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

ABSTRACT

Methamphetamine (Meth) abuse can cause neurodegenerative-like changes, such as those observed in Alzheimer's disease (AD), characterized by extracellular amyloid-ß (Aß) deposition. The "spreading hypothesis" suggests that pathological Aß spreads over the entire brain, which depends on Aß endocytosis, transport and clearance. However, whether Meth exposure impacts these effects remains poorly understood. Microglia play an important role in the clearance of Aß. Therefore, the effects of microglia on Aß ingestion, degradation, and efflux under Meth challenge were investigated. Meth significantly engulfed and elicited a massive accumulation of Aß42 when extracellular administration of FAM-Aß42, accompanied by an increase in endocytosis-associated mRNA and protein expression, including TREM2 and VSP35. Meanwhile, FAM-Aß42 degradation was obviously retarded, since the colocalization of Aß42 and LDL, Aß42 and lysosomes was decreased, and syntaxin 17 might be involved in this process. Intriguingly, Meth dramatically facilitated FAM-Aß42 dissemination in microglia, characterized by the massive overlap between FAM-Aß42 and transferrin, which is destined to be excreted out of the cells. The facilitation of FAM-Aß42 spreading was further validated by the increased colocalization of FAM-Aß42 and CD63. Mechanistically, Meth mediated Aß42 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 Aß1-42 efflux in microglia might provide beneficial effects for Meth-induced neural damage.