Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer\u2019s disease and other tauopathies

Yuxing Xia,Benoit I Giasson,Paramita Chakrabarty,Peter Davies,Zachary A Sorrentino,Alyssa N Manaois,Stefan Prokop,Justin D Kim,Brach M Bell,Kimberly-Marie M Gorion

doi:10.1186/s40478-020-00967-w

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.

Highlights

Alzheimer’s disease (AD) is the most common form of age-related dementia and affects over 25 million people worldwide [66]
Triple tau phosphomimetic S202E/T205E/S208E promotes aggregation of wild type (WT) tau in cultured cells A previous in vitro study indicated that the combined phosphorylation of Ser202, Thr205, and Ser208 residues promotes the polymerization of tau into filaments [19]
Combining the triple tau phosphomimetic S202E/T205E/S208E with the P301L mutation did not have an additive effect on tau aggregation more than P301L by itself (Fig. 1g)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of age-related dementia and affects over 25 million people worldwide [66]. Xia et al Acta Neuropathologica Communications (2020) 8:88 degeneration (FTLD) including Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and globular glial tauopathy (GGT) [23, 39, 80]. Tau is a microtubule-associated protein that is highly expressed in the distal axons of neurons in the central nervous system [9, 80]. Tau protein can be alternatively spliced into six major isoforms found in the brains of humans and rodents [30, 31]. The presence or absence of exon 10 can lead to either three or four MT binding repeats to generate either 3R or 4R isoforms

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Results

Conclusion