PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation

Cerebral small vessel disease (CSVD) is strongly linked to metabolic risk factors and represents a major cause of vascular cognitive impairment and dementia. The interactions of genetic and environmental risk factors driving cerebrovascular pathology in metabolic syndrome are poorly understood. Here, we characterize neuroinflammatory and neurodegenerative phenotypes in a mouse model of metabolic syndrome with atherosclerosis induced by hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression combined with high-fat diet (HFD). PCSK9+HFD mice exhibit hallmark features of CSVD including vascular rarefaction, impaired neurovascular coupling, blood-brain barrier disruption, white matter injury, neuronal loss, and cognitive deficits. Notably, we identify lipid-droplet accumulating microglia (LDAM) as a distinct cellular phenotype that emerges in response to metabolic stress and correlates with cerebrovascular dysfunction. Three-dimensional light sheet microscopy reveals widespread vascular network disruption. Immunophenotyping demonstrates that microglia in PCSK9+HFD group exhibit enhanced phagocytic activation and ramification complexity yet accumulate perivascular amyloid-β, suggesting impaired clearance capacity. Importantly, we observed vascular amyloid-β deposition in wild-type mice without genetic Alzheimer’s disease mutations, suggesting that metabolic stress contributes to cerebrovascular amyloid pathology. PCSK9+HFD mice displayed recognition memory deficits and increased anxiety-like behavior. Our findings establish that severe hypercholesterolemia accelerates CSVD pathogenesis, and identify LDAM as a distinct pathological feature linking systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.