Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau

Tatebayashi, Yoshitaka; Miyasaka, Tomohiro; Chui, Dehua; Akagi, Tomonori; Mishima, Kenichi; Iwasaki, Katsunori; Fujiwara, Michihiro; Tanemura, Kentaro; Murayama, Miyuki; Ishiguro, Koichi; Planel, Emmanuel; Sato, Shinji; Hashikawa, Tsutomu; Takashima, Akihiko

doi:10.1073/pnas.202205599

Cited by 249 publications

(152 citation statements)

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“…Tau oligomerization could play a key role in either mechanism. For example, several authors have suggested that the FTDP-17 tau mutations causing amino acid substitutions lead to an increased probability of forming abnormal tau oligomers and then fibers (paired helical filaments/ neurofibrillary tangles) (46,47). Abnormal oligomerization, the gained function, could be a precursor state to assembly of the larger cytotoxic fibers.…”

Section: Molecular Mechanisms By Which Tauopathies May Results In Neurmentioning

confidence: 99%

Microtubule-dependent Oligomerization of Tau

Makrides

Shen

Bhatia

et al. 2003

Journal of Biological Chemistry

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The accumulation of abnormal tau filaments is a pathological hallmark of many neurodegenerative diseases. In 1998, genetic analyses revealed a direct linkage between structural and regulatory mutations in the tau gene and the neurodegenerative disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Importantly, the FTDP-17 phenotype is transmitted in a dominant rather than a recessive manner. However, the underlying molecular mechanisms causing disease remain uncertain. The most common molecular mechanism generating dominant phenotypes is the loss of function of a multimeric complex containing both mutant and wild-type subunits. Therefore, we sought to determine whether tau might normally function as a multimer. We co-incubated 35 S-radiolabeled tau and biotinylated tau with taxol stabilized microtubules, at very low molar ratios of tau to tubulin. Subsequent covalent cross-linking followed by affinity-precipitation of the biotinylated tau revealed the formation of microtubule-dependent tau oligomers. We next used atomic force microscopy to independently assess this conclusion. Our results are consistent with the hypothesis that tau forms oligomers upon binding to microtubules. In addition to providing insights into normal tau action, our findings lead us to propose that one mechanism by which mutations in tau may cause cell death is through the formation of tau complexes containing mutant tau molecules in association with wild-type tau. These wildtype-mutant tau complexes may possess altered biological and/or biophysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by either altering normal tau-mediated regulation of microtubule-dependent cellular functions and/or promoting the formation of pathological tau aggregates.The microtubule-associated protein tau, localized predominantly in the cell bodies and axons of neuronal cells, is necessary for the establishment of neuronal cell polarity and axon outgrowth, for axonal transport, and the maintenance of axonal morphology (for example, see Refs. 1-6). Tau is also expressed in glial cells (7), although its role (8) there are less defined.Mechanistically, tau is well known to stimulate MT 1 polymerization, to stabilize MTs, and to modulate MT dynamics (9 -12). Since MT dynamics must be tightly regulated for cells to function and remain viable (e.g. see Refs. 13 and 14), it follows that tau action must also be finely regulated in cells.Alternatively, abnormal tau behavior is often associated with neurodegenerative diseases. In Alzheimer's disease, FTDP-17 and a large number of additional "tauopathies," necrotic neurons possess abnormal pathological fibers composed primarily of hyperphosphorylated and dysfunctional tau (for a recent review, see Ref. 15). Until recently, the relationship between tau and these various diseases was only correlative. However, in 1998, several groups reported a direct genetic linkage between mutations in the tau gene and FTDP-17, a group of related neurodegenerative con...

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Section: Molecular Mechanisms By Which Tauopathies May Results In Neurmentioning

confidence: 99%

Microtubule-dependent Oligomerization of Tau

Makrides

Shen

Bhatia

et al. 2003

Journal of Biological Chemistry

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“…However, R406W mutant tau also was in a lower phosphorylation state than wild type tau when expressed in more neurallike cell systems such as neuroglioma cells (55) and neuroblastoma cells (20). Interestingly, the one reported R406W mutant transgenic mouse model did show evidence of hyperphosphorylated tau inclusions in forebrain neurons (56). Therefore, it can be hypothesized that immortalized mouse cortical cells provide the appropriate cellular context for increases in R406W mutant tau phosphorylation to occur and thus model this feature of FTDP-17.…”

Section: Cellular Localization Of Wild Type and Mutant R406wmentioning

confidence: 99%

Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model

Krishnamurthy

Johnson

2004

Journal of Biological Chemistry

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Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the gene that encodes for tau, a microtubule-binding protein. Neuropathologically the disease is characterized by extensive neuronal loss in the frontal and temporal lobes and the filamentous accumulation of hyperphosphorylated tau. The R406W missense mutation was originally described in an American and a Dutch family. Although R406W tau is hyperphosphorylated in FTDP-17 cases, R406W tau expressed in cell model systems has not shown increased phosphorylation. The purpose of this study was to establish a neuronal model system in which the phosphorylation of R406W tau is increased and thus more representative of the in vivo situation. To accomplish this goal immortalized mouse cortical cells that express low levels of endogenous tau were stably transfected with human wild type or R406W tau. In this neuronal model R406W tau was more highly phosphorylated at numerous epitopes and showed decreased microtubule binding compared with wild type tau, an effect that could be reversed by dephosphorylation. In addition the expression of R406W tau in the cortical cells resulted in increased cell death as compared with wild type tau-expressing cells when the cells were exposed to an apoptotic stressor. These results indicate that in an appropriate cellular context R406W tau is hyperphosphorylated, which leads to decreased microtubule binding. Furthermore, expression of R406W tau sensitized cells to apoptotic stress, which may contribute to the neuronal cell loss that occurs in this FTDP-17 tauopathy.Frontotemporal dementia (FTD) 1 refers to a group of neurological disorders that are characterized clinically by progressive behavioral changes and neuropathologically by neuronal loss in the frontal and temporal lobes and the presence of filamentous deposits of abnormally hyperphosphorylated tau protein in neurons and/or glial cells (1-4). FTDs occur mainly as sporadic cases but also as familial forms with an autosomal dominant mode of inheritance and age-dependent penetrance (1). In 1998 it was demonstrated that several familial FTDs were due to mutations in the tau gene and have been referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) (5-7). Since these initial discoveries, additional tau mutations have been described in frontotemporal dementia families, and presently over 25 mutations in the tau gene have been identified (8, 9). They include missense mutations in coding regions, amino acid deletions, and intronic mutations in the region following exon 10. The mutations may be divided into two main groups, those that affect alternative splicing of exon 10, leading to changes in the ratio of tau mRNAs with or without exon 10, and thus the proportion of tau with three microtubule binding repeats versus tau with four microtubule binding repeats, and missense mutations.Tau is a microtubule-associated protein that facilitates microtubule assembly an...

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“…Some of these Tg mice also develop AD-like neurofibrillary tangles (NFTs) in neurons with advancing age (Ishihara et al, 2001b). Furthermore, there is accumulating evidence that FTDP-17 mutations, such as P301L (Lewis et al, 2000;Götz et al, 2001), V337M and R406W (Lim et al, 2001;Tatebayashi et al, 2002), accelerate the formation of NFTlike intraneuronal inclusions by mutant tau proteins and induce a more severe neurodegenerative phenotype in Tg mice that express mutant tau compared with hWT tau mice. Nonetheless, the mechanisms whereby tau mutations induce more profound accumulations of fibrillary tau inclusions in neuronal perikarya than hWT tau in Tg mice remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%