Innovative therapeutic strategies are urgently needed for Alzheimer’s disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extracellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited β-amyloid (Aβ) aggregation and rescued cells from Aβ misfolding–induced cytotoxicity. Furthermore, macrosome administration reduced Aβ plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted Aβ aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuroprotective proteins that inhibit Aβ misfolding. In particular, the small integral membrane protein 10–like protein 2B in macrosomes has been shown to inhibit Aβ aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.

中文翻译：

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分泌的内源性大体减少 Aβ 负担并改善阿尔茨海默病

由于人口老龄化程度的增加和缺乏有效的药物治疗，阿尔茨海默病 (AD) 迫切需要创新的治疗策略。在这里，我们报告了小胶质细胞分泌的细胞外囊泡 (EV) 对 AD 相关病理学的治疗作用，包括巨细胞和小 EV。大体强烈抑制 β-淀粉样蛋白 (Aβ) 聚集，并从 Aβ 错误折叠诱导的细胞毒性中拯救细胞。此外，大体给药减少了 AD 小鼠的 Aβ 斑块并改善了认知障碍。相比之下，小型 EV 略微促进了 Aβ 聚集，但并未改善 AD 病理学。小型 EV 和巨细胞的蛋白质组学分析表明，巨细胞含有几种重要的神经保护蛋白，可抑制 Aβ 错误折叠。尤其，巨细胞中的小整合膜蛋白 10 样蛋白 2B 已被证明可抑制 Aβ 聚集。我们的观察为治疗 AD 提供了一种替代传统无效药物治疗的治疗策略。