Chronic cerebral hypoperfusion exacerbates amyloid and tau pathology by impairing glymphatic transport via AQP4‐ and VEGF‐mediated pathways: insights from a vascular to mixed‐type dementia model

Abstract INTRODUCTION Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive impairment; however, its underlying mechanisms remain poorly understood. METHODS We investigated CCH‐induced glymphatic dysfunction and neurodegeneration in amyloid precursor protein (APP)/presenilin 1 (PS1) and wild‐type mice. Glymphatic transport was assessed using contrast‐enhanced magnetic resonance imaging (MRI) and real‐time femoral vein imaging. Aquaporin‐4 (AQP4) polarization and amyloid beta (Aβ)/phosphorylated tau 217 (p‐tau217) accumulation were examined by immunofluorescence staining. Single‐cell RNA sequencing (scRNA‐seq) identified molecular mechanisms and pathways. RESULTS CCH impaired glymphatic clearance by reducing AQP4 polarization, resulting in Aβ and p‐tau217 accumulation. scRNA‐seq revealed downregulation of vascular endothelial growth factor (VEGF), Rho GTPase, and integrin–actin signaling pathways. Restoring vascular tone with adrenergic receptor blocker normalized VEGF localization and vascular pulsatility/resistance, improved glymphatic clearance, and rescued cognitive function. DISCUSSION CCH impairs glymphatic function through AQP4 depolarization and VEGF suppression, causing toxic protein accumulation. Restoring vascular tone rescued cognition, establishing a mechanistic link between vascular dysfunction and neurodegeneration in cognitive impairment.