Abstract：
A hallmark of Alzheimer\'s disease (AD) is amyloid-β (Aβ) plaque deposition in the brain, causing deficits in cognitive function. Amyloid-beta oligomers (AβOs), the soluble precursor peptides producing Aβ plaques, also produce neurotoxicity and microgliosis together with glycolytic reprogramming. Recently, monocarboxylate transporter 1 (MCT1), a key glycolysis regulator, and its ancillary protein, CD147, are found to play an important role in the secretion of exosomes, 30-200 nm vesicles in size, which are considered as toxic molecule carriers in AD. However, the effect of low-concentration AβOs (1 nM) on microglia MCT1 and CD147 expression as well as 1 nM AβOs-treated microglia-derived exosomes on neuronal toxicity remain largely elusive. In this study, 1 nM AβOs induce significant axonopathy and microgliosis. Furthermore, 1 nM AβOs-treated neurons- or microglia-derived exosomes produce axonopathy through their autologous or heterologous uptake by neurons, supporting the role of exosomes as neurotoxicity mediators in AD. Interestingly, MCT1 and CD147 are enhanced in microglia by treatment with 1 nM AβOs or exosomes from 1 nM AβOs-treated- microglia or neurons, suggesting the implication of AβOs-induced enhanced MCT1 and CD147 in microglia with AD neuropathogenesis, which is consistent with the in-silico analysis of the single cell RNA sequencing data from microglia in mouse models of AD and AD patients.
摘要：
阿尔茨海默病（AD）的标志是淀粉样β（Aβ）斑块在大脑中沉积，导致认知功能的缺陷。淀粉样β寡聚体（AβOs），产生Aβ斑块的可溶性前体肽，还会产生神经毒性和小胶质细胞增生以及糖酵解重编程。最近,单羧酸转运蛋白1（MCT1），一个关键的糖酵解调节剂，和它的辅助蛋白质，发现CD147在外泌体的分泌中起重要作用，30-200nm大小的囊泡，被认为是AD中的毒性分子载体。然而,低浓度AβOs(1nM)对小胶质细胞MCT1和CD147表达的影响以及1nMAβOs处理的小胶质细胞来源的外泌体对神经元毒性的影响在很大程度上仍然难以捉摸。在这项研究中,1nMAβOs诱导显著的轴突病变和小胶质细胞增生。此外，1nMAβOs处理的神经元或小胶质细胞来源的外泌体通过神经元自体或异源摄取产生轴突病变，支持外泌体作为AD中神经毒性介质的作用。有趣的是,通过用1nMAβOs或来自1nMAβOs治疗的小胶质细胞或神经元的外泌体治疗，MCT1和CD147在小胶质细胞中得到增强，提示AβOs诱导的增强的MCT1和CD147在小胶质细胞与AD神经发病机制中的意义，这与来自AD和AD患者的小鼠模型中的小胶质细胞的单细胞RNA测序数据的计算机模拟分析一致。
