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PubMed2001

Tau-66: evidence for a novel tau conformation in Alzheimer's disease.

We have characterized a novel monoclonal antibody, Tau-66, raised against recombinant human tau. Immunohistochemistry using Tau-66 reveals a somatic-neuronal stain in the superior temporal gyrus (STG) that is more intense in Alzheimer's disease (AD) brain than in normal brain. In hippocampus, Tau-66 yields a pattern similar to STG, except that neurofibrillary lesions are preferentially stained if present. In mild AD cases, Tau-66 stains plaques lacking obvious dystrophic neurites (termed herein 'diffuse reticulated plaques') in STG and the hippocampus. Enzyme-linked immunosorbent assay (ELISA) analysis reveals that Tau-66 is specific for tau, as there is no cross-reactivity with MAP2, tubulin, Abeta(1-40), or Abeta(1-42), although Tau-66 fails to react with tau or any other polypeptide on western blots. The epitope of Tau-66, as assessed by ELISA testing of tau deletion mutants, appears discontinuous, requiring residues 155-244 and 305-314. Tau-66 reactivity exhibits buffer and temperature sensitivity in an ELISA format and is readily abolished by SDS treatment. Taken together these lines of evidence indicate that the Tau-66 epitope is conformation-dependent, perhaps involving a close interaction of the proline-rich and the third microtubule-binding regions. This is the first indication that tau can undergo this novel folding event and that this conformation of tau is involved in AD pathology.

Aged↗
PubMed2002

Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility.

Transgenic mice (JNPL3), which develop neurofibrillary degeneration and express four-repeat human tau with P301L missense mutation, were characterized biochemically to determine whether the development of aggregated tau from soluble tau involves an intermediate stage. Homogenates from mice of different ages were separated into buffer-soluble (S1), sarkosyl- and salt-extractable (S2) and sarkosyl-insoluble pellet (P3) fractions, and analyzed for human tau distribution, phosphorylation and filament formation. S1 and S2 fractions contained 50-60-kDa tau whereas the S2 fraction also had 64-kDa tau. The level of tau in the P3 fraction increased in an age-dependent manner and correlated positively with the soluble tau concentration. The P3 fraction from 2.5-6.5-month-old mice contained 64- and 50-60-kDa tau, whereas that from 8.5-month and older transgenic animals contained mostly 64-kDa and higher molecular weight tau. The S2 and P3 fractions contained comparable amounts of 64-kDa tau. The 64-kDa tau was predominantly human, and phosphorylated at multiple sites: Thr181, Ser202/Thr205, Thr212, Thr231, Ser262, Ser396/Ser404, Ser409 and Ser422. Most of these sites were phosphorylated to a lesser extent in S2 than in P3 fractions. Tau polymers were detected in P3 fractions from 3-month and older female JNPL3 mice, but not in non-transgenic controls. The results suggest that tau in S2 represents an intermediate from which insoluble tau is derived, and that phosphorylation may play a role in filament formation and/or stabilization.

Age Factors↗
PubMed1991

Difference between the tau protein of Alzheimer paired helical filament core and normal tau revealed by epitope analysis of monoclonal antibodies 423 and 7.51.

The microtubule-associated protein tau that is incorporated into paired helical filaments (PHFs) undergoes some form of aberrant posttranslational processing in Alzheimer disease. Difficulties in deciding which changes are critical for PHF formation stem in part from the lack of immunochemical markers specific for PHF tau. The only monoclonal antibody (mAb) that is known to react with PHF tau but not with the predominant normal adult tau species is mAb 423. Another mAb (7.51, described in this paper) recognizes a segment of tau that is included in the minimal recognition unit required by mAb 423. Unlike 423, which is PHF tau-specific, mAb 7.51 recognizes all PHF core-derived tau as well as native soluble tau and recombinant tau expressed in bacteria and so serves as a generic tau marker. Both epitopes are in the 12-kDa fragment released from the Pronase-resistant core of the PHF (which encompasses the tandem repeat region). The mAb 7.51 epitope requires segments located in the last two repeats, which are common to all tau isoforms. The mAb 423 epitope requires sequences located near both the N and the C terminus of the 12-kDa fragment common to three- and four-repeat tau isoforms. Fragments denatured by concentrated formic acid and SDS regain 423 reactivity when denaturing agents are removed. Since the primary amino acid sequences of PHF tau and normal tau are identical in the repeat region, we conclude that 423 reactivity also requires a modification(s) occurring within an approximately 90-residue segment that are not present in tau proteins so far described in the human brain.

Alzheimer Disease↗
PubMed1999

Fibrillogenesis of tau: insights from tau missense mutations in FTDP-17.

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a neurological disorder associated with tau pathology.Tau deposits in FTDP-17 brains consist of polymerized filaments of hyperphosphorylated tau, the morphology of which is determined by the nature of the tau gene mutation observed in each case. A number of mutations associated with FTDP-17 have been identified in the 5' splice site of exon 10 and in exons 9-13 of the tau gene. The exon 10 5' splice site mutations disrupt alternative splicing and thus alter the ratio of 4R and 3R Tau isoforms. The majority of Tau missense mutations decrease its ability to bind tubulin and promote microtubule assembly. The extent of reduction varies depending on the site and nature of the mutation. Some Tau missense mutations also have a direct effect on the rate and the extent of tau filament formation. In the presence of polymerization-inducing agents such as heparin or arachidonic acid, mutant tau forms polymers more efficiently than wild type tau in vitro. Tau mutations affect polymerization at both nucleation and elongation phases. One mutation (R406W) is also known to alter the susceptibility of tau to phosphorylation. Expression of mutant tau in cultured cells changes the cytoskeletal integrity of CHO and COS-7 cells, but none of the tau transfected cells display tau filament inclusions. These findings suggest involvement of at least two mechanisms in the pathogenesis of FTDP-17.

Humans↗
PubMed1992

Regions with abundant neurofibrillary pathology in human brain exhibit a selective reduction in levels of binding-competent tau and accumulation of abnormal tau-isoforms (A68 proteins).

Paired helical filaments, the dominant filamentous components of Alzheimer's disease (AD), neurofibrillary tangles (NFT), neuropil threads, and the dystrophic neurites associated with amyloid rich senile plaques, are composed of abnormally phosphorylated derivatives of tau known as A68 proteins. Indeed the inappropriate phosphorylation of Ser396, which is adjacent to the microtuble binding domain in tau, may contribute to the transformation of tau into A68 and prevent A68 from efficiently binding to microtubules. The reduced levels of normal soluble tau proteins in AD brains may be the consequence of a multi-step process whereby normal tau is converted into A68 and sequestered in paired helical filaments. To elucidate the events involved in this process, we compared the relative levels of binding-competent (BC) and binding-incompetent (BI) tau with the level of A68 in six different regions (hippocampus, fornix, frontal grey and white matter, and cerebellar grey and white matter) of fresh AD and control brains. When the AD brains were compared as a group with neurologically normal and diseased non-AD controls, quantitative immunoblot analysis demonstrated a selective reduction of BC tau in regions of the AD brains with abundant neurofibrillary lesions (NFTs, neuropil threads, and senile plaque neurites) and in their associated white matter areas. The level of BI tau was similar in both AD and control brains. In contrast, A68 was present only in the AD brains, but it was confined to those brain regions with abundant NFTs, neuropil threads, and senile plaques. We view the reductions in BC tau in fornix and frontal white matter to be a consequence of the reductions in their associated grey matter regions i.e., hippocampus and frontal grey matter. Although there is no strict relationship between the reduction of BC tau and the level of A68 within an individual brain, the comparison of the AD group with the control group suggests that the grey matter of the affected regions may be the site for the conversion of BC tau into A68. Further, this process may occur rapidly or via pathways that do not involve BI tau since the levels of BI tau were similar in AD and control brains. Although the complete sequence of events leading to the transformation of tau into A68 and paired helical filaments remains to be elucidated, our data provide compelling evidence that A68 proteins are generated from tau-proteins in selected regions of the AD brain where neurofibrillary lesions comprised of paired helical filaments accumulate.

Adult↗
PubMed2001

Relationship of the extended tau haplotype to tau biochemistry and neuropathology in progressive supranuclear palsy.

Two extended haplotypes of the tau gene (H1 and H2) have been described. The frequency of H1 haplotype is increased in progressive supranuclear palsy (PSP). PSP is associated with filamentous tau lesions in neurons and glia, which are reportedly composed exclusively of tau isoforms with four repeats in the microtubule-binding domain (4R tau). To determine the influence of the tau haplotype on tau isoform composition and neuropathology, we studied 25 PSP cases and 6 Alzheimer's disease patients matched for age, sex, and postmortem delay. In the basal ganglia, tau and amyloid burdens were determined to see if there was an effect of concurrent Alzheimer-type pathology, and the ratio of 4R to 3R tau was measured in detergent-insoluble tau fractions. Insoluble tau from PSP was not composed exclusively of 4R tau. All brains had a mixture of 4R and 3R tau, but the ratio was different in Alzheimer's disease and PSP. In Alzheimer's disease there was less 4R than 3R tau, whereas the ratio was reversed in PSP. In PSP cases with concurrent Alzheimer-type pathology, the ratio of 4R to 3R was intermediate between Alzheimer's disease and PSP. The H1 haplotype had no effect on the 4R to 3R ratio or on tau and amyloid burdens. In summary, the H1 haplotype does not have a major influence on the pathological or biochemical phenotype of PSP.

Adult↗
PubMed1995

Differential expression of exons 10 and 11 in normal tau and tau associated with paired helical filaments.

Antibodies were raised to two synthetic peptides with amino acid sequences encoded by a variable region of exons 10 and 11 of the tau gene. The affinity-purified antibodies, designated E-10 and E-11, were used to determine whether PHF-tau and normal tau differ in variants containing three or four repeats in the microtubule-binding domain, respectively. Normal adult human brain was shown by gel electrophoresis to contain six isoforms of tau. All of the isoforms reacted with E-11, whereas only four of them with slower electrophoretic mobility were recognized by E-10. Fetal brain tau was readily recognized by E-11 but reacted poorly with E-10. In PHF preparations, E-11 bound to all three polypeptides of PHF-tau of 68 kD, 64 kD, and 60 kD and reacted intensely with a material smearing from the top of the gel to about the 50-kD region. In contrast, E-10 only weakly recognized the two higher molecular weight PHF-tau polypeptides of 68 kD and 64 kD, as well as smeared material, and the binding was not affected by phosphatase treatment. Using recombinant tau with four repeats as a reference, the immunoreactivity of E-10 with PHF-tau was estimated to be approximately 5% of that of E-11. By comparison, the immunoreactivity of E-10 with four isoforms of normal tau was comparable to that of E-11. These results indicate that the ratio of three vs. four repeat variants in PHF-tau is higher than in normal tau and suggest that Alzheimer disease may be associated with the disproportional expression of fetal (or juvenile) forms of tau. Alternatively, the weak reactivity of PHF-tau with E-10 antibody could be due to post-translational modifications other than phosphorylation.

Adult↗
PubMed1990

Expression of Tau protein and Tau mRNA in the cerebellum during axonal outgrowth.

UNLABELLED: "In situ" hybridization and immunohistochemical analysis of the expression of Tau mRNAs and Tau proteins in the developing cerebellum showed that: 1. At early postnatal stages Tau mRNAs are expressed in the deeper region of the external granular layer (EGL II) i.e. in the cells that begin to migrate from the proliferative zone. Little labeling was seen in the upper layer (EGL I) where the cerebellar interneurons actively proliferate during the first two postnatal weeks. Anti-Tau antibodies failed to detect Tau proteins both in EGL I and II. 2. Tau transcripts were also clearly detected in the migrating cells present in the molecular layer; no Tau immunoreactivity was seen in this layer. This suggests that Tau mRNAs remain very poorly translated in the migrating granule cells and in the other interneurons. 3. Tau proteins begin to be detected at postnatal day 8 in the molecular layer but only at the level of the parallel fibers that are present in the Purkinje cell dendritic field. This suggests that the Tau mRNAs transcribed in the migrating cells are not actively translated for several days and that Tau proteins accumulate only in the more mature sections of their axons, the parallel fibers. IN CONCLUSION: Tau mRNAs are transcribed in the migrating cells several days before Tau proteins are actively translated and transported to their axons. Tau proteins accumulation occurs only at the end of granule cell migration i.e. when the parallel fibers interact with their post-synaptic counterparts, the dendrites of the Purkinje cells. Thus, axonal outgrowth and differentiation seem to be a multistep process.

Aging↗
PubMed2003

Advances in the development of biomarkers for Alzheimer's disease: from CSF total tau and Abeta(1-42) proteins to phosphorylated tau protein.

Advances have been made to establish biological markers of Alzheimer's disease (AD). Measurement of total tau (t-tau) and beta-amyloid(1-42) (Abeta(1-42)) in the cerebrospinal fluid (CSF) seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. New immunoassays to detect different phosphorylated tau epitopes (p-tau) have recently been developed. P-tau phosphorylated at threonine 231 (p-tau(231)) showed improvements compared to t-tau in the early detection of AD in subjects with mild cognitive impairment. As p-tau(231) declined during the course of AD, it may have potential to track disease progression. Additionally, p-tau(231) improved differential diagnosis between AD, frontotemporal dementia, and geriatric major depression. P-tau phosphorylated at threonine 181 improved diagnostic accuracy between AD and dementia with Lewy bodies. P-tau phosphorylated at serine 199 demonstrated high discriminative power between AD and non-Alzheimer's dementia. P-tau phosphorylated at serine 306/serine 404 improved differential diagnosis between AD and vascular dementia. A comparative study of the different p-tau epitopes is currently under way. In summary, first clinical multi-center studies suggest that measurement of phosphorylated tau proteins may significantly improve early and differential diagnosis and may come close to fulfilling proposed criteria of a biological marker for AD.

Aged↗
PubMed1995

Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau.

Tau is a neuronal microtubule-associated protein that plays an important role in stabilizing axonal microtubules and maintaining neuronal processes. To investigate the mechanisms by which tau performs these functions, we have determined the actions of full-length adult tau and tau peptides corresponding to two different microtubule-binding domains of tau (the first repeat, R1, VRSKIGSTENLKHQPGGG, and the first interrepeat, R1-R2 IR, KVQIINKK) on the growing and shortening dynamics at the plus ends of individual microtubules at steady state. Tau suppressed steady-state microtubule dynamics at very low molar ratios of tau to tubulin. At the lowest ratios examined (tau:tubulin ratios of 1:175 and 1:85), suppression of dynamics occurred in the absence of a detectable change in polymer mass. Tau reduced the mean rate and extent of shortening and, in contrast to previous work carried out under conditions of net polymer gain, tau also suppressed the mean rate and extent of growing. Tau also strongly increased the rescue frequency, it moderately suppressed the catastrophe frequency and it strongly increased the percentage of total time that the microtubules spent in an attenuated (pause) state, neither growing nor shortening detectably. In addition, both the R1 and R1-R2 IR tau peptides suppressed steady-state microtubule dynamics in a sequence-specific manner and in a manner that was qualitatively indistinguishable from full-length tau. The data provide significant support for a mechanism in which the binding of tau to individual tubulin subunits in microtubules induces a conformational change that strengthens inter-tubulin bonding.

Amino Acid Sequence↗
PubMed2001

Characterization of the in vitro phosphorylation of human tau by tau protein kinase II (cdk5/p20) using mass spectrometry.

Hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies, and tau protein kinase II is reported to play a role in the pathogenesis of Alzheimer's disease. Recently, we reported that tau protein kinase II (cdk5/p20)-phosphorylated human tau inhibits microtubule assembly, and tau protein kinase II (cdk5/p20) phosphorylation of microtubule-associated tau results in dissociation of phosphorylated tau from the microtubules and tubulin depolymerization. In the studies reported here, a combination of mass spectrometric techniques was used to study the phosphorylation of human recombinant tau by recombinant tau protein kinase II (cdk5/p20) in vitro. The extent of phosphorylation was determined by measuring the molecular mass of phosphorylated tau using mass spectrometry. Reaction of human recombinant tau with tau protein kinase II (cdk5/p20) resulted in the formation of two major species containing either five or six phosphate groups. The specific amino acid residues phosphorylated were determined by analyzing tryptic peptides by tandem mass spectrometry via either MALDI/TOF post-source decay or by electrospray tandem mass spectrometry. Based on these experiments, we conclude that tau protein kinase II (cdk5/p20) can phosphorylate human tau at Thr(181), Thr(205), Thr(212), Thr(217), Ser(396) and Ser(404).

Amino Acid Sequence↗
PubMed2004

Overexpression of tau leads to the stimulation of neurite outgrowth, the activation of caspase 3 activity, and accumulation and phosphorylation of tau in neuroblastoma cells on cAMP treatment.

To explore changes to the tau molecule in Alzheimer's disease, we studied the effect of tau expression in stably transfected neuroblastoma x glioma hybrid NG108-15 cells (tau cells). Tau cells had a similar shape to, but more neurites than, wild type NG108-15 cells (wild type cells). When treated with cAMP, tau cells began to form neurites within 2h. After that, these neurites became longer and thicker than those of wild type cells. An accumulation and increased phosphorylation of tau were observed after 8 h and caspase 3 activity was increased after 4 h in tau cells, but not in wild type cells, upon treatment with cAMP. Caspase 3 activity was activated after the initiation of morphological change, and before the accumulation of tau in tau cells. Under these conditions, apoptotic cell death was not observed and tau was colocalized with tubulin. However, the accumulated tau molecules did not associate with tubulin and were dislocated around and in the nuclei of tau cells. These observations have implications for the cellular causes of Alzheimer's disease where the accumulation and mislocation of tau occur concomitant with neuronal degeneration.

Animals↗
PubMed2000

Tau dephosphorylation at tau-1 site correlates with its association to cell membrane.

It has been considered that tau protein is mainly a cytoplasmic protein since it is a microtubule associated protein. However, it has also been suggested that tau could be located in the cell nucleus and membrane. In our work, the cellular distribution of tau has been studied by immunofluorescence and western blot analysis, after subcellular fractionation in neuroblastoma cells and in tau-transfected non neural cells using, mainly, two types of tau antibodies; antibody 7.51 (that recognizes tau independent of its phosphorylation level); and antibody Tau-1 (that recognizes tau only in its dephosphorylated form). Also, tau was expressed in COS-1 cells to test for the features involved in the sorting of tau to different cell localizations. Our results show that tau associated to cell membrane has a lower phosphorylation level in its proline-rich region. Additionally, in differentiated neuroblastoma cells, tau phosphorylation, at that region, decreases and the amount of tau associated to cell membrane increases.

Animals↗
PubMed2006

Site-specific phosphorylation and caspase cleavage differentially impact tau-microtubule interactions and tau aggregation.

The microtubule-associated protein tau is hyperphosphorylated and forms neurofibrillary tangles in Alzheimer disease. Additionally caspase-cleaved tau is present in Alzheimer disease brains co-localized with fibrillar tau pathologies. To further understand the role of site-specific phosphorylation and caspase cleavage of tau in regulating its function, constructs of full-length tau (T4) or tau truncated at Asp421 (T4C3) to mimic caspase-3 cleavage with and without site-directed mutations that mimic phosphorylation at Thr231/Ser235, Ser396/Ser404, or at all four sites (Thr231/Ser235/Ser396/Ser404) were made and expressed in cells. Pseudophosphorylation of T4, but not T4C3, at either Thr231/Ser235 or Ser396/Ser404 increased its phosphorylation at Ser262 and Ser199. Pseudophosphorylation at Thr231/Ser235 impaired the microtubule binding of both T4 and T4C3. In contrast, pseudophosphorylation at Ser396/Ser404 only affected microtubule binding of T4C3 but did make T4 less soluble and more aggregated, which is consistent with the previous finding (Abraha, A., Ghoshal, N., Gamblin, T. C., Cryns, V., Berry, R. W., Kuret, J., and Binder, L. I. (2000) J. Cell Sci. 113, 3737-3745) that pseudophosphorylation at Ser396/Ser404 enhances tau polymerization in vitro. In situ T4C3 was more prevalent in the cytoskeletal and microtubule-associated fractions compared with T4, whereas purified recombinant T4 bound microtubules with higher affinity than did T4C3 in an in vitro assay. These data indicate the importance of cellular factors in regulating tau-microtubule interactions and that, in the cells, phosphorylation of T4 might impair its microtubule binding ability more than caspase cleavage. Treatment of cells with nocodazole revealed that pseudophosphorylation of T4 at both Thr231/Ser235 and Ser396/Ser404 diminished the ability of tau to protect against microtubule depolymerization, whereas with T4C3 only pseudophosphorylation at Ser396/Ser404 attenuated the ability of tau to stabilize the microtubules. These results show that site-specific phosphorylation and caspase cleavage of tau differentially affect the ability of tau to bind and stabilize microtubules and facilitate tau self-association.

Alzheimer Disease↗
PubMed2000

Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells.

Multiple tau gene mutations are pathogenic for hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), with filamentous tau aggregates as the major lesions in the CNS of these patients. Recent studies have shown that bacterially expressed recombinant tau proteins with FTDP-17 missense mutations cause functional impairments, i.e., a reduced ability of mutant tau to bind to or promote the assembly of microtubules. To investigate the biological consequences of FTDP-17 tau mutants and assess their ability to form filamentous aggregates, we engineered Chinese hamster ovary cell lines to stably express tau harboring one or several different FTDP-17 mutations and showed that different tau mutants produced distinct pathological phenotypes. For example, delta K, but not several other single tau mutants (e.g., V337 M, P301L, R406W), developed insoluble amorphous and fibrillar aggregates, whereas a triple tau mutant (VPR) containing V337M, P301L, and R406W substitutions also formed similar aggregates. Furthermore, the aggregates increased in size over time in culture. Significantly, the formation of aggregated delta K and VPR tau protein correlated with reduced affinity of these mutants to bind microtubules. Reduced phosphorylation and altered proteolysis was also observed in R406W and delta K tau mutants. Thus, distinct pathological phenotypes, including the formation of insoluble filamentous tau aggregates, result from the expression of different FTDP-17 tau mutants in transfected Chinese hamster ovary cells and implies that these missense mutations cause diverse neurodegenerative FTDP-17 syndromes by multiple mechanisms.

Animals↗
PubMed2006

Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in tauopathies.

The microtubule-associated protein tau aggregates into filaments in the form of neurofibrillary tangles, neuropil threads and argyrophilic grains in neurons, in the form of variable astrocytic tangles in astrocytes and in the form of coiled bodies and argyrophilic threads in oligodendrocytes. These tau filaments may be classified into two types, straight filaments or tubules with 9-18 nm diameters and "twisted ribbons" composed of two parallel aligned components. In the same disease, the fine structure of tau filaments in glial cells roughly resembles that in neurons. In sporadic tauopathies, individual tau filaments show characteristic sizes, shapes and arrangements, and therefore contribute to neuropathologic differential diagnosis. In frontotemporal dementias caused by tau gene mutations, variable filamentous profiles were observed in association with mutation sites and insoluble tau isoforms, including straight filaments or tubules, paired helical filament-like filaments, and twisted ribbons. Pre-embedding immunoelectron microscopic studies were carried out using anti-3-repeat tau and anti-4-repeat tau specific antibodies, RD3 and RD4. Straight tubules in neuronal and astrocytic Pick bodies were immunolabeled by the anti-3-repeat tau antibody. The anti-4-repeat tau antibody recognized abnormal tubules comprising neurofibrillary tangles, coiled bodies and argyrophilic threads in progressive supranuclear palsy (PSP) and corticobasal degeneration. In the pre-embedding immunoelectron microscopic study using the phosphorylated tau AT8 antibody, tuft-shaped astrocytes of PSP were found to be composed of bundles of abnormal tubules in processes and perikarya of protoplasmic astrocytes. In this study, the 3-repeat tau or 4-repeat tau epitope was detected in situ at the ultrastructural level in abnormal tubules in representative pathological lesions in Pick's disease, PSP and corticobasal degeneration.

Astrocytes↗
PubMed2005

TAU haplotype and the Saitohin Q7R gene polymorphism do not influence CSF Tau in Alzheimer's disease and are not associated with frontotemporal dementia or Parkinson's disease.

BACKGROUND: Recent studies have described Saitohin(STH), a gene located in the human TAU gene. The corresponding protein shows a similar tissue expression to tau, which is involved in many neurodegenerative disorders including Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). A single nucleotide polymorphism in the STH gene has been suggested to be involved in sporadic AD and is in complete linkage disequilibrium with the TAU haplotype H1. OBJECTIVE: A case-control study was performed to further explore the possible involvement of the STH Q7R polymorphism and the extended TAU haplotype in AD, FTD or PD. METHODS: Patients with AD (n = 398), FTD (n = 96) and PD (n = 105), and controls (n = 186) were genotyped for the STH polymorphism and/or the TAU haplotype. Genotype data were related to levels of total-tau, phospho-tau and Abeta(1-42) in cerebral spinal fluid (CSF) in more than 300 AD patients and to an amount of senile plaques and neurofibrillary tangles in the frontal cortex and hippocampus in patients with autopsy-confirmed AD. RESULTS: The STH Q7R polymorphism and the TAU haplotype were in complete linkage disequilibrium in all patients (AD and FTD) and controls investigated for both genes. There were no significant differences in genotype or allele distributions in AD, FTD or PD cases compared to controls. Neither TAU haplotype nor STH influenced CSF levels of total-tau, phospho-tau and Abeta(1-42) significantly. In AD patients with neuropathological scores of plaque and tangles, no associations with TAU haplotype and STH were found. CONCLUSION: We found no evidence that could support a major pathogenic role of STH and TAU haplotype in AD, FTD or PD.

Aged↗
PubMed2000

Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation.

It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

Brain↗