Direct glia-to-neuron conversion mitigates hippocampal damage in a vascular dementia mouse model.

Vascular dementia, which is considered the second most common cause of dementia, has consistently remained a worldwide health concern. One possible approach to improving vascular dementia is by inducing neurogenesis. The asymmetric carotid artery stenosis (ACAS) model was employed and viral vectors were administered to induce an astrocytes-to-neuron conversion, including the Ptbp1 knockdown (KD) or transduction of Ascl1, NeuroD1, and Sox2 (ANS), with the aim of assessing their therapeutic effects. Mice were sacrificed 2 months after ACAS surgery and administration of the viral vector, followed by an immunohistochemical analysis that evaluated CA1 preservation, the inflammatory response and neurogenesis. CA1 was significantly thicker in the ACAS + ANS group than in the ACAS + Ptbp1 KD group. The inflammatory response in the hippocampus was suppressed in both the ACAS + ANS and ACAS + Ptbp1 KD groups. In the dentate gyrus, NeuN/mCherry double-positive cells were observed in both the ACAS + Ptbp1 KD and ACAS + ANS groups. On the other hand, in CA1, they were only found in the ACAS + ANS group. In conclusion, AAV-pGFAP-ANS efficiently induced glia-to-neuron reprogramming and suppressed hippocampal inflammation in the ACAS-induced microinfarction model.