Molecular Regulation Mechanism of Microglial Autophagy in the Pathology of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal protein aggregates, neuronal loss, synaptic dysfunction, and neuroinflammation. Microglia are resident macrophages of the central nervous system (CNS). Evidence has shown that impaired microglial autophagy exerts considerable detrimental impact on the CNS, thus contributing to AD pathogenesis. This review highlights the association between microglial autophagy and AD pathology, with a focus on the inflammatory response, defective clearance, and propagation of Aβ and Tau, and synaptic dysfunction. Mechanistically, several lines of research support the roles of microglial receptors in autophagy regulation during AD. In light of accumulating evidence, a strategy for inducing microglial autophagy has great potential in AD drug development.

Docosahexaenoic acid-acylated astaxanthin monoester enhances microglial autophagy for ameliorating amyloid-β load and cognitive deficits in models of Alzheimer’s disease

“…Induces autophagy is accompanied by increased protein expressions of autophagic protein markers, including Beclin1, ATG7, ATG5, or ATG12 [46]. In the present study, the early phase of autophagosome formation is observed in microglia-specific ATG7 knockout mice and si-ATG7-transfected microglia cells [21,47].…”

Mapping trends and hotspots of mitochondrial dysfunction in Alzheimer’s disease from 2013 to 2022: a bibliometric analysis of global research

“…Autophagy is a protective mechanism in the body that removes damaged organelles and abnormal proteins. Studies have shown the presence of autophagy abnormalities in AD, accompanied by neuroinflammation, clearance defects, Aβ and Tau deposition, and synaptic dysfunction ( Ou-Yang et al, 2023 ). The study has found that mitochondrial autophagy is reduced by 60% in the hippocampus of AD model mice ( Fang et al, 2019 ).…”

Clathrin mediated endocytosis in Alzheimer’s disease: cell type specific involvement in amyloid beta pathology

“…When considering microglial involvement in Tau pathology, to our knowledge there has been no specific link between microglial uptake and propagation of Tau via CME mechanisms. How microglia contribute to Tau pathology is reviewed in depth elsewhere ( Das et al, 2020 ; Ayyubova, 2023 ; Chen and Yu, 2023 ; Ou-Yang et al, 2023 ). CME in microglia needs to be further investigated to clarify what degree it and other endocytic mechanisms are disrupted in AD in relation to both Aβ and Tau pathology.…”