Frontal Cortex Lipid Alterations During the Onset of Alzheimer’s Disease

Article type: Research Article

Authors: Moreno-Rodriguez, Marta^a | Perez, Sylvia E.^a | Martinez-Gardeazabal, Jonatan^b | Manuel, Ivan^{b; c} | Malek-Ahmadi, Michael^d | Rodriguez-Puertas, Rafael^{b; c; 1} | Mufson, Elliott J.^{a; 1; *}

Affiliations: [a] Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA | [b] Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, Spain | [c] Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain | [d] Banner Alzheimer’s Institute, Phoenix, AZ, USA

Correspondence: [*] Correspondence to: Elliott J. Mufson, PhD, Director, Alzheimer’s Disease Research Laboratory, Greening Chair in Neuroscience, Professor, Department of Neurobiology, Barrow Neurological Institute, 350W. Thomas Rd., Phoenix, AZ 85013, USA. Tel.: +1 602 406 8525; Fax: +1 602 406 8520; E-mail: elliott.mufson@barrowneuro.org.

Note: [1] These authors contributed equally to the overall direction and planning of the research.

Abstract: Background:Although sporadic Alzheimer’s disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective:We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods:MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results:MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions:FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Keywords: Alzheimer’s disease, autoradiography, cholinergic, lipidomic, MALDI-MSI, mild cognitive impairment, muscarinic receptor

DOI: 10.3233/JAD-231485

Journal: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1515-1532, 2024