A Glial Cell Senescence Hypothesis for Alzheimer's Disease
Senescent cells accumulate with age throughout the body, and evidence is increasingly supportive of a role for cellular senescence in the development of Alzheimer's disease. This is particularly the case for senescent supporting cells in the brain, such as microglia and astrocytes, but the inflammatory signaling produced by senescent cells elsewhere in the body may well be just as influential on dysfunction in brain tissue. Given the capacity to clear senescent cells, and at least one recently launched trial of senolytic therapies to clear senescent cells in Alzheimer's patients, we should see some progress in the years ahead, towards a better understanding of the relevance of cellular senescence to age-related neurodegeneration.
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, as well as inflammation and oxidative stress. Homeostatic glial cell 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.