摘要PTEN-induced putative kinase 1(PINK1)/parkin pathway mediates mitophagy,which is a specialized form of autophagy.Evidence shows that PINK1 can exert protective effects against stress-induced neuronal cell death.In the present study we investigated the effects of PINK1 overexpression on tau hyperphosphorylation,mitochondrial dysfunction and oxidative stress in a specific rat model of tau hyperphosphorylation.We showed that intracerebroventricular(ICV)microinjection of forskolin(FSK,80 μmol)induced tau hyperphosphorylation in the rat brain and resulted in significant spatial working memory impairments in Y-maze test,accompanied by synaptic dysfunction(reduced expression of synaptic proteins synaptophysin and postsynaptic density protein 95),and neuronal loss in the hippocampus.Adeno-associated virus(AAV)-mediated overexpression of PINK1 prevented ICV-FSK-induced cognition defect and pathological alterations in the hippocampus,whereas PINK1-knockout significantly exacerbated ICV-FSK-induced deteriorated effects.Furthermore,we revealed that AAV-PINK1-mediated overexpression of PINK1 alleviated ICV-FSK-induced tau hyperphosphorylation by restoring the activity of PI3K/Akt/GSK3P signaling.PINK1 overexpression reversed the abnormal changes in mitochondrial dynamics,defective mitophagy,and decreased ATP levels in the hippocampus.Moreover,PINK1 overexpression activated Nrf2 signaling,thereby increasing the expression of antioxidant proteins and reducing oxidative damage.These results suggest that PINK1 deficiency exacerbates FSK-induced tau pathology,synaptic damage,mitochondrial dysfunction,and antioxidant system defects,which were reversed by PINK1 overexpression.Our data support a critical role of PINK1-mediated mitophagy in controlling mitochondrial quality,tau hyperphosphorylation,and oxidative stress in a rat model of Alzheimer's disease.