Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation

Abstract

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerative disease involve aging changes in microglia. If correct, targeting features of microglial senescence may constitute a feasible therapeutic strategy. This review explores this hypothesis and its implications by considering the current knowledge on how microglia undergo change during aging and how the emergence of these aging phenotypes relate to significant alterations in microglial function. Evidence and theories on cellular mechanisms implicated in driving senescence in microglia are reviewed, as are “rejuvenative” measures and strategies that aim to reverse or ameliorate the aging microglial phenotype. Understanding and controlling microglial aging may represent an opportunity for elucidating disease mechanisms and for formulating novel therapies.

Saffron reduces ATP-induced retinal cytotoxicity by targeting P2X7 receptors

“…However, results present in the literature suggest that the action of saffron can be more complex [22] and includes the modulation of gene expression [26,27], e.g., the downregulation of genes involved in neuroinflammation (chemokines) and reduce microglia activation (paper in preparation). Recently, the identification of purinergic receptors on microglia has driven a strong debate on the pivotal role played by microglia and local ATP release as an injury signal in the process of aging and age-related diseases such as AMD [42,43]. In this scenario, our data showing that Saf directly reduces the [Ca 2+ ] i response evoked by purinergic P2X7R stimulation unravels a novel mechanism through which Saf may exert its protective role in neurodegeneration.…”

“…In the brain, the P2X7R has been proposed to be involved in the signaling cascade leading to neuroinflammation and neurodegeneration [42,44]. How the receptor contributes to these processes is not yet unequivocally verified.…”

Enhanced microglial activity in FAAH−/− animals

“…Microglia in the brain of old individuals show activated morphology with bigger cell bodies. They are primed for pro-inflammatory responses and their constitutive release of pro-inflammatory cytokines is enhanced [30] . Astrocytes also undergo functional and morphological changes during ageing: astrocytes in the brain of old animals or humans show enhanced expression of glial fibrillary acidic protein (GFAP) and increased secretion of pro-inflammatory factors [31] .…”

Neurogenic Niche Microglia Undergo Positional Remodeling and Progressive Activation Contributing to Age-Associated Reductions in Neurogenesis

“…During aging, microglia become hypervigilant, expressing increased levels of proinflammatory cytokines and overreact to normal subthreshold immune challenges, leading to an exaggerated immune response deleterious to brain function [30][31][32]. In the hippocampus, microglia have been shown to be both positive and negative regulators of neurogenesis depending on activation state [33][34][35][36][37].…”