Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Abstract

Abstract:Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…Inhibition of mTORC1 kinase activity triggers the activation of transcription factor EB (TFEB) that promotes transcription of autophagy and lysosome related genes, including Atg5, Atg12 and Atg16 [48]. Through several phosphorylation events, mTORC1 can unleash the kinase activity of the ULK1 complex, which in turns activates its downstream complex Vps34.…”

Neuroprotection in Perimenopausal Women

“…The autophagy is crucial for neuronal health and survival, the delivery of toxic molecules and organelles from neuronal apoptotic cells to microglia lysosomes may be acutely and/or chronically dysregulated by senescence, affecting phagocytosis and inflammation-innate immune functions in all age-associated neurodegenerative diseases [83]. There are two phenotypes of activated microglia: M1 (the cells become more cytotoxic by releasing additional pro-inflammatory cytokines-TNF, Il-1β, Il-6, and free radicals [84]), and M2, which becomes more anti-inflammatory, by secreting anti-inflammatory cytokines and neurotrophic factors and helps repair local damage [82].…”

Commentary on interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

“…In patients affected by MS, several autophagy-related genes (e.g., ATG-16L2, ATG-9A, and ULK-1) are overexpressed [1] , therefore the hypothesis is that over-activation of autophagy may contribute to autoreactive T lymphocyte survival [18] . Given the pivotal roles of the autophagy in these neurodegenerative diseases, the targeting of some key pathways of the inflammatory process provides new insights into the diagnosis and the modulation of this process represents a new therapeutic strategy for neuroprotection [1] .…”

“…Autophagy is a fundamental regulatory cellular mechanism, which enables cells to survive after a checked clearance of damaged organelles and proteins and a recycle of necessary molecules like amino acids and fatty acids to maintain homeostasis [1] . There are a lot of factors able to influence autophagy in the states of health and disease.…”

“…Recent studies have demonstrated an intrinsic connection between selective autophagy impairment and neurodegenerative diseases, including Alzheimer's disease (AD) [4][5][6][7] , Parkinson's disease (PD) [8][9][10] , Huntington's disease (HD) [11][12][13][14] , amyotrophic lateral sclerosis (ALS) [15][16][17] , and multiple sclerosis (MS) [1,[18][19][20][21][22][23] .…”