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-β (Aβ) deposition. The "spreading hypothesis" suggests that pathological Aβ spreads over the entire brain, which depends on Aβ endocytosis, transport and clearance. However, whether Meth exposure impacts these effects remains poorly understood. Microglia play an important role in the clearance of Aβ. Therefore, the effects of microglia on Aβ ingestion, degradation, and efflux under Meth challenge were investigated. Meth significantly engulfed and elicited a massive accumulation of Aβ when extracellular administration of FAM-Aβ, accompanied by an increase in endocytosis-associated mRNA and protein expression, including TREM2 and VSP35. Meanwhile, FAM-Aβ degradation was obviously retarded, since the colocalization of Aβ and LDL, Aβ and lysosomes was decreased, and syntaxin 17 might be involved in this process. Intriguingly, Meth dramatically facilitated FAM-Aβ dissemination in microglia, characterized by the massive overlap between FAM-Aβ and transferrin, which is destined to be excreted out of the cells. The facilitation of FAM-Aβ spreading was further validated by the increased colocalization of FAM-Aβ and CD63. Mechanistically, Meth mediated Aβ 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 Aβ efflux in microglia might provide beneficial effects for Meth-induced neural damage.