Sulfatide Deficiency, an Early Alzheimer’s Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks

Juan Pablo Palavicini, Lin Ding, Meixia Pan, Shulan Qiu, Hu Wang, Qiang Shen, Jeffrey L. Dupree, Xianlin Han

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and a decline in activities of daily life. 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.

Original languageEnglish (US)
Article number233
JournalInternational journal of molecular sciences
Volume24
Issue number1
DOIs
StatePublished - Jan 2023

Keywords

  • Alzheimer’s disease
  • aquaporins
  • brain MRI
  • cerebroside sulfotransferase
  • sulfatide
  • ventricular enlargement

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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