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 Aβ42 when extracellular administration of FAM-Aβ42, accompanied by an increase in endocytosis-associated mRNA and protein expression, including TREM2 and VSP35. Meanwhile, FAM-Aβ42 degradation was obviously retarded, since the colocalization of Aβ42 and LDL, Aβ42 and lysosomes was decreased, and syntaxin 17 might be involved in this process. Intriguingly, Meth dramatically facilitated FAM-Aβ42 dissemination in microglia, characterized by the massive overlap between FAM-Aβ42 and transferrin, which is destined to be excreted out of the cells. The facilitation of FAM-Aβ42 spreading was further validated by the increased colocalization of FAM-Aβ42 and CD63. Mechanistically, Meth mediated Aβ42 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 Aβ1-42 efflux in microglia might provide beneficial effects for Meth-induced neural damage.
Keywords: Alzheimer's Disease; Degradation; Endocytosis; Excretion; Methamphetamine; Microglia; β-Amyloid.
Copyright © 2021. Published by Elsevier Inc.