Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer’s Disease

Article type: Research Article

Authors: Blusztajn, Jan Krzysztof^{a; b; *} | Aytan, Nurgul^{a; b} | Rajendiran, Thekkelnaycke^c | Mellott, Tiffany J.^a | Soni, Tanu^c | Burant, Charles F.^c | Serrano, Geidy E.^d | Beach, Thomas G.^d | Lin, Honghuang^e | Stein, Thor D.^{a; b; f; g; *}

Affiliations: [a] Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA | [b] Boston University Alzheimer’s Disease Research Center, Boston, MA, USA | [c] University of Michigan, Ann Arbor, MI, USA | [d] Banner Sun Health Research Institute, Sun City, AZ, USA | [e] University of Massachusetts Medical School, Worcester, MA, USA | [f] VA Boston Healthcare System, U.S. Department of Veteran Affairs, Jamaica Plain, MA, USA | [g] VA Bedford Healthcare System, U.S. Department of Veteran Affairs, Bedford, MA, USA

Correspondence: [*] Correspondence to: Jan Krzysztof Blusztajn PhD, 72 East Concord Street, Boston, MA 02118, USA. Tel.: +1 617 358 9588; E-mail: [email protected] and Thor D. Stein, 150S. Huntington Avenue, Boston, MA 02130, USA. Tel.: +1 857 364 5612; E-mail: [email protected].

Abstract: Background:Multiple studies have reported brain lipidomic abnormalities in Alzheimer’s disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. Objective:Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. Methods:We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer’s Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288). Results:We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes—the principal cell type of white matter. Conclusions:Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.

Keywords: Alzheimer’s disease, cerebral cortex, cerebrosides, gray matter, lipidomics, monogalactosyldiacylglycerol, white matter

DOI: 10.3233/JAD-230543

Journal: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1623-1634, 2023