Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; College of Nursing, Nanjing Vocational Health College, Nanjing, Jiangsu, China.
Key Laboratory of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
Toxicol Appl Pharmacol. 2022 Jul 15;447:116090. doi: 10.1016/j.taap.2022.116090. Epub 2022 May 26.
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.
甲基苯丙胺（冰毒）滥用可引起神经退行性样改变，如阿尔茨海默病（AD）中观察到的改变，其特征为细胞外淀粉样β（Aβ）沉积。“扩散假说”表明，病理性 Aβ 在整个大脑中扩散，这取决于 Aβ 的内吞作用、运输和清除。然而，Meth 暴露是否会影响这些作用仍知之甚少。小胶质细胞在 Aβ 的清除中起着重要作用。因此，研究了小胶质细胞在 Meth 挑战下对 Aβ 摄取、降解和外排的影响。当 FAM-Aβ 进行细胞外给药时，Meth 会明显吞噬并引起大量 Aβ 积累，同时内吞作用相关的 mRNA 和蛋白表达增加，包括 TREM2 和 VSP35。同时，FAM-Aβ 的降解明显减慢，因为 Aβ 和 LDL、Aβ 和溶酶体的共定位减少，并且 syntaxin 17 可能参与了这个过程。有趣的是，Meth 显著促进了 FAM-Aβ 在小胶质细胞中的扩散，特征是 FAM-Aβ 和转铁蛋白之间存在大量重叠，这注定要被排出细胞外。FAM-Aβ 扩散的促进作用通过 FAM-Aβ 和 CD63 的共定位增加进一步得到验证。从机制上讲，Meth 通过外体途径介导 Aβ 扩散，因为外体抑制剂显著阻碍了这一过程。因此，本研究阐明了 Meth 诱导神经退行性疾病进展加速的新机制，靶向抑制小胶质细胞中的 Aβ 外排可能对 Meth 诱导的神经损伤有益。
