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Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.

ABSTRACT: Tau protein abnormally aggregates in tauopathies, a diverse group of neurologic diseases that includes Alzheimer's disease (AD). In early stages of disease, tau becomes hyperphosphorylated and mislocalized, which can contribute to its aggregation and toxicity. We demonstrate that tau phosphorylation at Ser208 (pSer208) promotes microtubule dysfunction and tau aggregation in cultured cells. Comparative assessment of the epitopes recognized by antibodies AT8, CP13, and 7F2 demonstrates that CP13 and 7F2 are specific for tau phosphorylation at Ser202 and Thr205, respectively, independently of the phosphorylation state of adjacent phosphorylation sites. Supporting the involvement of pSer208 in tau pathology, a novel monoclonal antibody 3G12 specific for tau phosphorylation at Ser208 revealed strong reactivity of tau inclusions in the brains of PS19 and rTg4510 transgenic mouse models of tauopathy. 3G12 also labelled neurofibrillary tangles in brains of patients with AD but revealed differential staining compared to CP13 and 7F2 for other types of tau pathologies such as in neuropil threads and neuritic plaques in AD, tufted astrocytes in progressive supranuclear palsy and astrocytic plaques in corticobasal degeneration. These results support the hypothesis that tau phosphorylation at Ser208 strongly contributes to unique types of tau aggregation and may be a reliable marker for the presence of mature neurofibrillary tangles.

SUBMITTER: Xia Y

PROVIDER: S-EPMC7310041 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.

Xia Yuxing Y Prokop Stefan S Gorion Kimberly-Marie M KM Kim Justin D JD Sorrentino Zachary A ZA Bell Brach M BM Manaois Alyssa N AN Chakrabarty Paramita P Davies Peter P Giasson Benoit I BI

Acta neuropathologica communications 20200622 1

Tau protein abnormally aggregates in tauopathies, a diverse group of neurologic diseases that includes Alzheimer's disease (AD). In early stages of disease, tau becomes hyperphosphorylated and mislocalized, which can contribute to its aggregation and toxicity. We demonstrate that tau phosphorylation at Ser208 (pSer208) promotes microtubule dysfunction and tau aggregation in cultured cells. Comparative assessment of the epitopes recognized by antibodies AT8, CP13, and 7F2 demonstrates that CP13 a ...[more]

PMID: 32571418

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Project description:The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.

Dataset Information

Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.

Publications

Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.

Similar Datasets

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