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

Perspective https://doi.org/10.1038/s41467-023-37304-3 An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease Received: 5 August 2022 Victor Lau 1,2,3 , Leanne Ramer4 & Marie-Ève Tremblay 1,2,3,5,6,7,8 Check for updates 1234567890():,; 1234567890():,; Accepted: 7 March 2023 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 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. Alzheimer’s disease (AD) is characterized by cognitive decline, most prominently manifested as progressive memory loss. AD risk factors include vascular pathology, declining metabolism, and most significantly, aging1–4. These risk factors contribute towards sporadic or late onset AD (LOAD) (>90% of AD cases), and early-onset or inherited, familial AD (EOAD)3. In LOAD, synaptic loss is pathologically correlated with neurodegeneration and cognitive decline1,2. Widely accepted explanations for neuronal loss and LOAD progression have been proposed in the tau hypothesis and amyloid cascade (Box 1). While clinical trials targeting these two pathologies will hopefully halt AD3,4, focuses on understanding AD have more recently expanded into nextgeneration sequencing, aging-related oxidative stress, and glia. Particularly, genetic risk factors such as TREM2 and APOE have exclusive roles in glia among the central nervous system3. Some of these genes mediate increased phagocytic function in glia, whereas others allot glia towards adopting pro-inflammatory states leading to chronic damage to cell machinery (i.e., lipids, proteins, nucleic acids) and premature cell death. Possible roles of glial senescence in AD were also recently explored5,6. Cellular senescence is an irreversible cell arrest caused by replicative senescence or local, environmental challenges7–9. Senescence induction and characterization is heterogeneous, varying across cell types, as well as physiological and pathological environments; DNA damage, oxidative stress via the p38 MAPK pathway, and the NLRP3 1 Division of Medical Sciences, University of Victoria, Victoria, BC, Canada. 2Institute on Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada. Centre for Advanced Materials and Related Technology (CAMTEC), University of Victoria, Victoria, BC, Canada. 4Department of Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, BC, Canada. 5Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada. 6Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC, Canada. 7The Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, Canada. 8Department of Neurology and Neurosurgery, McGill University, Montréal, QC, e-mail: ; ; Canada. 3 Nature Communications | (2023)14:1670 1 Perspective https://doi.org/10.1038/s41467-023-37304-3 BOX 1: A brief summary of Braak staging and dominant LOAD theories of pathology The Amyloid Cascade and Tau hypotheses are the best characterized mechanisms for explaining synaptic loss and neurodegeneration observed over LOAD progression. The Amyloid Cascade Hypothesis asserts that amyloid-beta (Aβ) protein accumulation, especially Aβ oligomers, acts through multiple pathways to cause neurodegeneration and synaptic loss2,3. Misfolded Aβ monomers undergo a slow “seeding”, nucleating phase into damaging Αβ oligomers, which then further aggregate into insoluble Aβ fibrils and diffuse amyloid plaques without hp-tau aggregates3. Misfolded hp-tau and Aβ can also destabilize their respective native conformations and spread equivalently as prions in conditions including increased acidity3. Moreover, Aβ and hp-tau pathology can promote seeding and further accumulation of the other (Fig. 1)3. While Aβ protein levels are generally increased in patients with LOAD vs controls, diffuse amyloid plaques and insoluble Aβ fibril aggregation do not correlate well with LOAD progression1,120,125. The Tau Hypothesis suggests that upstream enzymes including p38 MAPK and GSK3 phosphorylate multiple residues in tau protein to create hyperphosphorylated tau (hp-tau)1,3. In this hypothesis, hp-tau starts as soluble monomers and oligomers but can form higher-complexity aggregates in insoluble fibrils, neuropil threads, and neurofibrillary tangles (NFTs). Neuritic plaques, which comprise compact amyloid plaques containing Aβ, hp-tau, and dystrophic neurites1,3,106,125, also constitute as hp-tau pathology. Together, all forms of hp-tau aggregation are classified as “neurofibrillary pathology”. Hp-tau or neurofibrillary pathology is considered to correlate well with cognitive impairment and dementia1,100,125. Braak Staging: Post-mortem assessments of cognitive decline and correlates of neurodegeneration severity in LOAD have been extensively tracked via Braak staging1,120. Here, hp-tau aggregation and neurofibrillary degeneration are clinically documented into a set of six Braak stages125. In stages I and II, initial neurofibrillary pathology spreads from the transentorhinal region into the entorhinal cortex and hippocampus. Stages III and IV involve increased lesions and pathologies in these areas, as well as novel spread into the temporal lobe and insular cortex. Stages V and VI affect the remaining superior temporal gyrus and neocortex. Braak staging tracking hp-tau pathology burden was notably shown to correlate with LOAD progression, where stage IV is associated with an overt dementia diagnosis (Fig. 2)1,100,125. Hypotheses outside the Tau Hypothesis and Amyloid Cascade Hypothesis focus on other contributors and risk factors associated with LOAD. Although this perspective hypothesizes that these factors eventually converge into increased glial senescence, comprehensive review of these theories is outside this pers (...truncated)