The Role Of Ubiquitin Specific Protease 25 In Pathogenesis Of Alzheimer's Disease

Down syndrome(DS)is the most common cause of intellectual disabilities,DS patients usually have one extra or partial chromosome 21.All individuals with DS will develop Alzheimer's disease(AD)pathology of AD by their 40s,which suggests that chromosome 21-encoded genes/protein products may play a role in the pathogenesis of AD.Ubiquitin-specific protease 25(USP25),a chromosome 21 encoded gene,is a member of the deubiquitinating enzyme USP family.It has been reported that knockdown of USP25 in vitro downregulates the expression of amyloid precursor protein(APP),this effect is probably mediated by a direct interaction between USP25 and APP.However,the role of USP25 in the development of AD has not been well studied yet.Amyloid plaque is a pathological hallmark of AD to investigate whether USP25 can regulate ?-amyloid(A?)production,we crossed Usp25+/-mice with 5×FAD mice to generate a AD mouse model with USP25 haploinsufficnecy.We found that the levels of full-length APP and its cleavage products(including ?-CTF,?-CTF and AP)are reduced in the brains of 5×<FAD;Usp25+/-mice compared to that in 5×FAD mice.In addition,histochemical analysis indicates that USP25 haploinsufficency reduced numbers of amyloid plaques in 5×FAD mouse cortex.Moreover,decreaed GFAP density suggests reduced astrocyte proliferation/activation in the cortex of 5×FAD;Usp25+/-mice.In this study,we first show that USP25 regulates APP cleavage/metabolism in vivo,and our studies suggest mechanism role of USP25 in AD pathogenesis.In addition,we display that USP25 deficiency in 5×FAD mice markedly reduces astrocyte proliferation/activation.In summary,our study determines the molecular mechanism of USP25 in AD pathogenesis,and provides a possible therapeutic target for AD treatment.