Abstract
<title>Abstract</title> <p>Background Chronic cerebral hypoperfusion (CCH) is a major contributor to vascular cognitive impairment (VCI), characterized by progressive neurovascular dysfunction, including neuroinflammatory activation and blood–brain barrier (BBB) disruption. Although autophagy dysregulation has been implicated in BBB damage, the upstream molecular mechanisms driving excessive autophagy activation during chronic hypoperfusion remain poorly understood. Methods/Results Using a bilateral carotid artery stenosis (BCAS)-induced mouse model of CCH and an oxygen–glucose deprivation/reoxygenation (OGD/R) endothelial cell model, this study investigated the role of poly (ADP-ribose) polymerase-1 (PARP1) in CCH-associated neurovascular injury. PARP1 expression was persistently increased following CCH, and pharmacological inhibition of PARP1 with Olaparib significantly improved cognitive deficits and attenuated neuroinflammatory responses, white matter injury, and BBB hyperpermeability. Mechanistically, this study demonstrated that excessive autophagy initiation, rather than lysosomal dysfunction, was a key driver of tight junction protein degradation and BBB disruption after CCH. Transcriptomic analysis identified FOXO signaling as a potential downstream pathway regulated by PARP1 inhibition. Further investigations revealed that PARP1 promoted FOXO3a activation and transcriptionally upregulated its downstream target Depp1, thereby inducing excessive autophagy initiation and BBB injury. In vitro, Depp1 overexpression abolished the inhibitory effect of Olaparib on autophagy activation, confirming the essential role of Depp1 in the PARP1–FOXO3a–Depp1 signaling axis. Conclusions This study identifies a previously unrecognized PARP1–FOXO3a–Depp1 signaling axis that drives excessive autophagy initiation and mediates BBB disruption during CCH. These findings provide new mechanistic insights into CCH-associated neurovascular injury and support the potential repurposing of the FDA-approved PARP1 inhibitor Olaparib as a therapeutic strategy for VCI.</p>