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Ventricular enlargement has been associated with worse performance on global cognitive tests and AD. Our previous studies demonstrated that brain sulfatides, myelin-enriched lipids, are dramatically reduced in subjects at the earliest clinically recognizable AD stages via an apolipoprotein E (APOE)-dependent and isoform-specific process. Herein, we provided pre-clinical evidence that sulfatide deficiency is causally associated with brain ventricular enlargement. Specifically, taking advantage of genetic mouse models of global and adult-onset sulfatide deficiency, we demonstrated that sulfatide losses cause ventricular enlargement without significantly affecting hippocampal or whole brain volumes using histological and magnetic resonance imaging approaches. Mild decreases in sulfatide content and mild increases in ventricular areas were also observed in human APOE4 compared to APOE2 knock-in mice. Finally, we provided Western blot and immunofluorescence evidence that aquaporin-4, the most prevalent aquaporin channel in the central nervous system (CNS) that provides fast water transportation and regulates cerebrospinal fluid in the ventricles, is significantly increased under sulfatide-deficient conditions, while other major brain aquaporins (e.g., aquaporin-1) are not altered. In short, we unraveled a novel and causal association between sulfatide deficiency and ventricular enlargement. Finally, we propose putative mechanisms by which sulfatide deficiency may induce ventricular enlargement.<\/jats:p>","DOI":"10.3390\/ijms24010233","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T02:36:46Z","timestamp":1671763006000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Sulfatide Deficiency, an Early Alzheimer\u2019s Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9667-8438","authenticated-orcid":false,"given":"Juan Pablo","family":"Palavicini","sequence":"first","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Ding","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Biochemistry and Molecular Biology, Soochow University Medical College, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixia","family":"Pan","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Wang","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Shen","sequence":"additional","affiliation":[{"name":"Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Dupree","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23284, USA"},{"name":"Research Service, McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-2413","authenticated-orcid":false,"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"},{"name":"Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and biomarker changes in dominantly inherited Alzheimer\u2019s disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N. 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