Hippocampal tau oligomerization early in tau pathology coincides with a transient alteration of mitochondrial homeostasis and DNA repair in a mouse model of tauopathy

Acta Neuropathologica Communications
Jin ZhengVilhelm A Bohr

Abstract

Insoluble intracellular aggregation of tau proteins into filaments and neurodegeneration are histopathological hallmarks of Alzheimer disease (AD) and other tauopathies. Recently, prefibrillar, soluble, oligomeric tau intermediates have emerged as relevant pathological tau species; however, the molecular mechanisms of neuronal responses to tau oligomers are not fully understood. Here, we show that hippocampal neurons in six-month-old transgenic mouse model of tauopathy, THY-Tau22, are enriched with oligomeric tau, contain elongated mitochondria, and display cellular stress, but no overt cytotoxicity compared to the control mice. The levels of several key mitochondrial proteins were markedly different between the THY-Tau22 and control mice hippocampi including the mitochondrial SIRT3, PINK1, ANT1 and the fission protein DRP1. DNA base excision repair (BER) is the primary defense system against oxidative DNA damage and it was elevated in six-month-old transgenic mice. DNA polymerase β, the key BER DNA polymerase, was enriched in the cytoplasm of hippocampal neurons in six-month-old transgenic mice and localized with and within mitochondria. Polβ also co-localized with mitochondria in human AD brains in neurons containing oligomer...Continue Reading

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Citations

Sep 5, 2020·International Journal of Molecular Sciences·Leonora SzaboAmandine Grimm
Nov 17, 2020·Frontiers in Molecular Biosciences·Timothy E HoffmanJulie A Moreno
Dec 11, 2020·Brain Sciences·Luca ColnaghiSarah Sertic
Jan 10, 2021·Life·Grazyna NiewiadomskaAnna Gasiorowska
Jun 24, 2021·Acta Neuropathologica Communications·Ching-Pang ChangYijuang Chern
Jul 10, 2021·Journal of Neuroscience Methods·Logan A CampbellShannon Farris

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Methods Mentioned

BETA
confocal microscopy
PCR
electrophoresis
transmission electron microscopy
transgenic
acetylation
immunoprecipitation

Software Mentioned

Image J
GraphPad Prism
ImageJ

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