ADIPONECTIN SIGNALING PRESERVES BLOOD–BRAIN BARRIER INTEGRITY AND COGNITIVE FUNCTION IN CHRONIC HYPOPERFUSION–INDUCED VASCULAR COGNITIVE IMPAIRMENT

Vascular cognitive impairment and dementia (VCID) is characterized by chronic cerebral hypoperfusion, blood–brain barrier (BBB) disruption, and progressive cognitive decline, yet no therapies directly target BBB dysfunction. Clinical studies report an inverse association between circulating adiponectin, the most abundant adipokine, and the severity of BBB damage and cognitive impairment, but causality remains unclear. This study examined whether adiponectin and adipoRon, a small-molecule adiponectin receptor agonist, promote BBB repair and cognitive recovery following hypoperfusion-induced VCID.

Sixteen– to eighteen-month-old male C57BL/6 wild-type and adiponectin knockout mice were subjected to bilateral common carotid artery stenosis (BCAS). BBB integrity was assessed by immunohistochemical detection of endogenous and exogenous tracer leakage. Primary brain microvascular endothelial cells (ECs) were exposed to oxygen–glucose deprivation (OGD) to model hypoperfusion in vitro. Cognitive performance was evaluated using the Morris water maze, Y-maze, novel object recognition, and passive avoidance tests.

Adiponectin deficiency significantly exacerbated BBB leakage and long-term cognitive deficits after BCAS. In contrast, adipoRon treatment reduced early and sustained BBB disruption and improved spatial and non-spatial cognition in aged mice. In vitro, adiponectin and adipoRon protect ECs from OGD-induced injury. Mechanistically, adipoRon enhanced endothelial nitric oxide production by increasing endothelial nitric oxide synthase activation and promoting heat shock protein-90–eNOS interactions. AdipoRon also suppressed endothelial inflammatory responses and preserved barrier integrity.

These findings demonstrate that adiponectin signaling maintains BBB integrity and supports cognitive recovery in chronic hypoperfusion-induced VCID, identifying adiponectin receptor activation as a promising noninvasive therapeutic strategy for age-related vascular dementia and related cerebrovascular neurodegenerative disorders.