, W. F., J. Rhees, et al. (1999). "Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease." Exp Neurol 155(1): 31-41.
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates hypochlorous acid and other reactive oxygen species. MPO is present at high levels in circulating neutrophils and monocytes but is not detectable in microglia, brain-specific macrophages, in normal brain tissue. However, an earlier study indicated that MPO is present in macrophage-microglia at multiple sclerosis lesions, suggesting that reactivation of MPO gene expression may play a role in neurodegenerative diseases involving macrophage-microglia. In the present study, MPO is shown to colocalize with amyloid beta (Abeta) in senile plaques in cerebral cortex sections from Alzheimer's disease (AD) brain tissue. Microglia costaining for MPO and CD68 are closely associated with plaques, suggesting that plaque components induce MPO expression in microglia. In support of this interpretation, treatment of rodent microglia with aggregated Abeta(1-42) was shown to induce MPO mRNA expression. Also, the ApoE4 allele, the major AD risk factor associated with increased Abeta deposition, was shown to correlate with increased MPO deposition in plaques (P = 0.01, ANOVA). Finally, a genetic polymorphism links MPO expression to Alzheimer's risk, in that a higher expressing SpSp MPO genotype was associated with increased incidence of AD in females, and decreased incidence in males (P = 0.006). These findings suggest that the MPO polymorphism is a gender-specific risk factor for Alzheimer's disease.

Revesz, T., J. L. Holton, et al. (1999). "Cytoskeletal pathology in familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation." Acta Neuropathol (Berl) 97(2): 170-6.
The histological features of familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation (FAB) include deposition of amyloid, (supposedly associated with the C-terminal fragments of both alpha- and beta-tubulin), in small cerebral and spinal arteries, hippocampal amyloid plaques and neurofibrillary tangles (NFTs) as well as ischaemic white matter changes. In the present study we report on the cytoskeletal pathology that occurs in association with FAB. Sections from the hippocampus and cerebellum of three cases from three unrelated families were stained with silver impregnation methods and antibodies to antigens including tau, neurofilaments, ubiquitin and glial fibrillary acidic protein. Electron microscopic examination of the hippocampus was carried out in one case. All hippocampal subregions contained large numbers of NFTs and neuropil threads (NT), which were stained with both phosphorylation-dependent and phosphorylation-independent tau antibodies and ultrastructurally were found to be composed of paired helical filaments (PHFs). Although the majority of the amyloid plaques were of the non-neuritic type, distended PHF-containing and tau-positive neurites were seen in close proximity of a minority of the hippocampal plaques. The perivascular amyloid deposits of the cerebellum contained numerous ubiquitin-positive granular elements similar to those seen in cerebellar A beta amyloid plaques in Alzheimer's disease. In FAB severe cytoskeletal pathology is present in areas most affected by amyloid plaque deposits, thus suggesting a localised neurotoxic effect of the poorly characterised amyloidogenic peptide characteristic of this condition.

Price, J. L. and J. C. Morris (1999). "Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease." Ann Neurol 45(3): 358-68.
The distribution and density of neurofibrillary tangles and amyloid plaques was studied in a unique series of cases whose premortem cognitive status had been assessed with the Clinical Dementia Rating (CDR), including 39 nondemented cases (CDR = 0; age, 51-88 years), 15 very mildly demented cases (CDR = 0.5), and 8 severely demented (CDR = 3) cases. The initial formation of tangles and plaques in healthy aging appeared to be independent of each other. Tangles were found in all the nondemented cases, especially in hippocampal and parahippocampal areas; the average tangle concentration increased exponentially with age. In contrast, plaques were absent in some brains up to age 88, and the earliest plaque formation in other cases occurred in the neocortex, in patches of diffuse plaques. Widely distributed neuritic as well as diffuse plaques throughout neocortex and limbic structures characterized a further group of nondemented cases. In these cases there was also a substantial increase over other nondemented cases, both in the number of tangles and in the rate of increase in tangles with age, suggesting an interaction between amyloid and neurofibrillary change at this stage. Such cases closely resemble CDR = 0.5 cases, and it is proposed they represent "preclinical" Alzheimer's disease.

Pluta, R., M. Barcikowska, et al. (1999). "Ischemic rats as a model in the study of the neurobiological role of human beta-amyloid peptide. Time-dependent disappearing diffuse amyloid plaques in brain." Neuroreport 10(17): 3615-9.
Brains from patients with Alzheimer's disease contain diffuse and senile amyloid plaques. Using an experimental model, we have addressed the issue whether diffuse plaques of amyloid persist, develop with time, or both, in rats injected with human beta-amyloid-(1-42)-peptide for 3 and 12 mon after brain ischemia. Rats receiving beta-amyloid peptide for 3 months after brain ischemia demonstrated widespread diffuse amyloid plaques in hippocampus and cerebral cortex. Neuronal, glial, ependymal, endothelial and pericyte cell bodies were observed filled with beta-amyloid peptide. No staining was observed in control brains. In the group alive 1 year no deposition of human beta-amyloid peptide was observed, too. Direct evidence that diffuse amyloid plaques can disappear in the brain is thus provided for the first time.

Paik, S. R., H. J. Shin, et al. (1999). "Copper(II)-induced self-oligomerization of alpha-synuclein." Biochem J 340 ( Pt 3): 821-8.
alpha-Synuclein is a component of the abnormal protein depositions in senile plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid beta/A4 protein (Abeta). We have shown previously that alpha-synuclein has experienced self-oligomerization when Abeta25-35 was present in an orientation-specific manner in the sequence. Here we examine this biochemically specific self-oligomerization with the use of various metals. Strikingly, copper(II) was the most effective metal ion affecting alpha-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated that monomeric alpha-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of alpha-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the Abeta25-35-induced oligomerizations of the intact and truncated forms of alpha-synuclein were not affected. This clearly indicated that the copper-induced oligomerization was dependent on the acidic C-terminal region and that its underlying biochemical mechanism was distinct from that of the Abeta25-35-induced oligomerization. Although the physiological or pathological relevance of the oligomerization remains currently elusive, the common outcome of alpha-synuclein on treatment with copper or Abeta25-35 might be useful in understanding neurodegenerative disorders in molecular terms. In addition, abnormal copper homoeostasis could be considered as one of the risk factors for the development of disorders such as AD or Parkinson's disease.

Ohyagi, Y. (1999). "[Mechanism of senile plaque formation in Alzheimer disease]." Fukuoka Igaku Zasshi 90(4): 113-7.

Namba, Y., Y. Ouchi, et al. (1999). "Bleomycin hydrolase immunoreactivity in senile plaque in the brains of patients with Alzheimer's disease." Brain Res 830(1): 200-2.
Bleomycin hydrolase (BH), a cysteine protease belonging to the papain superfamily, is one of the candidate beta secretases. We performed immunohistochemical studies of Alzheimer's disease (AD) brains using an antibody to BH. Polyclonal antibody to BH immunostained neocortical neurons. The immunoreactivity was also found in senile plaques in AD. These results may suggest a role of BH in amyloid formation.

Nagy, Z., M. M. Esiri, et al. (1999). "Mitochondrial enzyme expression in the hippocampus in relation to Alzheimer-type pathology." Acta Neuropathol (Berl) 97(4): 346-54.
Recent reports have suggested that mitochondrial dysfunction may contribute to the progression of the pathology of Alzheimer's disease (AD). However, both increases and decreases in the activity of cytochrome oxidase have been described in the hippocampi of AD patients. In this study we used immunohistochemistry and quantitative autoradiographic methods to study the expression pattern of two cytochrome oxidase subunit proteins (nuclear-encoded COX IV and mitochondrial-encoded COX I) in the hippocampus in relation to the development of AD-type pathology. We found heterogeneous expression of both COX subunits in AD with an increased expression of both subunit proteins in healthy, non-tangle-bearing, neurones but absence of both subunit proteins in tangle-bearing neurones. Levels of COX IV but not of COX I were related to the amount of hyperphosphorylated tau accumulated in the same hippocampal region but not to the amount of amyloid deposited in sporadic AD. In Down's syndrome COX I and COX IV were similarly increased in the presence of AD pathology in non-tangle-bearing neurones. However, in these cases levels of enzyme expression were correlated to the amount of amyloid accumulation but not the amount of hyperphosphorylated tau in the hippocampus. We believe that heterogeneity of expression of mitochondrial enzyme proteins between neurones may contribute to the conflicting conclusions in previous reports regarding relative levels of cytochrome oxidase activity in the hippocampus in AD. We hypothesise that the increased mitochondrial enzyme expression in healthy-appearing neurones of AD brains may represent a physiological response to increased functional demand on surviving neurones as a consequence of AD-related neuronal pathology.

Morelli, L., G. H. Giambartolomei, et al. (1999). "Internalization and resistance to degradation of Alzheimer's A beta 1-42 at nanomolar concentrations in THP-1 human monocytic cell line." Neurosci Lett 262(1): 5-8.
Microglial cell involvement in Alzheimer's disease has been related to amyloid beta (A beta) internalization, the release of inflammatory cytokines and the development of neuritic plaques. The human monocyte/macrophage THP-1 cell line has been widely used as a model of human microglial cells. We used THP-1 cells to study the adsorption, internalization and resistance to degradation of A beta1-40 and A beta1-42 isoforms offered at nanomolar concentrations and free of large aggregates, conditions that may mimic a pre-fibrillar stage of A beta in the brain. Under these conditions, A betas did not induce THP-1 activation, as assessed by interleukin-1beta expression. A beta1-42 showed a preferential adsorption and intracellular accumulation as compared to A beta1-40, supporting that competent nuclei for A beta1-42 ordered aggregation may be formed inside microglial cells. In light of the possible neurotoxicity of soluble A beta1-42, we propose that amyloid formation within brain phagocytic cells may be a protective mechanism in early stages of the disease.

Miller, M. M. and K. B. Franklin (1999). "Theoretical basis for the benefit of postmenopausal estrogen substitution." Exp Gerontol 34(5): 587-604.
Women are being presented with an increasing number of choices for health care management as they move through the aging process. Estrogen has positive effects on mood, sexual function, target end organs and cognitive function, and may play an important role in the etiology of Alzheimer's Disease by acting to prevent amyloid plaque formation, oxidative stress, or deterioration of the cholinergic neurotransmitter system. The benefits of estrogen therapy for osteoporosis, the cardiovascular system, and lipid metabolism are far reaching, but the possibility of developing breast cancer later in life is also relevant. Understanding the mechanisms for the action of the estrogens, anti-estrogens, and the selective estrogen receptor modulators, and possible alternative routes of symptom management for some menopausal events is important to make appropriate decisions on choice of therapy. This review discusses the theoretical basis for estrogen's actions in the management of the postmenopausal stage of the life cycle.

Meda, L., P. Baron, et al. (1999). "Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with beta-amyloid[25-35]." J Neuroimmunol 93(1-2): 45-52.
Growing evidence indicates that amyloid (A beta) deposition and phagocyte activation participate in inflammatory reactions in the brain during the course of Alzheimer's disease. To further investigate the effects of A beta-phagocyte interaction, we examined the production of proinflammatory (IL-1beta, IL-6), chemotactic (MIP-1alpha, IP-10) and inhibitory (IL-1Ra, IL-10 and TGFbeta1) cytokines by cultured human monocytes and mouse microglial cells upon stimulation with A beta[25-35]. Northern blot analysis and specific immunoassays demonstrated that A beta[25-35] triggers mRNA expression and release of IL-1beta, IL-1Ra and MIP-1alpha but not of IL-6, IL-10, TGFbeta1 and IP-10 from human monocytes. Similar results were obtained by examining the production of IL-1beta, IL-6 and IL-10 from mouse microglial cells in the same experimental conditions. Taken together, these data indicate that A beta-phagocyte interaction can drive a different response towards cytokine production by monocytes and microglia, with a particular proinflammatory trend, and further support a role for A beta deposition as a triggering factor of inflammatory events in Alzheimer's disease.

McLoughlin, D. M., N. G. Irving, et al. (1999). "Mint2/X11-like colocalizes with the Alzheimer's disease amyloid precursor protein and is associated with neuritic plaques in Alzheimer's disease." Eur J Neurosci 11(6): 1988-94.
Aberrant metabolism of the amyloid precursor protein (APP) is believed to be at least part of the pathogenic process in Alzheimer's disease. The carboxy-terminus of APP has been shown to interact with the Mint/X11 family of phosphotyrosine binding (PTB) domain-bearing proteins. It is via their PTB domains that the Mints/X11s bind to APP. Here we report the cloning of full-length mouse Mint2 and demonstrate that in primary cortical neurons, Mint2 and APP share highly similar distributions. Mint2 also colocalizes with APP in transfected CHO cells. In Mint2/APP-cotransfected cells, Mint2 reorganizes the subcellular distribution of APP and also increases the steady-state levels of APP. Finally, we demonstrate that Mint2 is associated with the neuritic plaques found in Alzheimer's disease but not with neurofibrillary tangles. These results are consistent with a role for Mint2 in APP metabolism and trafficking, and suggest a possible role for the Mints/X11s in the pathogenesis of Alzheimer's disease.

McLaurin, J., T. Franklin, et al. (1999). "A sulfated proteoglycan aggregation factor mediates amyloid-beta peptide fibril formation and neurotoxicity." Amyloid 6(4): 233-43.
Proteoglycans are associated with senile plaques in Alzheimer's disease and may be involved in A beta fibril formation and plaque formation. In vitro, glycosaminoglycans have been shown to inhibit the proteolysis of A beta fibrils, accelerate formation and maintain their stability. To model their interaction, we investigated the binding of a sulfated proteoglycan derived from a natural source; marine sponge Microciona prolifera aggregation factor (MAF). This species-specific re-aggregation of sponge cells has two functional properties, a Ca2+ independent cell binding activity and a Ca2+ dependent self-aggregation. It has been shown that a novel sulfated disaccharide and a pyruvylated trisaccharide are important in the Ca(2+)-dependent MAF aggregation. Aggregation demonstrated by homophilic binding of MAF subunits may be chemically distinct from other heterotypic binding effects. We investigated A beta-MAF interactions and show that MAF induces a structural transition in A beta 40 and A beta 42 from random to beta-structure as detected by circular dichroism spectroscopy. Electron microscopy revealed that the structural transition correlated with an increase in the number of A beta 40 and A beta 42 aggregated that have a truncated fibrillar morphology. Finally, MAF increased A beta-induced toxicity of nerve growth factor (NGF)-differentiated PC-12 cells in the absence of Ca2+. The addition of Ca2+ to MAF-A beta incubations resulted in a moderate attenuation of toxicity possibly due to a reduction in A beta-cell interactions caused by extensive lateral aggregation of the MAF-A beta complexes. Our results indicate that A beta is generally susceptible to proteoglycan-mediated aggregation and fibril formation. We also propose that the MAF model system may be useful in delineating these interactions and represent a means to develop and examine potential inhibitors of the proteoglycan effects.

Marinelli, L., S. Cammarata, et al. (1999). "Tyrosine kinase A-nerve growth factor receptor is antigenically present in dystrophic neurites from a variety of conditions but not in Alzheimer's disease." Neurosci Lett 273(1): 67-71.
Tyrosine kinase A (TrkA), a high affinity receptor for nerve growth factor (NGF), is activated during differentiation and regeneration of selective neuronal population. We investigated presence, distribution and expression of TrkA in frontal cortex from cases with Alzheimer's disease (AD), normal aging and a variety of conditions (AIDS, cystic fibrosis, cerebral infarcts) in which neuroaxonal dystrophy occurs. TrkA was immunocytochemically detected in 90% of dystrophic neurites surrounding amyloid deposits in normal aging, as well as in all not amyloid-related dystrophic neurites identified by ubiquitin immunoreactivity. Conversely, the amyloid associated dystrophic neurites were not TrkA reactive in AD tissue. The levels of TrkA protein and mRNA in AD frontal cortex did not significantly differ from those of non-demented aged controls. The absence of TrkA activation in amyloid associated neurites in AD, but not in normal aging, indicates a different reaction of neuronal tissue to amyloid (protein (Abeta) deposition, and suggests that other factors, besides Abeta, mediate neuronal degeneration in AD.

Lue, L. F., Y. M. Kuo, et al. (1999). "Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease." Am J Pathol 155(3): 853-62.
We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

Lippa, C. F., K. Ozawa, et al. (1999). "Deposition of beta-amyloid subtypes 40 and 42 differentiates dementia with Lewy bodies from Alzheimer disease." Arch Neurol 56(9): 1111-8.
BACKGROUND: Alterations in the metabolism of the amyloid precursor protein and the formation of beta-amyloid (Abeta) plaques are associated with neuronal death in Alzheimer disease (AD). The plaque subtype Abeta(x-42) occurs as an early event, with Abeta(x-40) plaques forming at a later stage. In dementia with Lewy bodies (DLB), an increase in the amount of cortical Abeta occurs without severe cortical neuronal losses. OBJECTIVE: To advance our understanding of the natural history of Abeta in neurodegenerative diseases. DESIGN: We evaluated the expression of Abeta(x-40) and Abeta(x-42) in DLB using monoclonal antibodies and immunohistochemical techniques in 5 brain regions. The data were compared with those elicited with normal aging and from patients with AD. SETTING AND PATIENTS: A postmortem study involving 19 patients with DLB without concurrent neuritic degeneration, 10 patients with AD, and 17 aged persons without dementia for control subjects. RESULTS: The Abeta plaques were more numerous in patients with DLB than in controls in most brain regions, although the Abeta(x-42) plaque subtype was predominant in both conditions. Overall, Abeta(x-42) plaque density was similar in patients with DLB and those with AD, but Abeta(x-40) plaques were more numerous in persons with AD than in those with DLB. The ratio of Abeta(x-40) to Abeta(x-42) plaques was significantly reduced in persons with DLB compared with patients with AD. CONCLUSIONS: The Abeta plaques were more numerous in patients with DLB than persons with normal aging, but the plaque subtypes were similar. The relative proportion of the 2 Abeta plaque subtypes in DLB is distinguishable from that in AD.

Lewandowska, E., E. Bertrand, et al. (1999). "Microglia and neuritic plaques in familial Alzheimer's disease induced by a new mutation of presenilin-1 gene. An ultrastructural study." Folia Neuropathol 37(4): 243-6.
The results of the ultrastructural study of the brains of two sisters with familial Alzheimer's disease (AD) induced by a new mutation of presenilin-1 (PS-1) gene who died at the young age (35 and 37 years) are presented. In both cases, the changes typical of AD with particularly large number of neuritic plaques (NPs) were found. Microglial cells were located between amyloid core and neurites. At the ultrastructural level, the content of microglial cytoplasm was differentiated (amyloid fibrils or/and phagocytic bodies). This may suggest that microglial cells participate in forming of amyloid fibrils and/or phagocytosis of amyloid.

Lemere, C. A., T. J. Grenfell, et al. (1999). "The AMY antigen co-occurs with abeta and follows its deposition in the amyloid plaques of Alzheimer's disease and down syndrome." Am J Pathol 155(1): 29-37.
Novel plaque-like "AMY" lesions were recently described in the brains of patients with Alzheimer's disease (AD). Using three Abeta antibodies, we now document the co-occurrence of AMY immunoreactivity (IR) with amyloid beta-peptide (Abeta) in the large majority of plaques in AD brain. AMY IR was detected in many compacted plaques, whereas its co-localization with early, diffuse Abeta deposits was rare. AMY IR overlapped considerably or fully with Abeta and, in more severely affected AD brains, decorated the periphery of some plaques. In a temporal series of 29 Down syndrome (DS) brains from patients aged 12 to 73 years, the earliest AMY IR was detected in some plaques at age 15, following the earliest appearance of Abeta plaques (age 12 years), and then accrued within a subset of Abeta deposits, namely, the more spherical, compacted plaques. Brains from DS patients 29 years and older showed AMY staining in many Abeta plaques, as seen in AD. Brains from eight monkeys aged 17 to 34 years and thirty APP transgenic mice aged 8 to 20 months showed Abeta IR but no AMY IR. We conclude that AMY IR represents an amyloid-associated antigen that co-deposits in most but not all Abeta plaques in AD and DS and that accumulation of the AMY antigen follows Abeta deposition in plaques.

Knowles, R. B., C. Wyart, et al. (1999). "Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease." Proc Natl Acad Sci U S A 96(9): 5274-9.
The brains of Alzheimer's disease patients contain extracellular Abeta amyloid deposits (senile plaques). Although genetic evidence causally links Abeta deposition to the disease, the mechanism by which Abeta disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Abeta deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.

King, D. L., G. W. Arendash, et al. (1999). "Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease." Behav Brain Res 103(2): 145-62.
To determine if early cognitive sensorimotor deficits exist in APP(SW) transgenic mice overexpressing human amyloid precursor protein (APP). Tg+ and Tg- animals at both 3 and 9 months of age (3M and 9M, respectively) were evaluated in a comprehensive battery of measures. The performance of all Tg+ mice at both ages was no different from all Tg- controls in Y-maze alternations, water maze acquisition, passive avoidance, and active avoidance testing. By contrast, results from other tasks revealed substantive cognitive deficits in Tg+ mice that were usually gender-dependent and sometimes progressive in nature. Between 3M and 9M, a progressive impairment was observed in circular platform performance by Tg+ males, as was a progressive deficit in visible platform testing for all Tg+ animals. Other transgenic effects included both impaired water maze retention and circular platform performance in 3M Tg+ females; this later effect was responsible for an overall (males + females) Tg+ deficit in circular platform performance at 3M. Sensorimotor testing revealed several Tg+ effects, most notably an increased activity of Tg+ males in both open field and Y-maze at 3M. Significant correlations between a number of behavioral measures were observed, although factor analysis suggests that each task measured components of sensorimotor/cognitive function not measured by other tasks. Finally, Tg+ mice had lower survivability than Tg- animals through 9M (85 vs. 96%). In summary, these results demonstrate the presence of gender-related and progressive cognitive deficits in APP(SW) transgenic mice at a relatively early age (i.e., prior to overt, beta-amyloid deposition in the brain), suggesting a pathophysiologic role for elevated levels of 'soluble' beta-amyloid in such impairments.

Kimura, M., T. Asada, et al. (1999). "Assessment of cerebrospinal fluid levels of serum amyloid P component in patients with Alzheimer's disease." Neurosci Lett 273(2): 137-9.
Serum amyloid P component (SAP) is a normal plasma constituent that is observed both in senile plaque and in neurofibrillary tangle in brains of patients with Alzheimer's disease (AD). In this study, we evaluated the SAP levels in cerebrospinal fluid (CSF) of 72 patients with AD, 11 frontotemporal dementia and nine normal control subjects. There was no significant difference in the SAP levels between the AD group and other groups. However, among AD patients, cognitive function was rated using the Mini-Mental State Examination and was correlated with the SAP level (R = 0.38, P < 0.05). Our results suggest that measurement of the SAP levels in CSF can be useful for assessing the degree of cognitive impairment in AD patients.

Kaltschmidt, B., M. Uherek, et al. (1999). "Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis." Proc Natl Acad Sci U S A 96(16): 9409-14.
One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide (Abeta) neurotoxicity. Abeta elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously we reported that NF-kappaB is activated by low doses of Abeta only. Here we show that NF-kappaB activation leads to neuroprotection. In primary neurons we found that a pretreatment with 0.1 microM Abeta-(1-40) protects against neuronal death induced with 10 microM Abeta-(1-40). As a known neuroprotective agent we next analyzed the effect of tumor necrosis factor alpha (TNF-alpha). Maximal activation of NF-kappaB was found with 2 ng/ml TNF-alpha. Pretreatment with TNF-alpha protected cerebellar granule cells from cell death induced by 10 microM Abeta-(1-40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-kappaB-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-kappaB activation. Overexpression of a transdominant negative IkappaB-alpha blocks NF-kappaB activation and potentiates Abeta-mediated neuronal apoptosis. Our findings show that activation of NF-kappaB is the underlying mechanism of the neuroprotective effect of low-dose Abeta and TNF-alpha. In accordance with these in vitro data we find that nuclear NF-kappaB immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls. Taken together these data suggest that pharmacological NF-kappaB activation may be a useful approach in the treatment of AD and related neurodegenerative disorders.

Hull, M., J. Eistetter, et al. (1999). "Glutamate but not interleukin-6 influences the phosphorylation of tau in primary rat hippocampal neurons." Neurosci Lett 261(1-2): 33-6.
Alzheimer's disease (AD) is characterized by amyloid plaques, neuritic degenerations, disturbed glutamatergic neurotransmission and a peculiar inflammatory response. Diffuse plaques develop into neuritic plaques when neurites undergo degeneration in the plaque area. Hyperphosphorylation of tau proteins is a major step in neuritic pathology. Interleukin-6 (IL-6) has been found in diffuse and neuritic amyloid plaques in AD. Therefore the question arises whether IL-6 is involved in the transformation of diffuse into neuritic plaques by affecting tau phosphorylation. We investigated the influence of glutamate and IL-6 on tau phosphorylation in cultured primary rat hippocampal neurons. Glutamate but not IL-6 induced a dephosphorylation of tau. Furthermore IL-6 did not influence the glutamate-induced dephoshorylation of tau. We conclude that the role of IL-6 in AD is not related to the phosphorylation of tau.

Huang, F., M. Buttini, et al. (1999). "Elimination of the class A scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors." Am J Pathol 155(5): 1741-7.
The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.

Hu, J. and L. J. Van Eldik (1999). "Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation." Brain Res 842(1): 46-54.
A prominent feature of Alzheimer's disease (AD) pathology is an abundance of activated glia (astrocytes and microglia) in close proximity to the amyloid plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of inflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 (Abeta), a major constituent of neuritic plaques, can itself induce glial activation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or modulate the effects of Abeta on glia. In this study, we focused on four glial proteins that are abundant in amyloid plaques and/or that are known to interact with Abeta: alpha1-antichymotrypsin (ACT), interleukin-1beta (IL-1beta), S100beta, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Abeta to activate astrocytes. Treatment of astrocytes with ACT, IL-1beta, or S100beta resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1beta, and production of inducible nitric oxide synthase and nitric oxide. The ability of Abeta to induce astrocyte activation was also enhanced in the presence of each of these three proteins. In contrast, BChE alone did not activate astrocytes and had no effect on Abeta-induced activation. These results suggest that certain proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directly or through their ability to modulate Abeta-induced activation.

Hsia, A. Y., E. Masliah, et al. (1999). "Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models." Proc Natl Acad Sci U S A 96(6): 3228-33.
Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation.

Holcomb, L. A., M. N. Gordon, et al. (1999). "Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits." Behav Genet 29(3): 177-85.
Mutations in the amyloid precursor protein (mAPP) and in presenilin 1 (mPS1) have both been linked to increased production of the beta-amyloid peptide (A beta). Doubly transgenic mice produced by mating of a parental line carrying the "Swedish" (K670N/M671L) APP mutation with a FAD4 (M146L) mutant presenilin 1 line developed numerous fibrillar A beta deposits by 6 months of age. Prior work demonstrated that mAPP and doubly transgenic (mAPP/mPS1) mice have deficits in Y-maze alternation behavior as early as 3 months of age. Increased activity was also apparent in the mAPP/mPS1 mice at this time point. These changes in Y-maze performance persisted in mAPP/mPS1 mice at 6 and 9 months of age. The mPS1 singly transgenic mice were not impaired on this task at any age. Six- and nine-month-old mice were also tested for spatial navigation behavior in the Morris water maze. In training trials, no differences in escape latency were detected among the four genotypes. In probe trials, no differences were detected in either the time spent in the trained quadrant or the number of platform crossings among the four groups. Histological staining for A beta amyloid deposits indicates that all doubly transgenic mice have amyloid deposits by 6 months of age (roughly 25 mice examined thus far), yet no 3-month-old mice have been found with deposits. A beta immunostaining confirmed that the 9-month-old mice tested behaviorally also have A beta deposits. Thus, doubly transgenic mice exhibited changes in Y-maze performance prior to the formation of amyloid deposits, which are essentially unchanged as the deposits increase in number and size to 9 months of age. Yet these mice fail to reveal impairments in spatial navigation at 6 or 9 months in spite of the increasing plaque burden. These data indicate that A beta deposits alone are not sufficient to cause robust spatial memory impairment in mice of this mixed background lineage and age.

Ho, L., C. Pieroni, et al. (1999). "Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease." J Neurosci Res 57(3): 295-303.
Cyclooxygenase-2 (COX-2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimer's disease (AD). In the present study, we explored the regulation of COX-2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age-matched controls) neurons of the CA1-CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX-2 signal; COX-2 levels correlated with amyloid plaque density. In contrast, the level of COX-2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX-2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX-2 are more susceptible to beta-amyloid (Abeta) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX-2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Abeta-mediated oxidative stress.

Hirakura, Y., M. C. Lin, et al. (1999). "Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo Red." J Neurosci Res 57(4): 458-66.
Substantial genetic and biochemical evidence implicates amyloid peptides (Abeta) in the etiology of Alzheimer's Disease (AD). Recent evidence indicates that Abeta1-42 is the predominant species in the hallmark senile amyloid plaque of AD. Furthermore, Abeta1-42 forms aggregates inside lysosomes of cultured neurons leading to lysosomal disruption and cell death. We report here that Abeta1-42 forms slightly cation selective, voltage-independent ion channels with multiple conductance levels at neurotoxic concentrations in planar bilayer membranes. The channels show substantial irregularity of activity, and the size of conductances and the length of open lifetimes depend on solvent history. Formation of channels requires anionic lipids, is enhanced in acidic solutions, and is inhibited by Congo Red. These properties suggest that the channels are formed by aggregates of Abeta1-42. In addition, the channels are reversibly blocked by zinc in a voltage-independent manner. The properties of these channels would likely render them neurotoxic to relevant neurons in vivo. These results are consistent with the channel hypothesis of A?fg neurotoxicity.

Hesse, C., N. Bogdanovic, et al. (1999). "A quantitative and immunohistochemical study on apolipoprotein E in brain tissue in Alzheimer's disease." Dement Geriatr Cogn Disord 10(6): 452-9.
Apoliprotein E (ApoE) has been implicated in the pathogenesis of Alzheimer's disease (AD). Antibodies to ApoE label senile plaques (SP), and an interaction between ApoE and beta-amyloid has been found in in vitro studies. Further, an increased frequency of the ApoE epsilon4 allele in AD has been reported in numerous papers. However, the pathogenetic mechanism of ApoE in AD is not known. We studied ApoE in brain tissue (hippocampus, cerebellum, frontal and temporal cortex) from patients with AD and age-matched control subjects, using both quantitative Western blotting and immunohistochemistry. In AD, a reduction of ApoE was found in the hippocampus (50% of the control value) and in the frontal cortex (52% of the control value), while no significant changes in ApoE levels were found in the temporal cortex or in the cerebellum. Also by immunohistochemistry, ApoE staining was generally decreased in AD brains, both in the neuropil and in the neuronal cellular compartments. Within the AD group, there was no significant correlation between the ApoE level and SP or neurofibrillary tangle (NFT) counts, either in the hippocampus (r = -0.14 and r = 0.55, respectively), or in the frontal cortex (r = -0.03 and r = 0.01, respectively). There were no significant differences in duration, severity of dementia, SP or NFT counts, or ApoE levels between AD patients with different numbers of ApoE epsilon4 alleles. After experimental brain damage in animals, marked increases in ApoE are found, probably as part of lipid recycling in neuronal and synaptic remodelling and regeneration. One may speculate whether the decrease in ApoE may suggest a disturbance in the ApoE system in AD that is unrelated to ApoE isoforms, beta-amyloid deposition and NFT formation. Copyrightz1999S.KargerAG,Basel

He, W. and C. J. Barrow (1999). "The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta." Biochemistry 38(33): 10871-7.
A beta isolated from neuritic plaque and vascular walls of the brains of patients with Alzheimer's disease has been shown to contain significant quantities of A beta peptides which begin at residue 3Glu or 11Glu in the form of pyroglutamyl residues (A beta 3pE and A beta 11pE). To investigate the effects of these N-terminal modifications on the biophysical properties of A beta, peptides A beta 1-40, A beta 3pE-40, A beta 11pE-40, A beta 1-28, A beta 3pE-28, and A beta 11pE-28 were synthesized. Using circular dichroism spectroscopy, we determined that the pyroglutamyl-containing peptides form beta-sheet structure more readily than the corresponding full-length A beta peptides, both in aqueous solutions and in 10% sodium dodecyl sulfate micelles. Trifluoroethanol spectra indicated that the relative beta-sheet to alpha-helical stability is higher for the pyroglutamyl-containing peptides. Sedimentation experiments show that the pyroglutamyl-containing peptides have greater aggregation propensities than the corresponding full-length peptides. Comparison between the A beta 40 and the A beta 28 series indicated that the greater beta-sheet forming and aggregation propensities of the pyroglutamyl peptides are not simply due to an increase in hydrophobicity.

Hashimoto, M. and E. Masliah (1999). "Alpha-synuclein in Lewy body disease and Alzheimer's disease." Brain Pathol 9(4): 707-20.
Alzheimer's disease (AD) and Lewy body disease (LBD) are the most common causes of dementia in the elderly population. Previous studies have shown that cognitive alterations in these disorders are associated with synaptic loss. Injury and loss of synapses might be associated with altered function of synaptic proteins. Among them, recent studies have shown that abnormal aggregation and accumulation of synaptic proteins, such as alpha-synuclein, might be associated with plaque formation in AD and Lewy body formation in LBD. Further reinforcing the hypothesis that alpha-synuclein plays a major role in the pathogenesis of these disorders, recent work has shown that mutations that alter the conformation of this molecule are associated with familial forms of Parkinson's disease. The mechanisms by which altered function or aggregation of alpha-synuclein might lead to neurodegeneration are not completely clear; however, new evidence points to a potential role for this molecule in synaptic damage and neurotoxicity via amyloid-like fibril formation and mitochondrial dysfunction. In this manuscript we review the data linking alpha-synuclein to the pathogenesis of AD and LBD.

Hartmann, T. (1999). "Intracellular biology of Alzheimer's disease amyloid beta peptide." Eur Arch Psychiatry Clin Neurosci 249(6): 291-8.
Strong evidence links excess production of a small peptide and the pathogenesis of Alzheimer's disease (AD). Originally this peptide, beta-amyloid 42 (Abeta42), was assumed to be released by a pathogenic event; it is now well established that Abeta42 is released from cells during normal cellular metabolism of the Alzheimer amyloid precursor protein. Recently, in a series of surprising reports it was discovered that Abeta42 is produced intracellularly, and what might have been regarded first as a strange abnormality of a few selected cell lines has now been recognized as an important cellular pathway for Abeta production. Moreover, the differences between secretory and intracellular Abeta production might hold the clues for brain specificity and cellular mechanisms of AD pathogenesis.

Hanzel, D. K., J. Q. Trojanowski, et al. (1999). "High-throughput quantitative histological analysis of Alzheimer's disease pathology using a confocal digital microscanner." Nat Biotechnol 17(1): 53-7.
To develop a rapid method of quantifying immunohistochemical information in tissue sections, we tested a confocal laser fluorescence microscanner initially designed for DNA microarray analysis. This instrument collects digital images at multiple wavelengths, scans entire sections at a resolution of 5 or 10 microm in less than 10 min, and quantifies structures labeled with fluorescent or nonfluorescent probes. We assessed the microscanner by studying immunostained amyloid plaques in the Alzheimer's disease (AD) brain and in the brain of a transgenic mouse model of AD amyloidosis, as efforts to correlate measures of amyloid plaques in brain sections with behavioral impairments are impeded by limitations in current morphometric methods. Microscanner analysis was used to determine amyloid burden in the occipital and entorhinal cortices of the mouse (3.7%) and human AD brain (1.6%). We also quantified the colocalization of plaque beta-amyloid (Abeta) with glial fibrillary acidic protein, a marker of gliosis (mouse 0.9%, human AD 3.7%). The microscanner may be generally applicable to a wide variety of human histopathologies and their animal models, wherever rapid unbiased quantitative analysis is needed.

Haass, C. and R. Baumeister (1999). "The biological and pathological function of presenilin proteins--simple cell systems and a worm in Alzheimer's disease research." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 23-7.
Alzheimer's disease (AD) is the most common form of dementia. In a small number of cases AD is genetically inherited. Mutations are associated with so far three genes. These genes encode the beta-amyloid precursor protein (beta APP), as well as presenilin (PS) 1 and -2. Mutations in all three genes affect the generation of amyloid beta-peptide (A beta), which is the major component of senile plaques. Mutations in the PS genes occur much more frequently as those associated with the beta APP gene and can cause the earliest onset of AD ever recorded. PS genes are not only involved in familial AD but also play a functional role in the general production of A beta. Therefore PS proteins are key molecules, which will allow us to understand fundamental aspects of the molecular mechanisms involved in AD. Here we will summarize the pathological as well as biological function of PS and demonstrate that simple systems, such as cultured cells and the worm Caenorhabditis elegans can be used for modern AD research.

Guenette, S. Y. and R. E. Tanzi (1999). "Progress toward valid transgenic mouse models for Alzheimer's disease." Neurobiol Aging 20(2): 201-11.
A transgenic mouse model for Alzheimer's disease (AD) should mimic the age-dependent accumulation of beta-amyloid plaques, neurofibrillary tangles, neuronal cell death as well as display memory loss and behavioral deficits. Age-dependent accumulation of A beta deposits in mouse brain has been achieved in mice overexpressing mutant alleles of the amyloid precursor protein (APP). In contrast, mice bearing mutant alleles of the presenilin genes show increased production of the A beta42 peptide, but do not form amyloid deposits unless mutant alleles of APP are also overproduced. Furthermore, the onset of A beta deposition is greatly accelerated, paralleling the involvement of presenilins in early onset AD. Studies of APP and presenilin transgenic mice have shown 1) the absence of a requirement for a maturation step in dense core plaque formation, 2) evidence that beta-amyloid deposition is directed by regional factors, and 3) behavioral deficits are observed before A beta deposition. Crosses of APP transgenic mice with mice modified for known AD risk factors and "humanizing" the mouse may be necessary for complete replication of AD.

Graeber, M. B. and P. Mehraein (1999). "Reanalysis of the first case of Alzheimer's disease." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 10-3.
When a disease becomes as important as Alzheimer's dementia, there is a natural interest in its medical history and in the origin of the underlying disease concept. Key to understanding Alois Alzheimer's views on the disease, which was named after him, are the histological sections of the cases he saw. This histological material was rediscovered in Munich in 1992 and 1997 (Neurogenetics 1997, 1:73-80; 1998, 1:223-228). An extensive neuropathological and molecular genetic analysis of the tissue is currently being carried out. The present article summarizes the history of the rediscovery and provides an analysis of the neuropathology of Alois Alzheimer's first case, Auguste D.

Gomez-Isla, T., W. B. Growdon, et al. (1999). "The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors." Brain 122 ( Pt 9): 1709-19.
To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.

Ginsberg, S. D., P. B. Crino, et al. (1999). "Predominance of neuronal mRNAs in individual Alzheimer's disease senile plaques." Ann Neurol 45(2): 174-81.
The sequestration of RNA in Alzheimer's disease (AD) senile plaques (SPs) and the production of intraneuronal amyloid-beta peptides (Abeta) prompted analysis of the mRNA profile in single immunocytochemically identified SPs in sections of AD hippocampus. By using amplified RNA expression profiling, polymerase chain reaction, and in situ hybridization, we assessed the presence and abundance of 51 mRNAs that encode proteins implicated in the pathogenesis of AD. The mRNAs in SPs were compared with those in individual CA1 neurons and the surrounding neuropil of control subjects. The remarkable demonstration here, that neuronal mRNAs predominate in SPs, implies that these mRNAs are nonproteinaceous components of SPs, and, moreover, that mRNAs may interact with Abeta protein and that SPs form at sites where neurons degenerate in the AD brain.

George, A. R. and D. R. Howlett (1999). "Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors." Biopolymers 50(7): 733-41.
We report the modeling of and possible interactions within the solid beta-amyloid (ABeta) 1-43 fibril, the most fibrillogenic peptide known. All models proposed are consistent with the known experimental structural data, in terms of both secondary structure and packing motifs. The model containing antiparallel beta-sheets, and a beta-turn at G(25)S(26)N(27)K(28) has the lowest calculated packing energy. As such, it can be considered a reasonable model for solid beta-amyloid in Alzheimer's disease plaques. Interestingly, with the turn located at this position, the 1-43 structure is stabilized by a number of complementary intermolecular interactions between the beta-sheets. These well-defined interactions exist for the side-chain residues of 41, 42, and 43 with adjacent ABeta molecules. These interactions would not be conserved in the 1-40 peptide, and indeed, this enhanced interaction is proposed to give rise to the increased fibrillogenic nature of the ABeta 1-43 species over the 1-40 form. The models are used to explain the increased fibrillogenic nature of the Dutch family mutation of ABeta. These models are also employed to examine possible docking interactions of previously reported antiaggregation inhibitors, such as 4'-deoxy-4'-iododoxorubicin (IDOX) onto the theoretical growing surface. A docked structure of IDOX with the model of the solid fibril is described and a proposal for the mechanism of its antiaggregation properties is presented.

Garcia-Jimenez, A., R. F. Cowburn, et al. (1999). "Quantitative autoradiography of [3H]forskolin binding sites in post-mortem brain staged for Alzheimer's disease neurofibrillary changes and amyloid deposits." Brain Res 850(1-2): 104-17.
Adenylyl cyclase (AC) signal transduction has been shown to be affected in Alzheimer's disease (AD). Deficits have been described in different components of the system, from the receptor to the effector level. [3H]forskolin is a diterpene that binds with high affinity to AC. In the present report, we used autoradiography to study [3H]forskolin binding to sections of entorhinal cortex and hippocampus from 23 cases staged for AD pathology according to Braak and Braak [Acta Neuropathol. 82 (1991) 239-259]. This protocol defines six stages according to neurofibrillary changes, which start in the entorhinal region (stages I-II), spread to the hippocampus (stages III-IV) and finally to the isocortical areas (stages V-VI). The amyloid classification includes three stages in which the basal isocortex is first affected (stage A), followed by other isocortical association areas (stage B) and finally the primary isocortical areas (stage C). We also studied the effects of the GTP-analogue Gpp[NH]p on binding, in order to detect changes in G-protein-AC coupling. We used two different concentrations of Gpp[NH]p, that were previously reported to inhibit and stimulate [3H]forskolin binding via Gi and Gs, respectively. Results showed that [3H]forskolin binding declined significantly with staging for neurofibrillary changes only in the entorhinal region (P < 0.05, ANOVA). In addition, the decrease in [3H]forskolin binding observed in the presence of 1 microM Gpp[NH]p diminished significantly with staging in the entorhinal region (P < 0.05, ANOVA). No significant changes were seen with amyloid staging, with the exception of the CA1 subfield of the hippocampus, where [3H]forskolin binding in the absence of Gpp[NH]p was significantly decreased at stage B compared with all other stages (P < 0.05, ANOVA). In conclusion, our results showed a very limited decrease in [3H]forskolin binding with the progression of AD pathology, suggesting that the AC levels may be largely preserved in the disease. The specific change in the effect of a low concentration of Gpp[NH]p on the binding could indicate the loss of Ca2+/calmodulin-sensitive AC isoforms in AD.

Garcia de Yebenes, E., A. Ho, et al. (1999). "Regulation of the heparan sulfate proteoglycan, perlecan, by injury and interleukin-1alpha." J Neurochem 73(2): 812-20.
Perlecan is a specific proteoglycan that binds to amyloid precursor protein and beta-amyloid peptide, is present within amyloid deposits, and has been implicated in plaque formation. Because plaque formation is associated with local inflammation, we hypothesized that the mechanisms involved in brain inflammatory responses could influence perlecan biosynthesis. To test this hypothesis, we first studied perlecan regulation in mice after inflammation induced by a brain stab wound. Perlecan mRNA and immunoreactivity were both increased 3 days after injury. Interleukin-1alpha (IL-1alpha) is a cytokine induced after injury and plays an important role in inflammation. As such, IL-1alpha may be one of the factors participating in regulating perlecan synthesis. We thus studied perlecan regulation by IL-1alpha, in vivo. Regulation of perlecan mRNA by this cytokine was area-specific, showing up-regulation in hippocampus, whereas in striatum, perlecan mRNA was unchanged. To support this differential regulation of perlecan mRNA by IL-1alpha, basic fibroblast growth factor (bFGF), a growth factor also present in plaques, was studied in parallel. bFGF mRNA did not show any regional difference, being up-regulated in both hippocampus and striatum in vivo. In vitro, both astrocyte and microglia were immunoreactive for perlecan. Moreover, perlecan mRNA was increased in hippocampal glial cultures after IL-1alpha but not in striatal glia. These results show an increase in perlecan biosynthesis after injury and suggest a specific regulation of perlecan mRNA by IL-1alpha, which depends on brain area. Such regulation may have important implications in the understanding of regional brain variations in amyloid plaque formation.

Funato, H., M. Enya, et al. (1999). "Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation." Am J Pathol 155(1): 23-8.
The amyloid cascade hypothesis of Alzheimer's disease postulates that accumulation of amyloid beta-protein (Abeta) precedes neurofibrillary tangle formation or neuronal loss in the cortex. Although this temporal profile has been proved in the neocortex by silver staining and immunocytochemical methods, CA1 of the hippocampus exhibits a distinct temporal profile during normal aging: the formation of neurofibrillary tangles precedes senile plaque formation. This temporal profile has been further confirmed by two-site enzyme immunoassay (EIA) quantitation of sodium dodecyl sulfate (SDS)-dissociable Abeta42; neurofibrillary tangles are already present despite undetectable levels of SDS-dissociable Abeta42. However, when the same specimens were subjected to Western blotting, many cases with or without neurofibrillary tangles showed some accumulation of SDS-stable Abeta dimers that cannot be detected by EIA. Thus, the temporal profile prerequisite for the hypothesis is still valid in CA1, and this finding also suggests that SDS-stable Abeta dimers have some significant effects on CA1 pyramidal neurons, which are most vulnerable to neurofibrillary tangle formation.

Fonseca, M. I., E. Head, et al. (1999). "The presence of isoaspartic acid in beta-amyloid plaques indicates plaque age." Exp Neurol 157(2): 277-88.
Extracellular deposits of fibrillar beta-amyloid are a characteristic neuropathology of Alzheimer's disease (AD). We have developed a novel antibody to a hypothesized "older isomer" of the amyloid protein. This antibody, raised against a synthetic beta-amyloid peptide containing isoaspartic acid at position 7 (isoaspartic-7-Abeta), reacts with isoaspartic-7-Abeta, a nonenzymatic modification found in long-lived proteins. Plaques stained with this antibody are thioflavine positive and are found throughout the frontal and entorhinal cortices of AD cases. In frontal cortex, isoaspartic-7-Abeta plaques are clustered but have a widespread distribution in all cortical layers. Isoaspartic-7-Abeta is found primarily in the core of individual plaques surrounded by nonisomerized amyloid. Activated microglia are associated with plaques containing isomerized and nonisomerized amyloid. In contrast to AD, isoaspartic-7-Abeta plaques in Down's syndrome (DS) cases are found primarily in the superficial layers of frontal cortex. Using image analysis isoaspartic-7-Abeta deposition was correlated with dementia severity in AD and with age in DS. The results indicate that this antibody against altered aspartyl amyloid could be a useful indicator of the age of amyloid plaques.

Felician, O. and T. A. Sandson (1999). "The neurobiology and pharmacotherapy of Alzheimer's disease." J Neuropsychiatry Clin Neurosci 11(1): 19-31.
Alzheimer's disease (AD), the most common cause of dementia, has become a major public health concern as our population ages. In recent years, AD has attracted the attention of a wide range of biological disciplines, and substantial progress has been made in understanding the mechanisms of neurodegeneration in AD. Four different genes have now been associated with AD and are providing insights into the pathogenesis of the disease. The roles of beta-amyloid, tau, hormonal changes, inflammation, and oxidative stress in the neurodegeneration of AD are also being delineated. Based on these discoveries, rational therapeutic strategies are developing rapidly. The authors review these and other recent advances in the neurobiology and pharmacotherapy of AD.

Eikelenboom, P. and R. Veerhuis (1999). "The importance of inflammatory mechanisms for the development of Alzheimer's disease." Exp Gerontol 34(3): 453-61.
A variety of inflammatory proteins has been identified in brains of patients with Alzheimer's disease. The current data suggest that the inflammatory processes are intimately involved in several crucial events in the pathological cascade. Immunohistochemical studies reveal that those parts of the brain wherein the amyloid-beta deposits are closely associated with a chronic inflammatory response are strongly related to the characteristic symptoms. An inflammation-based approach could also provide a valuable theoretical framework to study the influence of extracerebral factors (such as acute phase reactants) on the clinical course of Alzheimer's disease.

Egensperger, R., S. Weggen, et al. (1999). "Reverse relationship between beta-amyloid precursor protein and beta-amyloid peptide plaques in Down's syndrome versus sporadic/familial Alzheimer's disease." Acta Neuropathol (Berl) 97(2): 113-8.
Strong genetic evidence has been accumulated in favor of a central role of beta-amyloid precursor protein (APP) and beta-amyloid peptide (betaA4) in the pathogenesis of Alzheimer's disease (AD). We employed four newly developed APP and betaA4 antibodies and performed a comparative neuropathological study of patients with Down's syndrome (DS), early-onset familial AD and sporadic AD to investigate the distribution of APP and betaA4 plaque densities in the cerebral cortex of these disorders. Quantitative analysis of APP versus betaA4 plaques revealed that brains with early-onset familial AD and sporadic AD showed significantly more betaA4 plaques than brains with DS (P < 0.05). In contrast, APP plaques were more abundant in DS cerebral cortex (P < 0.02). These observations suggest that the development of pathological changes in DS brains does not parallel that observed in AD, which might be attributable to different causes in the pathogenesis of betaA4 formation. A comparison of these disorders may be useful to further complement our knowledge of the mechanisms leading to plaque development.

Duyckaerts, C., M. A. Colle, et al. (1999). "[Alzheimer's disease: lesions and their progression]." Rev Neurol (Paris) 155 Suppl 4: S17-27.
Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.

Durany, N., G. Munch, et al. (1999). "Investigations on oxidative stress and therapeutical implications in dementia." Eur Arch Psychiatry Clin Neurosci 249 Suppl 3: 68-73.
Alzheimer's disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death and formation of amyloid plaques and neurofibrillary tangles (NFTs) NFTs are composed of hyperphosphorylated tau protein, and senile plaques contain aggregates of the beta-peptide. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress during the course of the disease. Advanced glycation endproducts (AGEs), which are formed by a non-enzymatic reaction of glucose with long-lived protein deposits, are potentially toxic to the cell, are present in brain plaques in AD, and its extracellular accumulation in AD may be caused by an accelerated oxidation of glycated proteins. The microtubuli-associated protein tau is also subject to intracellular AGE formation. AGEs participate in neuronal death causing direct (chemical) radical production: Glycated proteins produce nearly 50-fold more radicals than non-glycated proteins, and indirect (cellular) radical production: Interaction of AGEs with cells increases oxidative stress. During aging cellular defence mechanisms weaken and the damages to cell constituents accumulate leading to loss of function and finally cell death. The development of drugs for the treatment of AD remains at a very unsatisfying state. However, pharmacological approaches which break the vicious cycles of oxidative stress and neurodegeneration offer new opportunities for the treatment of AD. Theses approaches include AGE-inhibitors, antioxidants, and anti-inflammatory substances, which prevent radical production. AGE inhibitors might be able to stop formation of AGE-modified beta-amyloid deposits, antioxidants are likely to scavenge intracellular and extracellular superoxide radicals and hydrogen peroxide before these radicals damage cell constituents or activate microglia, and anti-inflammatory drugs attenuating microglial radical and cytokine production.

Duque-Castano, A., M. I. Roldan, et al. (1999). "[Neuropathological findings in early-onset Alzheimer's disease (E280a-PS1 mutation)]." Rev Neurol 29(1): 1-6.
INTRODUCTION AND MATERIAL: Nine brains belonging to early onset Alzheimer disease (E280A-PS1 mutation) affected individuals from Antioquia, Colombia, were analyzed by neuropathological standard techniques. All individuals were ascertained from genealogies descendents from a common ancestor that shows a dominant autosomical pattern of inheritance. RESULTS: All cases analyzed were carriers to the E280A-PS1 mutation. This type of mutation produce beta-amyloid deposits of 42 aminoacids in the CNS. The mean of onset age was 48.4 years with an average of evolution time of 7.55 years and a mean of death age of 56.55. Although, all the cases showed symmetrical atrophy and them was more severe in the hippocampal region, a definitive anterior pattern (temporo-frontal) was showed. The higher the time of evolution of disease the lower the brain weight. CONCLUSIONS: All types of senile plaques and abundant neurofibrillary tanggles were found. In the stem, similar lesions were found but they were in lower number. Only the mesencephalic region showed a significative positive correlation between the number of senile plaques and the number of neurofibrillary tanggels (p < 0.05, r = 0.76). Only the parietal region showed a significant positive correlation between the number of senile plaques and the disease evolution time (p < 0.02, r = 0.74). Particularly, the cerebellum only showed senile plaques but neurofibrillary degeneration was not observed. With the exception of the Hirano bodies, all findings traditionally described were observed.

Dodel, R. C., Y. Du, et al. (1999). "Sodium salicylate and 17beta-estradiol attenuate nuclear transcription factor NF-kappaB translocation in cultured rat astroglial cultures following exposure to amyloid A beta(1-40) and lipopolysaccharides." J Neurochem 73(4): 1453-60.
In recent years inflammatory mechanisms have become increasingly appreciated as important steps in the Alzheimer's pathogenic pathway. There is accumulating evidence that amyloid beta-peptide (A beta), the peptide product of the cleavage of amyloid precursor protein, may promote or exacerbate local inflammation by stimulating glial cells to release immune mediators. In addition, clinical studies using nonsteroidal antiinflammatory drugs have found a reduced risk for Alzheimer's disease with their use. Here we show that the neurotoxic A beta, a major plaque component, and lipopolysaccharides (LPS), an immune reaction-triggering portion of bacterial membranes, are both potent activators of the nuclear transcription factor NF-kappaB in primary rat astroglial cells. The activation was found to be concentration- and time-dependent and could be attenuated in the presence of NF-kappaB decoy nucleotides. The pretreatment by either 17beta-estradiol (1-10 microg) or sodium salicylate (3-30 mM) reduced the A beta (LPS)-induced activation of NF-kappaB by 48 (50%) and 60% (50%) of activated levels, respectively. In addition, 17beta-estradiol (10 microM) and sodium salicylate (10 mM) were able to attenuate the increase in interleukin-1beta levels following exposure to 25 microM A beta. Our data suggest that the aberrant gene expression is at least in part due to A beta-induced activation of NF-kappaB, a potent immediate-early transcriptional regulator of numerous proinflammatory genes; this event takes place in astroglial cells. The results of our experiments provide a further understanding of the effects of estrogen and aspirin on astroglial cells exposed to A beta and LPS.

Dodart, J. C., H. Meziane, et al. (1999). "Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein." Behav Neurosci 113(5): 982-90.
PDAPP transgenic mice have been shown to develop age dependently much of the cerebral histopathology associated with Alzheimer's disease. PDAPP mice (3-10 months old) were tested in a battery of memory tasks to determine whether they develop memory-behavioral deficits and whether these deficits occur before or after amyloid deposition. PDAPP mice manifest robust impairments in a radial-maze spatial discrimination task at all ages tested. Mild deficits were observed in a barpress learning task in 3-month-old PDAPP mice. In contrast, PDAPP mice show an age-dependent decrease in spontaneous object-recognition performance that appears to be severe at ages when amyloid deposition is known to occur. Thus, the PDAPP mouse shows severe deficits in the radial maze well before amyloid plaque deposition, whereas object-recognition performance decreases with age and may be associated with amyloid deposition.

Diehlmann, A., N. Ida, et al. (1999). "Analysis of presenilin 1 and presenilin 2 expression and processing by newly developed monoclonal antibodies." J Neurosci Res 56(4): 405-19.
Because distinct mutations in presenilin 1 and presenilin 2 are a major cause of early-onset familial Alzheimer's disease, we generated four monoclonal antibodies for the identification, localization, and investigation of presenilins in various cell lines and tissues from patients and controls. We show that these antibodies are specific for the N- and C-terminal domains of human presenilin 1 and presenilin 2. They recognize presenilin full-length proteins and their approximately 28-35 kDa N-terminal fragments and approximately 18-20 kDa C-terminal fragments. None of the antibodies showed cross-reaction in their specific detection ability. We demonstrated that presenilin 1 and presenilin 2 are proteolytically processed in human glioma cell lines, transfected and untransfected human neuroblastoma SH-SY5Y cells, COS-7 cells, rat cerebellar neuronal ST15 cells, mouse and human brain. Remarkably, we observed that presenilin 2 is alternatively cleaved during apoptosis, producing smaller C-terminal fragments. By analyzing the subcellular distribution of presenilins, we found reticular and fine vesicular staining throughout the cell bodies. In addition, staining of Golgi compartments and the perinuclear envelope was observed. Alzheimer's disease brain showed strong immunoreactivity of presenilin 1 in reactive astrocytes and senile plaques. This high expression of presenilin 1 may explain the increased production and accumulation of the amyloid-beta peptide in patients with sporadic Alzheimer's disease in the absence of familial presenilin mutation.

Dickson, D. W. (1999). "Microglia in Alzheimer's disease and transgenic models. How close the fit?" Am J Pathol 154(6): 1627-31.

Dickson, T. C., C. E. King, et al. (1999). "Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's disease." Exp Neurol 156(1): 100-10.
We examined the neurochemical and morphological diversity of abnormal neurites associated with beta-amyloid plaque formation in the early and late stages of Alzheimer's disease. Preclinical Alzheimer's disease was characterised by the presence of abnormal neurites containing either neurofilament or chromogranin A immunoreactivity. All clustered dystrophic neurites in these cases were associated with beta-amyloid plaques. Neurofilament immunoreactive dystrophic neurites in preclinical Alzheimer's disease could be further subclassified into bulb- and ring-like structures, and these abnormal neurites contained both phosphorylated and dephosphorylated neurofilament epitopes. Dystrophic neurites in Alzheimer's disease could be subdivided into predominantly neurofilament, tau, or chromogranin A immunolabeled forms. Some neurofilament immunoreactive neurites had a core region labeled for tau. The neurofilaments of the dystrophic neurites in Alzheimer's disease had the same complement of phosphorylation- and dephosphorylation-dependent epitopes as observed in preclinical cases. Therefore, an abnormal accumulation of variably phosphorylated neurofilaments represent the earliest cytoskeletal alteration associated with dystrophic neurite formation. Furthermore, these data indicate that dystrophic neurites may "mature" through neurofilament-abundant forms to the neurites containing the profoundly altered filaments labeled for tau. The precise morphological and neurochemical changes associated with dystrophic neurite formation suggests that beta-amyloid plaques are causing physical damage to surrounding axons. The resultant axonal sprouting and profound cytoskeletal alterations would follow the chronic stimulation of the stereotypical reaction to such physical trauma.

Di Patre, P. L., S. L. Read, et al. (1999). "Progression of clinical deterioration and pathological changes in patients with Alzheimer disease evaluated at biopsy and autopsy." Arch Neurol 56(10): 1254-61.
OBJECTIVES: To quantify the progression of senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, and microglial activation in the cortex and white matter of patients with Alzheimer disease evaluated at both biopsy and subsequent autopsy and correlate these changes with the progression of neurologic impairment. SETTING: Academic referral center for patient with Alzheimer disease. PATIENTS: Four patients meeting the clinical criteria for Alzheimer disease, e