Cu(II) disrupts autophagy-mediated lysosomal degradation of oligomeric Aβ in microglia via mTOR-TFEB pathway

Toxicology and Applied Pharmacology
Xiaofang TanJuan Li

Abstract

Copper dyshomeostasis is involved in the pathogenesis of Alzheimer's disease (AD). Microglia play a major role in the proteolytic clearance of oligomeric β-amyloid (Aβo). Here, we investigated whether Cu(II) affects microglial Aβo clearance and whether this effect involves autophagy-lysosomal pathway. Microtubule associated protein 1 light chain 3 (LC3)-II and p62 protein levels and autophagic flux in Cu(II)-treated microglia were detected. Aβo clearance was detected by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. In vivo, Cu(II) and Aβo were injected into mouse hippocampus to evaluate Aβ clearance. The results showed that Cu(II) inhibited phagocytic uptake and intracellular degradation of Aβo in microglial cultures. Additionally, Cu(II) elevated LC3-II and p62 protein levels and impaired autophagic flux. It also inhibited transcription factor EB (TFEB) expression and lysosomal biogenesis. Moreover, Cu(II) activated mammalian target of rapamycin kinase (mTOR), an upstream signaling of TFEB. The mTOR inhibitor PP242 ameliorated Cu(II)-impaired TFEB expression, lysosomal biogenesis, autophagic flux, and Aβo clearance in microglia. In vivo, Cu(II) inhibited microglial Aβo clearance in mouse hippocampus, an eff...Continue Reading

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