Role of microglia autophagy and mitophagy in age-related neurodegenerative diseases

Abstract

Microglia, characterized by responding to damage, regulating the secretion of soluble inflammatory mediators, and engulfing specific segments in the central nervous system (CNS), function as key immune cells in the CNS. Emerging evidence suggests that microglia coordinate the inflammatory responses in CNS system and play a pivotal role in the pathogenesis of age-related neurodegenerative diseases (NDDs). Remarkably, microglia autophagy participates in the regulation of subcellular substances, which includes the degradation of misfolded proteins and other harmful constituents produced by neurons. Therefore, microglia autophagy regulates neuronal homeostasis maintenance and process of neuroinflammation. In this review, we aimed at highlighting the pivotal role of microglia autophagy in the pathogenesis of age-related NDDs. Besides the mechanistic process and the co-interaction between microglia autophagy and different kinds of NDDs, we also emphasized potential therapeutic agents and approaches that could be utilized at the onset and progression of these diseases through modulating microglia autophagy, including promising nanomedicines. Our review provides a valuable reference for subsequent studies focusing on treatments of neurodegenerative disorders. The exploration of microglia autophagy and the development of nanomedicines greatly enhances current understanding of NDDs.

Proteostasis and neurodegeneration: a closer look at autophagy in Alzheimer's disease

“…Microglial autophagy is involved in the regulation of neuronal homeostasis and the process of neuroinflammation. Dysregulation of microglial autophagy has been implicated in the pathogenesis of NDDs, including AD, PD, and HD (Navone et al, 2015;Lin et al, 2022). These findings suggest that the regulation of microglia autophagy and mitophagy may be a potential therapeutic target for the treatment of NDDs.…”

“…Microglia, the resident immune cells of the CNS, play a crucial role in the pathogenesis of age-related neurodegenerative diseases (NDDs). Emerging evidence suggests that microglia coordinate the inflammatory responses in the CNS and contribute to the progression of NDDs (Lin et al, 2022). Microglial autophagy is involved in the regulation of neuronal homeostasis and the process of neuroinflammation.…”

Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

“…Intracellular clearance processes cells play a crucial role in maintaining retinal health. Autophagy, a mechanism for intracellular degradation of damaged or unused biomolecules or organelles, is widely employed in eukaryotic cells and is fundamental for cellular homeostasis [211,212]. RPE cells implement this phenomenon through the formation of extensive doublemembrane vacuoles, termed autophagosomes, which sequester undesired and non-functional macromolecules, complexes, or organelles.…”

Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

“…On the other hand, dysfunctional microglia with lysosomal acidification impairment and the associated lysosomal membrane permeabilization (LMP) increase inflammatory cytokine secretion and induce neuronal death via mechanisms such as necroptosis [ 22 , 23 ]. In addition, these impaired microglia have reduced phagocytic and autophagic capabilities in the clearance of damaged organelles such as mitochondria [ 24 , 25 ], toxic protein aggregates [ 26 ], and myelin debris [ 27 ], as well as in synaptic pruning [ 3 ], leading to eventual neuronal death and neurodegeneration (Fig. 1 c).…”