Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease.
Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease.
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fe65工程化的神经元外泌体包封紫杉醇- b改善阿尔茨海默病的认知和病理。
DOI：
10.1038/s41392-023-01657-4
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发表时间：
2023-10-23
影响因子：
39.3
通讯作者：
Li, Min
中科院分区：
文献类型：
--
作者：
Iyaswamy, Ashok;Thakur, Abhimanyu;Guan, Xin-Jie;Krishnamoorthi, Senthilkumar;Fung, Tsz Yan;Lu, Kejia;Gaurav, Isha;Yang, Zhijun;Su, Cheng-Fu;Lau, Kwok-Fai;Zhang, Kui;Ng, Roy Chun-Laam;Lian, Qizhou;Cheung, King-Ho;Ye, Keqiang;Chen, Huanhuan Joyce;Li, Min
阿尔茨海默病 (AD) 是一种神经退行性疾病，其特征是海马神经元主要受损，并在大脑中形成淀粉样斑块、过度磷酸化 tau 蛋白和神经原纤维缠结。 AD 脑中淀粉样蛋白-β 前体蛋白 (APP) 的过度表达导致 APP 胞内结构域 (AICD) 通过 C 端 Fe65-PTB2 相互作用与 Fe65 蛋白结合，然后触发淀粉样蛋白-β 的分泌以及随后的 AD 发病机制。显然，针对 APP 和 Fe65 之间的相互作用可以为 AD 提供一种有前景的治疗方法。最近，外泌体是一种直径约为 30-200 nm 的细胞外囊泡，由于其能够穿越血脑屏障、被自体细胞有效摄取以及能够用靶标特异性受体配体进行表面修饰，因此作为治疗 AD 等脑部疾病的潜在递送工具而受到广泛关注。在这里，海马神经元细胞衍生的外泌体过度表达 Fe65，使得一种新型的基于外泌体的靶向药物递送系统的开发成为可能，该系统将 Corynoxine-B（Cory-B，一种自噬诱导剂）运送到 AD 小鼠大脑中 APP 过度表达的神经元细胞。 Fe65 工程改造的 HT22 海马神经元细胞来源的外泌体 (Fe65-EXO) 装载了 Cory-B (Fe65-EXO-Cory-B) 劫持了信号传导并阻断了 Fe65 和 APP 之间的自然相互作用，从而实现了 Cory-B 的 APP 靶向递送。值得注意的是，Fe65-EXO-Cory-B 诱导表达 APP 的神经元细胞自噬，从而改善 AD 小鼠的认知衰退和发病机制，证明 Fe65-EXO-Cory-B 作为 AD 有效治疗干预的潜力。
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30–200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood–brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.
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通讯作者：
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