Preprint Hypothesis Version 1 Preserved in Portico This version is not peer-reviewed

How Senescent Glia Drive And Underlie Alzheimer’s Disease: A Predictive Model

Version 1 : Received: 23 September 2021 / Approved: 24 September 2021 / Online: 24 September 2021 (14:08:13 CEST)

How to cite: Lau, V.; Ramer, L.; Tremblay, M. How Senescent Glia Drive And Underlie Alzheimer’s Disease: A Predictive Model. Preprints 2021, 2021090437 (doi: 10.20944/preprints202109.0437.v1). Lau, V.; Ramer, L.; Tremblay, M. How Senescent Glia Drive And Underlie Alzheimer’s Disease: A Predictive Model. Preprints 2021, 2021090437 (doi: 10.20944/preprints202109.0437.v1).

Abstract

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD hallmarks in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD hallmarks; however, other glial states involve increased pro-inflammatory cytokine release and further hallmark accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This Perspective proposes that traditional AD hallmarks induce glial senescence in LOAD, where sufficient senescent glia exacerbate ongoing AD pathology and primarily drive LOAD into clinical, cognitive decline. We first explore age-related increases in pro-inflammatory glial activity, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor, and astrocyte senescence. Our evidence-based model mainly predicts that senescent astrocytes and oligodendrocyte progenitors together pressure microglia to phagocytose neurons containing tau pathology, where resulting senescent microglia create neuritic plaques and induce paracrine senescence transitioning into and progressing clinical, dementia presentation. This predictive model accounts for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD involving the amyloid cascade, tau, glia and inflammation, creates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

Keywords

Alzheimer's; Cellular senescence; Neurodegeneration; Microglia; Astrocytes; Oligodendrocyte Progenitor Cells; TREM2; Braak staging; Oxidative stress; Phapoptosis, Amyloid-beta; Tau; Neuritic plaques

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