ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026
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.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- GPER in murine astrocytes and mural cells promotes neurovascular coupling and Aβ clearance.Research square · 2026Article
- Anemia, iron deficiency, and blood biomarkers for Alzheimer disease: clinical interpretation and dementia risk stratification.Frontiers in nutrition · 2026Review
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Authors and funding
9 authors.
Funding
Abstract
introductionChronic cerebral hypoperfusion (CCH) is a major contributor to cognitive impairment; however, its underlying mechanisms remain poorly understood.
methodsWe 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.
resultsCCH 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.
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