Alzheimer's Disease (AD), as the most common neurodegenerative disease worldwide, severely impairs patients' cognitive functions. Although its exact etiology remains unclear, the abnormal aggregations of misfolded β-amyloid peptide and tau protein are considered pivotal in its pathological progression. Recent studies identify ubiquitin-specific protease 11 (USP11) as the key regulator of tau deubiquitination, exacerbating tau aggregation and AD pathology. Thereby, inhibiting USP11 function, via either blocking USP11 activity or lowering USP11 protein level, may serve as an effective therapeutic strategy against AD. Our research introduces IsoLiPro, a unique lithium isobutyrate-L-proline coordination compound, effectively lowers USP11 protein level and enhances tau ubiquitination in vitro. Additionally, long-term oral administration of IsoLiPro dramatically reduces total and phosphorylated tau levels in AD transgenic mice. Moreover, IsoLiPro also significantly lessens β-amyloid deposition and synaptic damage, improving cognitive functions in these animal models. These results indicate that IsoLiPro, as a novel small-molecule USP11 inhibitor, can effectively alleviate AD-like pathologies and improve cognitive functions, offering promise as a potential multi-targeting therapeutic agent against AD.

中文翻译：

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通过新型锂有机配位化合物靶向 USP11 调节可改善阿尔茨海默病转基因小鼠的神经病理学和认知功能。


阿尔茨海默病 （AD） 是全球最常见的神经退行性疾病，严重损害患者的认知功能。尽管其确切病因尚不清楚，但错误折叠的 β-淀粉样蛋白肽和 tau 蛋白的异常聚集被认为是其病理进展的关键。最近的研究确定泛素特异性蛋白酶 11 （USP11） 是 tau 去泛素化的关键调节因子，加剧了 tau 聚集和 AD 病理。因此，通过阻断 USP11 活性或降低 USP11 蛋白水平来抑制 USP11 功能，可能是对抗 AD 的有效治疗策略。我们的研究引入了 IsoLiPro，一种独特的异丁酸锂-L-脯氨酸配位化合物，在体外有效降低 USP11 蛋白水平并增强 tau 泛素化。此外，长期口服 IsoLiPro 可显著降低 AD 转基因小鼠的总和磷酸化 tau 水平。此外，IsoLiPro 还显著减少了 β-淀粉样蛋白沉积和突触损伤，改善了这些动物模型的认知功能。这些结果表明，IsoLiPro 作为一种新型小分子 USP11 抑制剂，可以有效缓解 AD 样病变并改善认知功能，有望成为潜在的 AD 多靶点治疗剂。