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

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.