Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer's disease.
Microglial cathepsin E plays a role in neuroinflammation and amyloid β production in Alzheimer's disease.
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作者：
Xie Z;Meng J;Kong W;Wu Z;Lan F;Narengaowa;Hayashi Y;Yang Q;Bai Z;Nakanishi H;Qing H;Ni J
神经炎症和 β-淀粉样蛋白 (Aβ) 产生的调节是阿尔茨海默病 (AD) 发病机制的关键因素。组织蛋白酶 E (CatE) 是一种天冬氨酸蛋白酶，作为多种癌细胞生长停滞和凋亡的诱导剂而被广泛研究。然而，CatE 在 AD 中的功能尚不清楚。在这项研究中，我们证明，在人类淀粉样前体蛋白敲入小鼠（称为 APPNL−G−F 小鼠）中消除 CatE 可显着减少 Aβ 积累、神经炎症和认知障碍。从机制上讲，小胶质细胞 CatE 参与可溶性 TNF 相关凋亡诱导配体的分泌，该配体在小胶质细胞介导的 NF-κB 依赖性神经炎症和 β 位点 APP 裂解酶 1 产生神经元 Aβ 中发挥重要作用。此外，插管递送的 CatE 抑制剂可改善记忆功能并减少记忆功能。 AD 小鼠中 Aβ 积累和神经炎症。我们的研究结果表明，CatE 作为 AD 中小胶质细胞激活和神经变性的调节剂，并建议 CatE 通过针对神经炎症和 Aβ 病理学作为 AD 的治疗靶点。小胶质细胞组织蛋白酶 E 参与 TRAIL 的分泌，导致 AD 期间小胶质细胞介导的神经炎症和神经元 Aβ 的产生。插管递送的组织蛋白酶 E 抑制剂可改善 AD 小鼠的记忆功能并减少神经炎症和 Aβ 的产生。
Regulation of neuroinflammation and β‐amyloid (Aβ) production are critical factors in the pathogenesis of Alzheimer's disease (AD). Cathepsin E (CatE), an aspartic protease, is widely studied as an inducer of growth arrest and apoptosis in several types of cancer cells. However, the function of CatE in AD is unknown. In this study, we demonstrated that the ablation of CatE in human amyloid precursor protein knock‐in mice, called APPNL−G−F mice, significantly reduced Aβ accumulation, neuroinflammation, and cognitive impairments. Mechanistically, microglial CatE is involved in the secretion of soluble TNF‐related apoptosis‐inducing ligand, which plays an important role in microglia‐mediated NF‐κB‐dependent neuroinflammation and neuronal Aβ production by beta‐site APP cleaving enzyme 1. Furthermore, cannula‐delivered CatE inhibitors improved memory function and reduced Aβ accumulation and neuroinflammation in AD mice. Our findings reveal that CatE as a modulator of microglial activation and neurodegeneration in AD and suggest CatE as a therapeutic target for AD by targeting neuroinflammation and Aβ pathology. Microglial cathepsin E involves the secretion of TRAIL, resulting in microglia‐mediated neuroinflammation and neuronal Aβ production during AD. Cannula‐delivered Cathepsin E inhibitor improves memory function and reduced neuroinflammation and Aβ production in AD mice.
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