Microglial Senescence and Activation in Healthy Aging and Alzheimer’s Disease: Systematic Review and Neuropathological Scoring

Abstract

The greatest risk factor for neurodegeneration is the aging of the multiple cell types of human CNS, among which microglia are important because they are the “sentinels” of internal and external perturbations and have long lifespans. We aim to emphasize microglial signatures in physiologic brain aging and Alzheimer’s disease (AD). A systematic literature search of all published articles about microglial senescence in human healthy aging and AD was performed, searching for PubMed and Scopus online databases. Among 1947 articles screened, a total of 289 articles were assessed for full-text eligibility. Microglial transcriptomic, phenotypic, and neuropathological profiles were analyzed comprising healthy aging and AD. Our review highlights that studies on animal models only partially clarify what happens in humans. Human and mice microglia are hugely heterogeneous. Like a two-sided coin, microglia can be protective or harmful, depending on the context. Brain health depends upon a balance between the actions and reactions of microglia maintaining brain homeostasis in cooperation with other cell types (especially astrocytes and oligodendrocytes). During aging, accumulating oxidative stress and mitochondrial dysfunction weaken microglia leading to dystrophic/senescent, otherwise over-reactive, phenotype-enhancing neurodegenerative phenomena. Microglia are crucial for managing Aβ, pTAU, and damaged synapses, being pivotal in AD pathogenesis.

West Nile Virus-Induced Expression of Senescent Gene Lgals3bp Regulates Microglial Phenotype within Cerebral Cortex

“…We began by comparing the dataset generated by single cell RNA-sequencing of WNV-activated microglia [7] to a published dataset of RNA-sequencing performed on aged microglia [22], which revealed broad similarities between WNV-and aging-induced transcriptomic changes in microglia: genes induced by microglial activation in the context of WNV infection were also induced by aging, while homeostatic microglial genes maintained consistent expression levels between the two conditions. Microglial activation has been previously reported during aging and recovery from WNV in mice [1,5,7,[33][34][35], with a number of inflammation-induced genes being implicated in both of these conditions.…”

Satellite Glial Cells in Human Disease

“…Glial cells are essential for the normal development and function of the nervous system. They have a protective role, but they may also contribute to pathological states [17][18][19]. For example, prolonged astrocyte reactivity during autoimmune or neurodegenerative disorders can lead to excessive inflammation [18].…”