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

• Main Authors: Yuxing Xia, Stefan Prokop, Kimberly-Marie M. Gorion, Justin D. Kim, Zachary A. Sorrentino, Brach M. Bell, Alyssa N. Manaois, Paramita Chakrabarty, Peter Davies, Benoit I. Giasson
• Format: Article
• Language: English
• Published: BMC 2020-06-01
• Series: Acta Neuropathologica Communications
• Subjects: Alzheimer’s disease; tau; Neurodegeneration; Neurofibrillary tangle; Microtubule-associated protein tau (MAPT); Protein aggregation
• Online Access: http://link.springer.com/article/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.