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  3. Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice

Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice

  • EMBO Mol Med. 2024 Nov;16(11):2856-2881. doi: 10.1038/s44321-024-00146-7.
Yi Guo 1,  Chuanbin Cai 1,  Bingjie Zhang 2,  Bo Tan 3,  Qinmin Tang 1,  Zhifeng Lei 1,  Xiaolan Qi 1,  Jiang Chen 1 4,  Xiaojiang Zheng 2,  Dan Zi 5,  Song Li 6,  Jun Tan 7 8 9
Affiliations

Affiliations

  • 1 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education; Key Laboratory of Molecular Biology, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
  • 2 Anyu Biotechnology (Hangzhou) Co., Ltd., Hangzhou, 310000, Zhejiang, China.
  • 3 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
  • 4 Department of Pharmacy, School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
  • 5 Department of Gynecology, Guizhou Provincial People's Hospital, Guiyang, 550025, Guizhou, China.
  • 6 First Affiliated Hospital of Dalian Medical University, Dalian, 116021, Liaoning, China. lisong@dmu.edu.cn.
  • 7 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education; Key Laboratory of Molecular Biology, Guizhou Medical University, Guiyang, 550025, Guizhou, China. tanjun@anyuhz.cn.
  • 8 Anyu Biotechnology (Hangzhou) Co., Ltd., Hangzhou, 310000, Zhejiang, China. tanjun@anyuhz.cn.
  • 9 Institute of Translational Medicine; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310015, Zhejiang, China. tanjun@anyuhz.cn.
PMID: 39394468 DOI: 10.1038/s44321-024-00146-7
Abstract

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.

Keywords

Alzheimer’s Disease; Synaptic Damage; Tau; USP11 Inhibition; Ubiquitination.

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