Background: The transgenic mice models overexpressing human p25 contribute greatly to the invivo neurotoxic mechanism of p25 in neurodegenerative diseases.However,it is time-consuming to manipulate existing transgenic mice models.Objective: Here,we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9(rAAV9).Methods: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter,and the control,AAV9-GFP,were delivered in mice by tail-vein injection.Assessments of p25 expression,neurodegenerative pathology,and behavioral changes were performed.Results: GFP expression was detected by in-vivo imaging as early as one week after virus injection.Notably,widespread expression of p25 was obviously found in cortex,hippocampus and cerebellum in AAV9-GFP-p25 mice.Moreover,decreased hippocampus volumes in AAV9-GFPp25 mice were detected by 7T MRI examination about one month after injection.Further,these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection.At last,hyper-phosphorylated tau,neurofibrillary tangles,activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery.However,amyloid-β(Aβ)plaque,overt neuronal loss and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression.Conclusion: The AAV9-mediated p25 overexpression mouse model,which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes,provides an easier and time-saving method to explore the functions of p25 in vivo,as well as an alternative tool for development of drugs against neurotoxic of p25.