Microglial Autophagy in the Context of Neurodegenerative Conditions

Changes in the function and activity of microglia in the brain, innate immune cells analogous to the macrophages present in the rest of the body, are known to be involved in the onset and progression of neurodegenerative conditions. Aging and neurodegeneration are associated with a growing presence of both senescent microglia and activated microglia Both of these states producing inflammatory signaling, contributing to the chronic, unresolved inflammation of brain tissue that is also characteristic of later life.

Autophagy is the name given to a collection of cellular maintenance processes responsible for recycling damaged and unwanted proteins and structures within the cell. Autophagy is thought to decline in effectiveness with age, and this leads to a growing garbage catastrophe in cells, particularly in long-lived cells. Here, researchers discuss the connection between failing autophagy in immune cells such as microglia and trigger mechanisms such as the inflammasome that are responsible for a sizable fraction of inflammatory signaling. It may be that inflammation will prove to be the central pillar of neurodegeneration, but that inflammation has numerous contributing causes.

Microglial autophagy in Alzheimer's disease and Parkinson's disease

Autophagy and its dysfunction are associated with a variety of human pathologies, including aging, neurodegenerative disease, heart disease, cancer, and metabolic diseases, such as diabetes. A plenty of drugs and natural products have been found to modulate autophagy function through multiple signaling pathways. Small molecules or nanomedicine that can regulate autophagy seem to have great potential to intervene in neurodegenerative diseases that are largely due to the accumulation of misfolded proteins.

In general, microglia participate in autophagy by phagocytosis in the central nervous system (CNS). Because of the critical role of autophagy in protein and organelle quality control, the impairment of autophagy will result in accumulation of aggregated proteins and damaged organelles, which are common pathological hallmarks in AD and PD. Accumulating evidence indicates that the autophagy machinery in microglia can contribute to the emergence, acceleration, or amelioration of CNS disease conditions. So far, two specific mechanisms appear to be relevant to CNS pathology: activation of the inflammasome and increase of autophagy protein-mediated endocytosis/phagocytosis. Autophagy pathways are implicated in the regulation of inflammasome function at various steps by removing triggering agents, inflammasome constituents, or downstream effector molecules. As the major cellular component of the innate immune system in the brain, microglia have been found to execute pivotal functions during CNS homeostasis and pathology.

Microglial autophagy and inflammatory response are necessary for protecting against external stimuli. When the inflammatory response in the brain is continuously activated, overactivated inflammasomes can cause neuronal damage. As early as 2006, it was reported that neuronal autophagy dysfunction induces neurodegenerative diseases in mice, and recent studies have linked microglial autophagy to NLR family pyrin domain 3 (NLRP3) inflammasomes, elucidating the important role of NLRP3 inflammasomes activation triggered by autophagy deficiency in microglial cells in the development of Parkinson's disease (PD).

NLRP3, a widely studied oligomeric multiprotein inflammasome complex, is highly expressed in microglia. Microglial hyperactivation of the NLRP3 inflammasome has been well-documented in various neurodegenerative diseases, including PD. Autophagy protects the nervous system by clearing NLRP3 inflammasome activation. Likewise, inflammasome signaling pathways can also regulate microglia activation necessary to balance between required host defense inflammatory response and to prevent excessive and detrimental inflammation.

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