Conversion of astroglia into functional neurons has been considered as a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, PTBP1, converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathological phenotypes associated with Parkinson’s disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female WT, and β-amyloid (5×FAD) and tau (PS19) Alzheimer’s disease (AD) mouse models, and fails to reverse synaptic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disease therapy through manipulating one single gen...