The Study Of USP25 In The Pathogenesis Of Down Syndrome-Alzheimer’s Disease

Down syndrome(DS)is the most common chromosomal abnormality.Patients with DS exhibit severe developmental retardation and intellectual disability due to an extra or partial copy of chromosome 21.All individuals with DS develop Alzheimer’s disease(AD)-like pathological features by the age of 40,suggesting an important role of chromosome 21 genes in AD pathogenesis.The deubiquitinating protease USP25,a chromosome 21-encoded gene,has been reported to regulate innate immune response.However,it remains unkown whether USP25 plays a role in the pathogenesis of DS and AD.In this thesis,using behavioral and electrophysiological tests,we found that BACTg-USP25 transgenic mice display severe cognitive and synaptic deficits.In addition,by crossing a DS mouse model Dp 16 with Usp25+/-mice,we found that knockout of Usp25 can reverse synaptic impairments in DS mice.Moreover,we crossed an AD mouse model 5×FAD with Usp25+/-mice and found that Usp25 deficiency restored the excitability/inhibition balance in hippocampal neurons of AD mice,and reversed synaptic dysfunction in AD mice.In summary,our study identified a key role of ubiquitin-specific protease USP25 in the pathogenesis of DS and AD.Usp25 deficiency reverses synaptic defects in both DS and AD mice.Our research not only provides a new perspective for understanding the pathogenesis of AD from the perspective of DS,but also provides potential drug targets for the treatment of DS and AD.