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Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.

ABSTRACT: In Alzheimer's disease (AD), tau undergoes numerous modifications, including increased phosphorylation at serine-422 (pS422). In the human brain, pS422 tau protein is found in prodromal AD, correlates well with cognitive decline and neuropil thread pathology, and appears associated with increased oligomer formation and exposure of the N-terminal phosphatase-activating domain (PAD). However, whether S422 phosphorylation contributes to toxic mechanisms associated with disease-related forms of tau remains unknown. Here, we report that S422-pseudophosphorylated tau (S422E) lengthens the nucleation phase of aggregation without altering the extent of aggregation or the types of aggregates formed. When compared to unmodified tau aggregates, the S422E modification significantly increased the amount of SDS-stable tau dimers, despite similar levels of immunoreactivity with an oligomer-selective antibody (TOC1) and another antibody that reports PAD exposure (TNT1). Vesicle motility assays in isolated squid axoplasm further revealed that S422E tau monomers inhibited anterograde, kinesin-1 dependent fast axonal transport (FAT). Unexpectedly, and unlike unmodified tau aggregates, which selectively inhibit anterograde FAT, aggregates composed of S422E tau were found to inhibit both anterograde and retrograde FAT. Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT. Taken together, these findings identify a novel mechanistic basis by which pS422 confers upon tau a toxic effect that may directly contribute to axonal dysfunction in AD and other tauopathies.

SUBMITTER: Tiernan CT

PROVIDER: S-EPMC4992631 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.

Tiernan Chelsea T CT Combs Benjamin B Cox Kristine K Morfini Gerardo G Brady Scott T ST Counts Scott E SE Kanaan Nicholas M NM

Experimental neurology 20160630 Pt A

In Alzheimer's disease (AD), tau undergoes numerous modifications, including increased phosphorylation at serine-422 (pS422). In the human brain, pS422 tau protein is found in prodromal AD, correlates well with cognitive decline and neuropil thread pathology, and appears associated with increased oligomer formation and exposure of the N-terminal phosphatase-activating domain (PAD). However, whether S422 phosphorylation contributes to toxic mechanisms associated with disease-related forms of tau ...[more]

PMID: 27373205

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Project description:Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.

Dataset Information

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.

Publications

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.

Similar Datasets

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