An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease

Date

2023

Authors

Lau, Victor
Ramer, Leanne
Tremblay, Marie-Ève

Journal Title

Journal ISSN

Volume Title

Publisher

Nature Communications

Abstract

Alzheimer’s disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, aswell as inflammation and oxidative stress. Homeostatic glial states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation. In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.

Description

Keywords

Alzheimer’s disease, Cognitive ageing, Complexity, Microglia, Neuroimmunology

Citation

Lau, V., Ramer, L., & Tremblay, M-È. (2023). An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer's disease. Nature Communications, 14, 1670. https://doi.org/10.1038/s41467-023-37304-3