An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
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, 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.
Figures:
Fig. 1 | Central Alzheimer’s pathologies.
Risk factors for late-onset Alzheimer’s disease (LOAD) are proposed to contribute to at least one of six main pathologies:
oxidative stress and oxysterol production, phosphatidylserine (PS)-exposed neurons, pro-inflammatory cytokines, amyloid-beta aggregation and vascular pathology, tau pathology, and glial cell reactivity. Each main pathology likely eventually adds to and increases the burden of other main AD pathologies. These pathologies may ultimately converge to drive improper neuronal support, synaptic loss, and death, resulting in neurodegeneration clinically corresponding to cognitive decline. Centrally, the repeated buildup of these six LOAD pathologies proposedly pushes an aged glial system into senescence induction and accumulation.
This burden of senescent glia is predicted to sustain a disease environment that determines local neurodegeneration involved in LOAD progression. Glial senescence is briefly characterized as dysfunctional glial states with impaired endolysosomal function and support for nearby cells. What constitutes glial senescence burden may well vary per an individual’s genetics, physiology, and environmental experiences; nonetheless, it is predicted that the glial senescence burden differentiates a cognitively healthy or resilient individual from one diagnosed with LOAD. Purple color designates associations with senescence and dementia progression. Figure created with BioRender.com.
Fig. 2 | Alzheimer’s: aging into disease. A late-onset Alzheimer’s disease (LOAD)
framework is proposed from healthy cognitive aging to late-stage Alzheimer’s
disease (AD), presenting the following testable hypothesis: Glial senescence accumulation, particularly requiring increased senescent microglia burden, may correspond to clinical LOAD progression.
Darker and deeper purple coloring denotes more severe senescent glia burden and Braak staging progression in LOAD. The hypothesis presents that: (i) Aging and AD pathologies from Fig. 1 (including amyloid-beta (Aβ), neurofibrillary pathology in hyper-phosphorylated tau (hp-tau), oxidative stress, and chronic inflammation) are predicted to progressively accrue throughout aging as by-products of central nervous system function and metabolism. (ii) Main AD pathology levels are likely enhanced by inflammatory glial states, and would be sufficiently cleared by glia performing homeostatic roles.
However, homeostatic glial functions that putatively decline throughout aging
would decrease proficiency in containing AD pathologies. (iii) In preclinical AD,
increasing proportions of aged glia likely interact with AD pathologies to become senescent. This would include oligodendrocyte progenitor cells and astrocytes.
Microglia performing homeostatic roles would also become senescent especially after engulfing neurons containing hp-tau. (iv) Senescent microglia then likely become incompetent in breaking down further phagocytosed hp-tau and Aβ aggregates, and instead secrete hp-tau to induce paracrine senescence in other microglia, especially those which are actively engulfing Aβ. Failure to suddenly degrade both hp-tau and Aβ likely induces secretion of Aβ and hp-tau aggregates that coalesce into neuritic amyloid plaques.
These neuritic plaques correspond to Braak staging and clinical LOAD progression. Finally, this combination of senescent glia, reduced homeostatic glial support, and non-senescent, inflammatory glial states is predicted to drive neurodegeneration and cognitive decline in LOAD.
While senescent glia burden is cleared out by immune cells, increasing immunosenescence over aging due to genetic and environmental circumstances likely slowly declines; thus, senescent glia burden is predicted to ultimately differentiate healthy cognition from mild cognitive impairment and LOAD. Figure created with BioRender.com.
Fig. 3 | Likely senescence pathways in Alzheimer’s.
Explanations for Alzheimer’s disease (AD) pathologies inducing senescence are proposed. Oligodendrocyte progenitor cells (OPCs) and astrocytes likely both react with amyloid-beta (Aβ) to become senescent. Oxidative stress and DNA damage may specifically lead to Aβ −induced senescence. Senescent OPCs and astrocytes are predicted to indirectly increase four pathologies: pro-inflammatory cytokines and reactive microglial states, oxidative stress, and Aβ accumulation. In neurons, oxidative stress, inflammation, and possibly DNA damage likely induce tau hyperphosphorylation; this process may also render the affected neurons senescent.
Oxidative stress and hyperphosphorylated tau (hp-tau) aggregation likely prompt neurons to translocate and expose outer phosphatidylserine (PS). While aging predisposes sustained increases in local levels of inflammation, oxidative stress, and Aβ pathology burden, senescent OPCs and astrocytes are proposed to further worsen AD pathology.
Senescent OPCs and astrocytes speculatively favor AD pathology buildup and
environmental conditions that induce exacerbated microglial senescence in LOAD. Particularly, Aβ pathology contributes buildup to oxidative stress that oxidizes cholesterol to form oxysterols; these oxysterols may bind with liver-X-receptor expressed by homeostatic microglia states, resulting in upregulated apolipoprotein E (APOE) expression. Oxidative stress can also prime APOE-upregulated microglia to bind with neuronal PS using various receptors, enabling microglia to prematurely phagocytose and kill PS-exposed neurons containing hp-tau.
This likely renders microglia senescent and unable to effectively phagocytose further AD pathologies, becoming proposed subtype or state “A” senescent microglia increasing type I interferon signaling, displaying dystrophic morphology, accumulating ferritin, and facilitating increased synaptic loss. They also proposedly secrete soluble hp-tau rendering paracrine senescence in nearby glia, thereby preceding neurofibrillary tangle accumulation in neurons. Local microglia attempting to actively phagocytose Aβ are predicted to be caught in this paracrine senescence feedback loop, becoming subtype or state “B” senescent microglia characterized by simultaneous dystrophy and a hypertrophic or “ameboid” appearance.
We hypothesize that these hypertrophic, dystrophic, and senescent
microglia secrete partially-digested aggregates that form neuritic plaques and
further induce paracrine glial senescence. Finally, fewer homeostatic microglia
proposedly remain available to degrade Aβ; Aβ would likely continuously accumulate and initiate increased pro-inflammatory responses, APOE, and KCNA3 upregulation in state “B” senescent microglia. Figure created with BioRender.com
Fig. 4 | Killing senescent glia to treat Alzheimer’s disease.
Building on evidence collected from studies involving mouse models, we conceptually provide a hypothesized outcome of using senolytics to treat Alzheimer’s disease (AD). Senolytics are drugs that selectively kill senescent cells, and were shown to reduce cognitive decline in disease mouse models. If senescent glia sustain synaptic loss and accumulation of the main AD pathologies, senolytics are predicted to provide a best chance for optimal outcomes in individuals with subjective cognitive decline, mild cognitive impairment, and early to mid-stage dementia.
Alternatively put, senolytic interventions may best target earlier timepoints across the cognitive aging axis when one has a larger brain reserve, as late-stage AD may have already resulted in too much neurodegeneration and cell death. Remaining glial populations are predicted to repopulate and renew glial homeostatic functions to effectively clear out and reduce main AD pathologies, as reduced senescent glia counts should critically reduce AD pathology accumulation. Resulting plasticity should hopefully revert the aging brain back to a healthy cognition or preclinical late-onset AD (LOAD) state; minimally, we predict that optimized senolytic treatments can halt
further LOAD progression at least transiently after administration. We also highly support the combination of other pharmacological and non-pharmacologicaltreatment strategies with senolytics.
This would hypothetically allow for better restoring of glial homeostatic functions, and would minimize damage accrued by pro-inflammatory glial states and other AD pathologies. The question mark denotes
that it is currently unknown whether disease-associated microglial states are targeted by senolytics. Figure created with BioRender.com.
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