Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Lin Ding
,
Juan Pablo Palavicini
ORCID logo ,
Meixia Pan
,
Shulan Qiu
,
Hu Wang
,
Qiang Shen
,
Jeffrey L. Dupree
,
Xianlin Han
* ORCID logo
Version 1 : Received: 14 September 2022 / Approved: 20 September 2022 / Online: 20 September 2022 (03:56:30 CEST)

A peer-reviewed article of this Preprint also exists.

Palavicini, J.P.; Ding, L.; Pan, M.; Qiu, S.; Wang, H.; Shen, Q.; Dupree, J.L.; Han, X. Sulfatide Deficiency, an Early Alzheimer’s Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks. Int. J. Mol. Sci. 2023, 24, 233. Palavicini, J.P.; Ding, L.; Pan, M.; Qiu, S.; Wang, H.; Shen, Q.; Dupree, J.L.; Han, X. Sulfatide Deficiency, an Early Alzheimer’s Lipidomic Signature, Causes Brain Ventricular Enlargement in the Absence of Classical Neuropathological Hallmarks. Int. J. Mol. Sci. 2023, 24, 233.

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 molecular mechanism that may contribute to ventricular enlargement in AD.

Keywords

Sulfatide; cerebroside sulfotransferase; ventricular enlargement; Alzheimer’s disease; brain MRI; aquaporins

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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