Research Paper Volume 16, Issue 10 pp 9168—9187
Chronic stress induces Alzheimer’s disease-like pathologies through DNA damage-Chk1-CIP2A signaling
- 1 Department of Pathophysiology, Key Laboratory of Ministry of Education/Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 2 Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China
- 3 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China
- 4 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 5 Institute for Brain Research, Wuhan Center of Brain Science, Huazhong University of Science and Technology, Wuhan, China
- 6 Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, China
Received: December 19, 2023 Accepted: March 19, 2024 Published: May 30, 2024
https://doi.org/10.18632/aging.205862How to Cite
Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Stress is an important initiating factor in promoting Alzheimer’s disease (AD) pathogenesis. However, the mechanism by which stress induces AD-like cognitive impairment remains to be clarified. Here, we demonstrate that DNA damage is increased in stress hormone Corticotropin-releasing factor (CRF)-treated cells and in brains of mice exposed to chronic restraint stress. Accumulation of DNA damage drives activation of cell cycle checkpoint protein kinase 1 (Chk1), upregulation of cancerous inhibitor of PP2A (CIP2A), tau hyperphosphorylation, and Aβ overproduction, eventually resulting in synaptic impairment and cognitive deficits. Pharmacological intervention targeting Chk1 by specific inhibitor and DNA damage by vitamin C, suppress DNA damage-Chk1-CIP2A signaling pathway in chronic stress animal model, which in turn attenuate AD-like pathologies, synaptic impairments and cognitive deficits. Our study uncovers a novel molecular mechanism of stress-induced AD-like pathologies and provides effective preventive and therapeutic strategies targeting this signaling pathway.