miRNA-137-5p improves spatial memory and cognition in Alzheimer's mice by targeting ubiquitin-specific peptidase 30

Background:Alzheimer’sdisease(AD)is a prevalent neurodegenerative disorder causing progressive dementia.Research suggests that microRNAs(miRNAs)could serve as biomarkers and therapeutic targets for AD.Reduced levels of miR-137 have been observed in the brains of AD patients,but its specific role and down stream mechanisms remain unclear.This study sought to examine the therapeutic potential of miR-137-5p agomir in alleviating cognitive dysfunction induced in AD models and explore its potential mechanisms.Methods:This study utilized bioinformatic analysis and a dual-l uciferase reporter assay to investigate the relationship between miR-137-5p and ubiquitin-specific peptidase 30(USP30).In vitro experiments were conducted using SH-SY5Y cells to assess the impact of miR-137-5p on Aβ1-42 neurotoxicity.In vivo experiments on AD mice evaluated the effects of miR-137-5p on cognition,Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis,as well as its influence on USP30 levels.Results:It was discovered that miR-137-5p mimics efficiently counteract Aβ1-42 neurotoxicity in SH-SY5Y cells,a protective effect that is negated by USP30 overexpression.In vivo experiments demonstrated that miR-137-5p enhances the cognition and mobility of AD mice,significantly reducing Aβ1-42 deposition,Tau hyperphosphorylation,and neuronal apoptosis within the hippocampus and cortex regions.Mechanistically,miR-137-5p significantly suppresses USP30 levels in mice,though USP30 overexpression partially buffers against miR-137-5p-i nduced AD symptom improvement.Conclusion:Our study proposes that miR-137-5p,by instigating the downregulation of USP30,has the potential to act as a novel and promising therapeutic target for AD.