Synaptic dysfunction with reduced synaptic protein levels is a core feature of Alzheimer’s disease (AD). Synaptic proteins play a central role in memory processing, learning, and AD pathogenesis. Evidence suggests that synaptic proteins in plasma neuronal-derived extracellular vesicles (EVs) are reduced in patients with AD. However, it remains unclear whether levels of synaptic proteins in EVs are associated with hippocampal atrophy of AD and whether upregulating the expression of these synaptic proteins has a beneficial effect on AD. In this study, we included 57 patients with AD and 56 healthy controls. We evaluated their brain atrophy through magnetic resonance imaging using the medial temporal lobe atrophy score. We measured the levels of four synaptic proteins, including synaptosome-associated protein 25 (SNAP25), growth-associated protein 43 (GAP43), neurogranin, and synaptotagmin 1 in both plasma neuronal-derived EVs and cerebrospinal fluid (CSF). We further examined the association of synaptic protein levels with brain atrophy. We also evaluated the levels of these synaptic proteins in the brains of 5×FAD mice. Then, we loaded rabies virus glycoprotein-engineered EVs with messenger RNAs (mRNAs) encoding GAP43 and SNAP25 and administered these EVs to 5×FAD mice. After treatment, synaptic proteins, dendritic density, and cognitive function were evaluated. The results showed that GAP43, SNAP25, neurogranin, and synaptotagmin 1 were decreased in neuronal-derived EVs but increased in CSF in patients with AD, and the changes corresponded to the severity of brain atrophy. GAP43 and SNAP25 were decreased in the brains of 5×FAD mice. The engineered EVs efficiently and stably delivered these synaptic proteins to the brain, where synaptic protein levels were markedly upregulated. Upregulation of synaptic protein expression could ameliorate cognitive impairment in AD by promoting dendritic density. This marks the first successful delivery of synaptic protein mRNAs via EVs in AD mice, yielding remarkable therapeutic effects. Synaptic proteins are closely related to AD processes. Delivery of synaptic protein mRNAs via EVs stands as a promising effective precision treatment strategy for AD, which significantly advances the current understanding of therapeutic approaches for the disease.

中文翻译：

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通过细胞外囊泡传递突触蛋白 mRNA 可改善阿尔茨海默病小鼠模型的认知障碍

突触功能障碍和突触蛋白水平降低是阿尔茨海默病 (AD) 的核心特征。突触蛋白在记忆处理、学习和 AD 发病机制中发挥着核心作用。有证据表明，AD 患者血浆神经元来源的细胞外囊泡 (EV) 中的突触蛋白减少。然而，目前尚不清楚 EV 中突触蛋白的水平是否与 AD 的海马萎缩有关，以及上调这些突触蛋白的表达是否对 AD 有有益作用。在这项研究中，我们纳入了 57 名 AD 患者和 56 名健康对照者。我们使用内侧颞叶萎缩评分通过磁共振成像评估了他们的脑萎缩情况。我们测量了血浆神经元源性 EV 和脑脊液 (CSF) 中四种突触蛋白的水平，包括突触体相关蛋白 25 (SNAP25)、生长相关蛋白 43 (GAP43)、神经粒蛋白和突触结合蛋白 1。我们进一步检查了突触蛋白水平与脑萎缩的关联。我们还评估了 5×FAD 小鼠大脑中这些突触蛋白的水平。然后，我们将编码 GAP43 和 SNAP25 的信使 RNA (mRNA) 加载到狂犬病病毒糖蛋白工程 EV 中，并将这些 EV 给予 5×FAD 小鼠。治疗后，评估突触蛋白、树突密度和认知功能。结果显示，AD患者神经源性EV中GAP43、SNAP25、神经粒蛋白和突触结合蛋白1减少，而CSF中增加，且这些变化与脑萎缩的严重程度相对应。 5×FAD 小鼠大脑中的 GAP43 和 SNAP25 减少。工程化的电动汽车有效、稳定地将这些突触蛋白传递到大脑，其中突触蛋白水平显着上调。突触蛋白表达的上调可以通过提高树突密度来改善 AD 中的认知障碍。这标志着首次通过 EV 成功将突触蛋白 mRNA 递送到 AD 小鼠体内，并产生了显着的治疗效果。突触蛋白与 AD 过程密切相关。通过 EV 传递突触蛋白 mRNA 是一种有前途的有效的 AD 精准治疗策略，它显着增进了目前对该疾病治疗方法的理解。