Methamphetamine-mediated dissemination of β-amyloid: Disturbances in endocytosis, transport and clearance of β-amyloid in microglial BV2 cells

Methamphetamine (Meth) abuse can cause neurodegenerative-like changes, such as those observed in Alzheimer's disease (AD), characterized by extracellular amyloid-beta (A beta) deposition. The spreading hypothesis suggests that pathological A beta spreads over the entire brain, which depends on A beta endocytosis, transport and clearance. However, whether Meth exposure impacts these effects remains poorly understood. Microglia play an important role in the clearance of A beta. Therefore, the effects of microglia on A beta ingestion, degradation, and efflux under Meth challenge were investigated. Meth significantly engulfed and elicited a massive accumulation of A beta(42) when extracellular administration of FAM-A beta(42), accompanied by an increase in endocytosis-associated mRNA and protein expression, including TREM2 and VSP35. Meanwhile, FAM-A beta(42) degradation was obviously retarded, since the colocalization of A beta(42) and LDL, A beta(42) and lysosomes was decreased, and syntaxin 17 might be involved in this process. Intriguingly, Meth dramatically facilitated FAM-A beta(42) dissemination in microglia, characterized by the massive overlap between FAM-A beta(42) and transferrin, which is destined to be excreted out of the cells. The facilitation of FAM-A beta(42) spreading was further validated by the increased colocalization of FAM-A beta(42) and CD63. Mechanistically, Meth mediated A beta(42) spreading through the exosomal pathway, since an exosomal inhibitor remarkably hindered this process. Therefore, the current study elucidated a novel mechanism of Meth-induced accelerated progression in neurodegenerative disease, and targeting the inhibition of A beta(1-42) efflux in microglia might provide beneficial effects for Meth-induced neural damage.

Automated summary

This study revealed that Meth significantly impacted the ingestion and accumulation of Aβ(42) in microglia and led to impaired degradation of Aβ, promoting Aβ(42) spreading through the exosomal pathway.