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

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. Synopsis: In Alzheimer's disease (AD), USP11 interacts with and deubiquitinates tau, leading to its accumulation and accelerating tau pathology. IsoLiPro promotes the ubiquitination and proteolysis of tau protein by inhibiting the expression of USP11, thereby alleviating AD-associated tau pathologies. IsoLiPro, a small molecule inhibitor targeting USP11, was synthesized and demonstrated the ability to enhance tau ubiquitination. Inhibition of USP11 expression by IsoLiPro accelerates tau proteolysis, mitigating AD-associated tau pathology. A significant reduction in β-amyloid deposition was observed in 5xFAD mice treated with IsoLiPro. IsoLiPro improved synaptic integrity and cognitive function in AD model mice. IsoLiPro shows promise as a potential therapeutic agent for AD. In Alzheimer's disease (AD), USP11 interacts with and deubiquitinates tau, leading to its accumulation and accelerating tau pathology. IsoLiPro promotes the ubiquitination and proteolysis of tau protein by inhibiting the expression of USP11, thereby alleviating AD-associated tau pathologies. [ABSTRACT FROM AUTHOR]