The Role Of Deubiquitinase USP25 In The Pathogenesis Of Alzheimer’s Disease

Down syndrome(DS),also known as trisomy 21,is a critical risk factor for earlyonset Alzheimer’s disease(AD),suggesting that chromosome 21-encoded genes play key roles in the pathogenesis of AD.However,it remains unknown why the individuals with DS with higher risk to develop AD-like neuropathology.Exploring how patients with DS develop early-onset AD would shed light on the pathogenesis of AD,and deciphering the underlying mechanism can also provide clues for the identification of novel drug targets for DS and AD intervention.Ubiquitin-specific protease(USP25)is a chromosome 21-encoded deubiquitinase that plays a critical role in regulating innate immunity.In 5×FAD mice,overexpression of USP25 leads to microglial activation,synaptic and cognitive dysfunction,while USP25 haploinsufficency reduces neuroinflammation and restores synaptic and cognitive function.Mechanistically,Usp25 haploinsufficency reduces microgliamediated overproduction of pro-inflammatory cytokines and synaptic phagocytosis.Phamrcological inhibition of USP25 restores microglia homeostasis and ameliorates synaptic and cognitive deficits in 5×FAD mice.However,it remains unknown whether USP25 affects other pathological features of AD,such as amyloid plaque deposition.We generated a combined DS-AD mouse model by breeding 5 xFAD with Dp 16 mice,and found that trisomy 21 promotes amyloid deposition in DS-AD mouse brain.Furthermore,we found that USP25 overexpression facilitates the accumulation of amyloid plaques in 5×FAD mice,while USP25 haploinsuffiency reduces amyloid deposition.Mechanistically,USP25 promotes Aβ production by reducing ubiquitination and lysosomal degradation of APP and BACE1.Moreover,pharmacological inhibition of USP25 alleviates amyloid pathology in 5×FAD mice.In summary,we demonstrated that the increased dosage of chromosome 21encoded genes contributes to trisomy 21-mediated hyperactivation of microglia,and USP25 plays a key role in regulating microglial homeostasis in AD brain.In addition to regulating microglial homeostasis,USP25 also acts as a key regulator of AD neuropathology through regulating Aβ production.Pharmacological inhibition of USP25 activity reduces microglia-associated neuroinflammation and the accumulation of amyloid plaques,suggesting that USP25 could be a potential drug target for DS and AD.