Aquaporin-4 and caveolin-1 as mediators of fibrinogen-driven cerebrovascular pathology in cerebral amyloid angiopathy.

Abstract

INTRODUCTION: Cerebral amyloid angiopathy (CAA), marked by amyloid beta (Aβ) accumulation in perivascular spaces (PVSs), contributes to vascular injury and inflammation in Alzheimer's disease. The mechanisms underlying CAA-related vascular pathology remain unclear. Increasing evidence indicates fibrinogen, the main component in blood clots, interacts with Aβ and exacerbates inflammation and co-deposits in PVS of CAA-positive vessels, yet its role in cerebrovascular dysfunction remains poorly defined. METHODS: Using TgSwDI transgenic mice, which develop robust CAA, we examined fibrin(ogen) deposition, aquaporin-4 (AQP4) polarization, and caveolin-1 (Cav-1) expression. We further assessed the effects of fibrinogen depletion via small interfering RNA. RESULTS: TgSwDI mice showed increased fibrin(ogen) extravasation, colocalization with Aβ in PVS, AQP4 depolarization, and elevated Cav-1 expression. Fibrinogen depletion reduced CAA, restored AQP4 polarization, decreased Cav-1 levels, attenuated microglial activation, and improved spatial memory. DISCUSSION: These findings suggest that modulating fibrinogen-related pathways could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology. HIGHLIGHTS: Fibrin(ogen)-Aβ colocalization aggravates CAA. AQP4 depolarization links fibrinogen-Aβ deposits to impaired clearance in CAA. Cav-1 increase drives fibrinogen leakage and neuroinflammation. Fibrinogen depletion reduces CAA, restores AQP4 polarity, and improves memory.