P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease

• DOI: 10.1186/s40478-020-01012-6
• Publication Date: 2020-08-10T19:04:07Z
• Authors: Kathleen M. Farmer; Gaurav Ghag; Nicha Puangmalai; Mauro Montalbano; Nemil Bhatt; Rakez Kayed
• Keywords: Neuropathology

The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results a wide range disorders cancer, metabolic diseases, neurodegenerative diseases. Alzheimer's disease (AD) disorder characterized by protein aggregates that contribute to pathology. Although known aggregate, its propensity aggregate AD has never been assessed. Moreover, neuropathology includes lethal re-entry, excessive damage, abnormal death which are all controlled p53. Here, we show forms oligomers fibrils human brain, but not control brain. can also be detected htau P301L mouse models. Additionally, demonstrate interacts with tau, specifically tau oligomers, brain recapitulated vitro exogenous oligomer treatment C57BL/6 primary neurons. colocalize, potentially seeding, endogenous Lastly, the presence phosphorylated mislocalized outside nucleus p53-mediated responders significantly decreased Control shows healthy indicating loss nuclear function may due aggregation and/or interactions oligomers. Given role physiology, disruption this crucial factor set an irreversible course towards neurodegeneration other tauopathies, warranting further investigation.