Trojanowski, J. Q. and V. M. Lee (2002). "The role of tau in Alzheimer's disease." Med Clin North Am 86(3): 615-27.
Despite earlier uncertainties about the role of tau pathology in AD, the discovery of multiple mutations in the tau gene that lead to the abnormal aggregation of tau and the onset/progression of FTDP-17 demonstrates that tau dysfunction is sufficient to produce neurodegenerative disease. The mutations lead to specific cellular alterations, including altered expression, function and biochemistry of tau. The finding that specific tau gene mutations lead to diverse FTDP-17 phenotypes raises the possibility that the clinical and pathological expression of hereditary and related sporadic tauopathies may be influenced by tau gene polymorphisms, other genetic factors and epigenetic events. However, the precise mechanisms whereby tau assembles into filaments and causes neurodegeneration in the human brain remain to be elucidated, but further investigation into the mechanisms of tau dysfunction, as well as the identification of potential disease-modifying factors, will provide additional insight into novel strategies for the treatment and prevention of AD and related disorders. Moreover, development of additional animal models of tauopathies that more closely recapitulate human diseases will facilitate this undertaking, and this is likely to have implications for other neurodegenerative disorders since the aggregation of tau in AD and and related tauopathies is an example of abnormal protein-protein interactions resulting in the intracellular accumulation of filamentous proteins that is a common feature of many fatal CNS diseases characterized by relentlessly progressive brain degeneration [1-3]. Thus, the fibrillization and aggregation of proteins in the brain is a common theme in a diverse group of neurodegenerative disorders and insight into the pathogenesis of any one of these disorders may have implications for understanding the mechanisms that underlie all these diseases as well as for the discovery of better strategies to treat them [1-3].

Pastor, P., M. Ezquerra, et al. (2002). "Further extension of the H1 haplotype associated with progressive supranuclear palsy." Mov Disord 17(3): 550-6.
The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800-D17S791), associated with some cases of familial frontotemporal dementia (FTDP-17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice-site region of the exon 10 and in the microtubule-binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5' or in the 3' flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP.

Morris, H. R., R. Katzenschlager, et al. (2002). "Sequence analysis of tau in familial and sporadic progressive supranuclear palsy." J Neurol Neurosurg Psychiatry 72(3): 388-90.
Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene. Rare familial forms of PSP have been described. Recently familial frontotemporal dementia linked to chromosome 17 (FTDP-17) has been shown to be due to mutations in tau and there may be a clinical and pathological overlap between PSP and FTDP-17. In this study we have analysed the tau sequence in two small families with PSP, and a number of clinically typical and atypical sporadic cases with pathological confirmation of the diagnosis. The tau mutations described in FTDP-17 were not found in the most clinically diagnosed patients with PSP. This suggests that usually FTDP-17 and PSP, including the rare familial form of PSP, are likely to be separate conditions and that usually PSP and typical PSP-like syndromes are not due to mutations in tau.

Ikeda, K., H. Akiyama, et al. (2002). "Pick-body-like inclusions in corticobasal degeneration differ from Pick bodies in Pick's disease." Acta Neuropathol (Berl) 103(2): 115-8.
In corticobasal degeneration (CBD), tau-positive cytoplasmic inclusions resembling Pick bodies (PBs) appear in the cerebral cortex. Tau immunoreactivity in PBs is expressed mainly on filamentous elements, whereas that of PB-like inclusions in CBD is expressed on granules, which are densely packed mainly in the periphery of inclusions. PBs are clearly detectable by conventional Bodian silver impregnation but negative for the Gallyas-Braak (G-B) method and for PS262, which recognizes phosphorylation at Ser 262 of the entire tau sequence. Almost all PBs are negative for Ex10, which recognizes 4-repeat tau specifically. In contrast to PBs, PB-like inclusions in CBD could not be detected by the Bodian method, but were positive for the G-B method, PS262 and Ex10. In summary, PBs and PB-like inclusions exhibit distinct differences. These results are useful for the argument of an overlap between PiD and CBD as well as discussion of the phenotypic resemblance of PB-like inclusions bearing types of FTDP-17 to Pick's disease.

Zhukareva, V., V. Vogelsberg-Ragaglia, et al. (2001). "Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia." Ann Neurol 49(2): 165-75.
Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.

Yoshiyama, Y., V. M. Lee, et al. (2001). "Frontotemporal dementia and tauopathy." Curr Neurol Neurosci Rep 1(5): 413-21.
The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as "tauopathies." The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them.

Tolnay, M. and A. Probst (2001). "Frontotemporal lobar degeneration. An update on clinical, pathological and genetic findings." Gerontology 47(1): 1-8.
Frontotemporal lobar degeneration is the second most common form of cortical dementia in the presenium after Alzheimer's disease. Clinically, based on consensus guidelines, three distinct disease entities can be distinguished: frontotemporal dementia, semantic dementia and progressive nonfluent aphasia. Dementia of frontal type and motor neuron disease inclusion dementia are the most frequent neuropathological subtypes of frontotemporal lobar degeneration. By using immunohistochemistry, the latter is characterized by the presence of filamentous ubiquitin-reactive but tau-negative inclusions in nerve cell bodies and neurites. In contrast, Pick's disease and familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are both characterized by abundant filamentous nerve cell inclusions made up of the microtubule-associated protein tau. The recent discovery of more than 15 different mutations in the tau gene in FTDP-17 brought the tau protein to the centre stage. These findings had a major impact on our understanding of neurodegenerative disorders characterized by tau filamentous inclusions in neurones and/or glial cells which are grouped under the generic term of tauopathies. However, as exciting these new molecular insights are, it would be inappropriate to lump frontotemporal lobar degeneration as tauopathies. Recent neuropathological and genetic data strongly suggest that there is more than one genetic background for frontotemporal lobar degeneration.

Reed, L. A., Z. K. Wszolek, et al. (2001). "Phenotypic correlations in FTDP-17." Neurobiol Aging 22(1): 89-107.
Frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) are hereditary tauopathies affecting at least 50 known kindred worldwide. Most kindred present with severe behavioral or psychiatric manifestations progressing to dementia, while some kindred first manifest a parkinsonian-plus syndrome. Nine missense mutations, one deletion mutation, and two transition mutations not altering the encoded amino acid, have been described in or near the microtubule-binding domains within exons 9, 10, 12, and 13. In addition, five different intronic mutations have been reported in the 5' splice-site of the alternatively spliced exon 10. Missense mutations affecting constitutively expressed exons affect all six major tau isoforms and result in neurofibrillary tangles similar to those present in secondary tauopathies, such as Alzheimer's disease. In contrast, mutations that affect the alternatively spliced exon 10 or its 5' splice regulatory region alter the ratio of the tau isoforms incorporated into the tangles and result in filamentous inclusions resembling those seen in the primary tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and Pick's disease.The severity and heterogeneity of the clinicomorphologic phenotype may, in part, reflect the diversity in the primary molecular mechanisms of disease in FTDP-17.

Nagiec, E. W., K. E. Sampson, et al. (2001). "Mutated tau binds less avidly to microtubules than wildtype tau in living cells." J Neurosci Res 63(3): 268-75.
Some forms of genetically inherited dementia, including frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in tau. We have examined several mutations in the microtubule-binding portion of tau for their effect on microtubule binding, cellular distribution and cytoskeletal structure in mammalian cells. Using constructs coding for mutant (P301L and V337M) and wildtype human tau fused to a green fluorescent protein analog (EGFP) we followed the disposition of tau in live cells after transient transfection using confocal microscopy. Most of the tau protein localized to structures that resembled microtubules or microtubule bundles and co-localized with tubulin. At 3 days post-transfection mutant tau proteins showed a higher abundance of free tau in the cytoplasm than did wildtype tau. Cells expressing the P301L mutation showed proportionally more cytoplasmic localization of tau. Confirming these results, fractionated cells with mutant tau had a higher percentage of tau in the cytoplasmic compartment as compared to the cytoskeletal compartment. Cells with wildtype tau had most tau in the cytoskeletal fraction. Because the mutations (V337M, P301L) are associated with genetic tauopathies, these results suggest that a factor in disease etiology of genetic tauopathies and other dementias with altered tau is a greater abundance of tau in the cytoplasm due to decreased binding to microtubules. This increased cytoplasmic presence may be a significant factor in promoting tau aggregation.

Miyasaka, T., M. Morishima-Kawashima, et al. (2001). "Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation." Am J Pathol 158(2): 373-9.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder, characterized genetically by autosomal dominant inheritance, clinically by behavioral abnormalities and parkinsonism, and neuropathologically by tauopathy. Linkage analyses of affected families have led to identification of several exonic and intronic mutations in the tau gene. In this study, we analyzed molecular species of tau in the soluble and insoluble fractions of brain affected by the FTDP-17 R406W mutation. Protein chemical analysis and Western blotting using site-specific antibodies indicated that almost equal amounts of wild-type and mutant tau were present in the Sarkosyl-insoluble fraction of the R406W brain. Consistent with this, wild-type and mutant tau colocalized in neurofibrillary tangles in the frontal cortex and hippocampus of the R406W brain. In contrast to soluble R406W tau, which was less phosphorylated than soluble wild-type tau, the Sarkosyl-insoluble mutant tau was highly phosphorylated as well as the insoluble wild-type tau.

Mack, T. G., R. Dayanandan, et al. (2001). "Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells." Neuroscience 108(4): 701-12.
The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated.We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport.

Ludolph, A. C., A. Sperfeld, et al. (2001). "[Tauopathies--a new class of neurodegenerative diseases]." Nervenarzt 72(2): 78-85.
Recently it was shown by several research groups that mutations in the gene encoding for the tau protein associated with microtubuli on chromosome 17 caused a distinct form of dementia named frontotemporal dementia and parkinsonism (FTDP-17). This disease includes familial asymmetrical frontal and, in the further course, frontotemporal dementia, parkinsonism, which is often initially sensitive to levodopa, signs of upper motor neuron degeneration, and, less commonly, amyotrophy. Tau is an intracellular protein of the cytoskeleton, which is responsible for the arrangement and stabilization of microtubuli. The discovery of mutations in the tau gene causing a distinct neurodegenerative disease in humans has firmly established the importance of the tau gene for neurodegenerative processes, not only in tauopathies but also in other degenerative disorders with tau pathology, such as corticobasal degeneration, supranuclear progressive paralysis, amyotropic lateral sclerosis, parkinsonism-dementia complex of Guam, and Alzheimer's disease. Our experience with patients suffering from PTDP-17 shows that its phenotype varies more than was described in the first consensus conferences. In the future, it will be important to designate the diagnostic gold standard not by clinical description, but etiologic classification.

Lim, F., F. Hernandez, et al. (2001). "FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain." Mol Cell Neurosci 18(6): 702-14.
The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates. That Tau dysfunction can cause neurodegeneration is indicated by pathogenic tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To investigate how Tau alterations provoke neurodegeneration we generated transgenic mice expressing human Tau with four tubulin-binding repeats (increased by FTDP-17 splice donor mutations) and three FTDP-17 missense mutations: G272V, P301L, and R406W. Ultrastructural analysis of mutant Tau-positive neurons revealed a pretangle appearance, with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD. Lysosomal alterations were confirmed by activity analysis of the marker acid phosphatase, which was increased in both transgenic mice and transfected neuroblastoma cells. Our results show that Tau modifications can provoke lysosomal aberrations and suggest that this may be a cause of neurodegeneration in tauopathies.

Lee, V. M., M. Goedert, et al. (2001). "Neurodegenerative tauopathies." Annu Rev Neurosci 24: 1121-59.
The defining neuropathological characteristics of Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar amyloid beta peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of beta-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick's disease, as well as by hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed, emerging data support the hypothesis that different tau gene mutations are pathogenic because they impair tau functions, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau. Nonetheless, different members of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influence the phenotypic manifestations of neurodegenerative tauopathies. Although these and other hypothetical mechanisms of neurodegenerative tauopathies remain to be tested and validated, transgenic models are increasingly available for this purpose, and they will accelerate discovery of more effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer's disease.

Hutton, M. (2001). "Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms." Neurology 56(11 Suppl 4): S21-5.
Recent identification of mutations in the gene encoding the microtubule-associated protein tau in the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has demonstrated that tau dysfunction can lead to neurodegeneration. At least nine missense mutations and one deletion mutation (DeltaK280) have been identified in exons 9 through 13 that encode the microtubule-binding domains of tau. In addition, five mutations have been found close to the 5' splice site of exon 10. The FTDP-17 missense and splice site mutations have multiple effects on the biology and function of tau. It is likely that these varied pathogenic mechanisms explain the wide range of clinical and neuropathologic features observed in the FTDP-17 tauopathies.

Hartmann, A. M., D. Rujescu, et al. (2001). "Regulation of alternative splicing of human tau exon 10 by phosphorylation of splicing factors." Mol Cell Neurosci 18(1): 80-90.
Tau is a microtubule-associated protein whose transcript undergoes regulated splicing in the mammalian nervous system. Exon 10 of the gene is an alternatively spliced cassette that is adult-specific and encodes a microtubule-binding domain. Mutations increasing the inclusion of exon 10 result in the production of tau protein which predominantly contains four microtubule-binding repeats and were shown to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we show that exon 10 usage is regulated by CDC2-like kinases CLK1, 2, 3, and 4 that phosphorylate serine-arginine-rich proteins, which in turn regulate pre-mRNA splicing. Cotransfection experiments suggest that CLKs achieve this effect by releasing specific proteins from nuclear storage sites. Our results show that changing pre-mRNA-processing pathways through phosphorylation could be a new therapeutic concept for tauopathies.

Gotz, J. (2001). "Tau and transgenic animal models." Brain Res Brain Res Rev 35(3): 266-86.
Advances in genetics and transgenic approaches have a continuous impact on our understanding of Alzheimer's disease (AD) and related disorders, especially as aspects of the histopathology and neurodegeneration can be reproduced in animal models. AD is characterized by extracellular Abeta peptide-containing plaques and neurofibrillary aggregates of hyperphosphorylated isoforms of microtubule-associated protein tau. A causal link between Abeta production, neurodegeneration and dementia has been established with the identification of familial forms of AD which are linked to mutations in the amyloid precursor protein APP, from which the Abeta peptide is derived by proteolysis. No mutations have been identified in the tau gene in AD until today. Tau filament formation, in the absence of Abeta production, is also a feature of several additional neurodegenerative diseases including progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene which are linked to FTDP-17 established that dysfunction of tau can, as well as Abeta formation, lead to neurodegeneration and dementia. In this review, newly recognized cellular functions of tau, and the neuropathology and clinical syndrome of FTDP-17 will be presented, as well as recent advances that have been achieved in studies of transgenic mice expressing tau and AD-related kinases and phosphatases. These models link neurofibrillary lesion formation to neuronal loss, provide an in vivo model in which therapies can be assessed, and may contribute to determine the relationship between Abeta production and tau pathology.

de Silva, R., M. Weiler, et al. (2001). "Strong association of a novel Tau promoter haplotype in progressive supranuclear palsy." Neurosci Lett 311(3): 145-8.
The microtubule associated protein, tau, is found in fibrillar lesions that characterise progressive supranuclear palsy (PSP) and related tauopathies. Mutations in the tau gene in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and genetic association of the H1 haplotype of the tau gene with PSP has firmly established a direct role for tau in disease pathogenesis. However, the functional significance of the tau genetic association in PSP is unknown. We analysed the tau gene promoter sequence and identified two novel single nucleotide polymorphisms. Here we report the genetic association of a novel tau promoter haplotype with PSP which may influence tau transcription.

Arai, T. and K. Ikeda (2001). "Phenotypic heterogeneity of FTDP-17: implications for the differences of pathological phenotype among sporadic tauopathies." Neurobiol Aging 22(1): 127-9.

van Slegtenhorst, M., J. Lewis, et al. (2000). "The molecular genetics of the tauopathies." Exp Gerontol 35(4): 461-71.
The identification of mutations in the tau gene in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) demonstrated that there is a direct link between tau dysfunction and neurodegeneration. At least 11 missense mutations and a three base pair deletion (DeltaK280) have been identified in exons 9-13. Additionally, five splice site mutations have been found in intron 10. The different FTDP-17 mutations have multiple effects on the biology and function of tau. These varied pathogenic mechanisms likely explain the wide range of clinical and neuropathological features observed in different families with FTDP-17. In addition to the tau mutations, a common extended haplotype in the tau gene also appears to be a risk factor in the development of the apparently sporadic tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The mechanism by which this common variability in the tau gene influences the development of these neurodegenerative diseases is unclear; however, it further suggests a central role for tau in the pathogenesis of several neurodegenerative conditions including Alzheimer's disease (AD).

Sahara, N., T. Tomiyama, et al. (2000). "Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation." J Neurosci Res 60(3): 380-7.
Missense and splicing point mutations have been found in the tau gene in families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Of these mutations, we examined four exonic missense point mutations (G272V, P301L, V337M and R406W) in 3-repeat or 4-repeat tau isoform on the transfection experiment. The effects of two mutations (G272V or P301L) on microtubules were subtle whereas those of two other mutations (V337M or R406W) were dramatically significant when these two mutations were constructed into 3-repeat tau but not into 4-repeat tau. The R406W mutation induced an alternation of microtubules to form dotted or fragmented forms retaining colocalization of tau with tubulin whereas the V337M mutation predominantly disrupted microtubule networks and diminished colocalization of tau and tubulin. The effect of the mutations on microtubules were thus site-dependent and isoform-dependent. Tau with R406W mutation was found to be colocalized with tubulin without filamentous structures on confocal views, suggesting that the carboxyl region of tau played a different role from tubulin-binding domain on microtubule assemble. Another abnormal property was identified in tau with R406W mutation that failed to suffer phosphorylation. Thus, diverse effects of tau mutations on microtubules may explain the various clinicopathologies of FTDP-17 and related tauopathies.

Lewis, J., E. McGowan, et al. (2000). "Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein." Nat Genet 25(4): 402-5.
Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

Kim, H., H. Xia, et al. (2000). "Attenuation of neurodegeneration-relevant modifications of brain proteins by dietary soy." Biofactors 12(1-4): 243-50.
Epidemiological studies show that postmenopausal women who undertake estrogen-replacement therapy have significantly lower risk for the onset of Alzheimer's disease (AD) than women who do not. Animal behavior studies have shown that ovariectomy results in the development of cognitive dysfunction that is prevented by estrogen-replacement, suggesting that normal mammalian cognitive function is impaired by estrogen reduction. Soy isoflavones in particular genistein have been demonstrated to have weak and selective estrogenic actions in various models of human chronic diseases. A hallmark of several human dementias including AD and fronto temporal dementia with Parkinsonism on chromosome 17 (FTDP-17) is the hyperphosphorylation of the microtubule-associated protein tau. Preliminary experiments are discussed here which show that isoflavones delivered in a soy protein matrix attenuated selected AD-relevant tau phosphorylations in a primate model of menopause. The rationale is discussed for the use of soy-based foods for protection against postmenopausal neurodegeneration.

Jellinger, K. A. (2000). "Morphological substrates of mental dysfunction in Lewy body disease: an update." J Neural Transm Suppl 59: 185-212.
Mental dysfunction including cognitive, behavioural changes, mood disorders, and psychosis are increasingly recognized in patients with Parkinson's disease (PD) and related disorders. Their morphological correlates are complex due to multiple system degeneration. CNS changes contributing to cognitive changes in PD include 1. Dysfunction of subcorticocortical networks with neuron losses in a) the dopaminergic nigrostriatal loop, causing striato-(pre)frontal deafferentation and mesocortico-limbic system (medial substantia nigra, ventral tegmentum); b) noradrenergic (locus coeruleus), and serotonergic systems (dorsal raphe nuclei), c) cholinergic forebrain system (nucleus basalis of Meynert, etc), and d) specific nuclei of amygdala and limbic system (thalamic nuclei, hippocampus); 2. Limbic and/or cortical Lewy body and Alzheimer type pathologies with loss of neurons and synapses, 3. Combination of subcortical, cortical, and other pathologies. In general, degeneration of subcortical and striato-frontal networks causes cognitive, executive, behavioural, and mood disorders but less severe dementia than cortical changes which, when present in sufficient numbers, are important factors for overt dementia. In PD, cortical tau pathology with similar or differential patterns than in Alzheimer disease (AD) shows significant linear correlation with cognitive decline. In dementia with Lewy bodies (DLB), the second most frequent cause of dementia in the elderly, cortical Lewy bodies (LB) may or may not be associated with amyloid plaques and neuritic AD lesions. They predominantly affect the limbic system with less frequent isocortical Braak stages, whereas the cholinergic forebrain system is more severely affected than in AD. Both neuritic degeneration in limbic system in PD and DLB and the density of cortical synapse markers correlate with neuritic AD pathology and less with cortical LB counts. Apolipoprotein E epsilon4 allele frequency may represent a common genetic background for both AD and LB pathologies but there are different proportions of plaques between DLB (less Abeta1-40) and AD (more frequent Abeta1-40). Familial parkinsonism with dementia, linked to chromosome 17 (frontotemporal dementia with Parkinsonism (FTDP-17), and other tauopathies pathologically resembling PD plus AD, are often related to mutations of the tau gene, whereas familial PD with alpha-synuclein and Parkin mutations usually show no cognitive impairment. Mood disorders, in particular depression, and psychotic complications in both PD and DLB are related to complex involvement of noradrenergic and serotonergic systems, not confirmed in AD with depression, and both the prefrontal and limbic dopaminergic systems. The specific contributions of cortical and subcortical pathologies to mental dysfunction in PD and related disorders, their relationship to AD, and their genetic and aetiological backgrounds await further elucidation.

Iwatsubo, T. (2000). "[Alzheimer's disease: basic aspects]." Nippon Ronen Igakkai Zasshi 37(3): 207-11.
The deposition of amyloid beta peptides (A beta) in one of the pathological hallmarks of Alzheimer's disease (AD). A beta are composed of 40-42 amino acid peptides that are proteolytically cleaved from beta amyloid precursor proteins (beta APP). The deposition as diffuse plaques of a species of A beta ending at the 42nd residue residue (A beta 42) is one of the earliest pathological changes of AD. Importantly, mutations in beta APP genes located in positions flanking the A beta sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytropic membrane proteins that were identified as causative molecules for the majority of early onset FAD, also increase the secretion and deposition of A beta 42. These results support the notion that A beta 42 plays a key role in the pathogenesis of AD. Recently, it was suggested that PS1 is a coactivator of gamma-cleavage of beta APP as well as gamma-like cleavage of Notch protein which plays an essential role in morphogenesis and development. In addition, the pathogenic role of tau in neuronal death is highlighted based on the identification of mutations in tau gene in a dominantly-inherited neurodegenerative dementia FTDP-17. These novel findings regarding the protein aggregates and causative genes for AD and related disorders will facilitate our understanding of the pathogenesis of AD, as well as development of therapeutic strategies against it.

Iqbal, K., A. D. Alonso, et al. (2000). "Mechanism of neurofibrillary degeneration and pharmacologic therapeutic approach." J Neural Transm Suppl 59: 213-22.
Neurofibrillary degeneration is a key histopathological brain lesion of Alzheimer disease (AD) and related neurodegenerative disorders such as frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17), commonly referred to as tauopathies. Microtubule associated protein (MAP) tau, which is a major MAP of a normal mature neuron is abnormally hyperphosphorylated in tauopathies and is the major protein subunit of paired helical filaments (PHF)/straight filaments (SF) which accumulate in the soma (as neurofibrillary tangles) and dystrophic neurites (as neuropil threads and as dystrophic neurites surrounding the beta-amyloid core in neuritic plaques in AD) of the affected neurons. Unlike normal tau which stimulates assembly and stabilizes microtubules, the abnormally hyperphosphorylated tau inhibits assembly and disrupts microtubules. The abnormally hyperphosphorylated tau competes with tubulin/microtubules in associating with normal tau, MAP1 and MAP2. This sequestration of normal MAPs by the abnormal tau results in the breakdown of the microtubules. The association of the abnormal tau with normal tau and not with MAP1 or MAP2 results in the formation of tangles of tau filaments. All these toxic properties of the abnormally hyperphosphorylated tau are eliminated by its enzymatic dephosphorylation. Activities of phosphoseryl/phosphothreonyl protein phosphatases (PP)-2A and PP-1 which can dephosphorylate the abnormal tau to a normal-like state are compromised in AD brain. Dephosphorylation by PP-2A and PP-2B and to a lesser extent by PP-1 restores the normal microtubule assembly promoting activity in AD P-tau in vitro. Neurofibrillary tangles of PHF isolated from AD brain are also dissociated on in vitro dephosphorylation with PP-2A, and the tau released by this treatment can stimulate microtubule assembly. Thus, it appears that the abnormal hyperphosphorylation of tau leads to neurodegeneration through breakdown of the microtubule network and that the abnormal tau on association with normal tau forms neurofibrillary tangles of tau filaments i.e. PHF/SF. Increase in tau phosphatase activity is a promising approach to inhibit neurofibrillary degeneration and thereby the diseases characterized by this lesion.

Hutton, M. (2000). "Molecular genetics of chromosome 17 tauopathies." Ann N Y Acad Sci 920: 63-73.
The identification of mutations in the gene encoding the microtubule associated protein tau in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) demonstrated that tau dysfunction can lead to neurodegeneration. At least 11 missense mutations and 1 deletion mutation (delta K280) have been identified in exons 9-13 that encode the microtubule binding domains of tau. In addition, five mutations have been found close to the 5' splice site of exon 10. The different FTDP-17 mutations have multiple effects on the biology and function of tau. These varied pathogenic mechanisms likely explain the wide range of clinical and neuropathological features observed in different families with FTDP-17. In addition to the highly penetrant mutations that are found in large families with FTDP-17, a common extended haplotype in the tau gene also appears to be a risk factor in the development of the apparently sporadic tauopathy, progressive supranuclear palsy (PSP). The mechanism by which this common variability in the tau gene influences the development of PSP is unclear; however, it further suggests a central role for tau in the pathogenesis of several neurodegenerative conditions including Alzheimer's disease (AD).

Goedert, M. and M. G. Spillantini (2000). "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease." Biochim Biophys Acta 1502(1): 110-21.
Alzheimer's disease is characterised by the degeneration of selected populations of nerve cells that develop filamentous inclusions prior to degeneration. The neuronal inclusions of Alzheimer's disease are made of the microtubule-associated protein tau, in a hyperphosphorylated state. Abundant filamentous tau inclusions are not limited to Alzheimer's disease. They are the defining neuropathological characteristic of frontotemporal dementias, such as Pick's disease, and of progressive supranuclear palsy and corticobasal degeneration. The discovery of mutations in the tau gene in familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided a direct link between tau dysfunction and dementing disease. Known mutations produce either a reduced ability of tau to interact with microtubules, or an overproduction of tau isoforms with four microtubule-binding repeats. This leads in turn to the assembly of tau into filaments similar or identical to those found in Alzheimer's disease brain. Several missense mutations also have a stimulatory effect on heparin-induced tau filament formation. Assembly of tau into filaments may be the gain of toxic function that is believed to underlie the demise of affected brain cells.

Nacharaju, P., J. Lewis, et al. (1999). "Accelerated filament formation from tau protein with specific FTDP-17 missense mutations." FEBS Lett 447(2-3): 195-9.
Tau is the major component of the neurofibrillar tangles that are a pathological hallmark of Alzheimers' disease. The identification of missense and splicing mutations in tau associated with the inherited frontotemporal dementia and Parkinsonism linked to chromosome 17 demonstrated that tau dysfunction can cause neurodegeneration. However, the mechanism by which tau dysfunction leads to neurodegeneration remains uncertain. Here, we present evidence that frontotemporal dementia and Parkinsonism linked to chromosome 17 missense mutations, P301L, V337M and R406W, cause an accelerated aggregation of tau into filaments. These results suggest one mechanism by which these mutations can cause neurodegeneration and frontotemporal dementia and Parkinsonism linked to chromosome 17.

Mirra, S. S., J. R. Murrell, et al. (1999). "Tau pathology in a family with dementia and a P301L mutation in tau." J Neuropathol Exp Neurol 58(4): 335-45.
Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.

Ishihara, T., M. Hong, et al. (1999). "Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform." Neuron 24(3): 751-62.
Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).

Buee, L. and A. Delacourte (1999). "Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease." Brain Pathol 9(4): 681-93.
Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule-binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R-tau isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R-tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto-temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.

Bonifati, V., M. Joosse, et al. (1999). "The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases." Neurosci Lett 274(1): 61-5.
Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

Spillantini, M. G., J. R. Murrell, et al. (1998). "Mutation in the tau gene in familial multiple system tauopathy with presenile dementia." Proc Natl Acad Sci U S A 95(13): 7737-41.
Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.

Spillantini, M. G. and M. Goedert (1998). "Tau protein pathology in neurodegenerative diseases." Trends Neurosci 21(10): 428-33.
Abundant tau-positive neurofibrillary lesions constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau pathology is also central to a number of other dementing disorders, such as Pick's disease, progressive supranuclear palsy, corticobasal degeneration and familial frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the tau gene in FTDP-17 has firmly established the relevance of tau pathology for the neurodegenerative process. Experimental studies have provided a system for the assembly of full-length tau into Alzheimer-like filaments, providing an assay for the testing of compounds that inhabit the formation of tau filaments.