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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-\u03b2, suggesting impaired clearance capacity. Importantly, we observed vascular amyloid-\u03b2 deposition in wild-type mice without genetic Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.1101\/2025.10.29.685380","type":"posted-content","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T09:35:12Z","timestamp":1761903312000},"source":"Crossref","is-referenced-by-count":0,"title":["PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation"],"prefix":"10.64898","author":[{"given":"Mengqi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anudari","family":"Letian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A","family":"Mohl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brynn","family":"Kroke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kajsa","family":"Arkelius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire D","family":"Clelland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3848-6590","authenticated-orcid":false,"given":"Emily L","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1605-4444","authenticated-orcid":false,"given":"Neel S.","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110303551052000_2025.10.29.685380v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/str.0000000000000431"},{"key":"2025110303551052000_2025.10.29.685380v1.2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.123.19943"},{"key":"2025110303551052000_2025.10.29.685380v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03552-7"},{"key":"2025110303551052000_2025.10.29.685380v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30079-1"},{"key":"2025110303551052000_2025.10.29.685380v1.5","doi-asserted-by":"crossref","unstructured":"Liu X , Cheng R , Chen L , Gong J , Luo T , Lv F : Altered Neurovascular Coupling in Subcortical Ischemic Vascular Disease. 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