Failure of DNA double-strand break repair by tau mediates Alzheimer's disease pathology in vitro

This study investigates the role of DNA double-strand breaks (DSBs) in Alzheimer's disease (AD) pathology, focusing on the microtubule-associated protein tau. Immunohistochemistry revealed frequent coexistence of DSBs and phosphorylated tau in AD patients' cortex. In vitro studies using mouse cortical neurons showed that DSB induction leads to perinuclear accumulation of non-phosphorylated tau with tubulin, followed by phosphorylated tau accumulation. Tau knockdown exacerbated DSBs, suggesting a protective role in DNA repair. Synergistic exposure to microtubule disassembly and DSBs augmented aberrant phosphorylated tau aggregation and apoptosis. These findings suggest that DSB repair failure contributes to AD-tau pathology.

Megumi Asada-Utsugi, Kengo Uemura, Takashi Ayaki, Maiko T. Uemura, Sumio Minamiyama, Ryota Hikiami, Toshifumi Morimura, Akemi Shodai, Takatoshi Ueki, Ryosuke Takahashi, Ayae Kinoshita, Makoto Urushitani