Correlates and Predictors of Cerebrospinal Fluid Cholesterol Efflux Capacity from Neural Cells, a Family of Biomarkers for Cholesterol Epidemiology in Alzheimer’s Disease

Article type: Research Article

Authors: Cipollari, Eleonora^a | Szapary, Hannah J.^a | Picataggi, Antonino^a | Billheimer, Jeffrey T.^a | Lyssenko, Catherine A.^b | Ying, Gui-Shuang^c | Shaw, Leslie M.^d | Kling, Mitchel A.^{e; f} | Kaddurah-Daouk, Rima^{g; h; i} | Rader, Daniel J.^{a; j} | Praticò, Domenico^k | Lyssenko, Nicholas N.^{k; *} | for the Alzheimer’s Disease Metabolomics Consortium

Affiliations: [a] Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | [b] Office of Institutional Research & Analysis, University of Pennsylvania, Philadelphia, PA, USA | [c] Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | [d] Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | [e] Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | [f] Behavioral Health Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA | [g] Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA | [h] Duke Institute for Brain Sciences, Duke University, Durham, NC, USA | [i] Department of Medicine, Duke University School of Medicine, Durham, NC, USA | [j] Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA | [k] Alzheimer’s Center at Temple, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

Correspondence: [*] Correspondence to: Nick Lyssenko, Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Medicine Education & Research Building 1148A, 3500 N. Broad St., Philadelphia, PA 19140, USA. Tel.: +1 215 707 9380; E-mail: [email protected].

Abstract: Background:Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer’s disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD. Objective:To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects. Methods:We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis. To measure cerebrospinal fluid (CSF) CECs from neurons, microglia, and astrocytes, CSF was exposed to, correspondingly, neuronal, microglial, and astrocytic cholesterol source cells. Human neuroblastoma SH-SY5Y, mouse microglial N9, and human astroglial A172 cells were used as the cholesterol source cells. CSF samples were screened for contamination with blood. CSF CECs were measured in a small cohort of 22 individuals. Results:CSF CECs from neurons, microglia, and astrocytes were moderately to moderately strongly correlated with CSF concentrations of cholesterol, apolipoprotein A-I, apolipoprotein E, and clusterin (Pearson’s r = 0.53–0.86), were in poor agreement with one another regarding CEC of the CSF samples (Lin’s concordance coefficient rc = 0.71–0.76), and were best predicted by models consisting of, correspondingly, CSF phospholipid (R2 = 0.87, p < 0.0001), CSF apolipoprotein A-I and clusterin (R2 = 0.90, p < 0.0001), and CSF clusterin (R2 = 0.62, p = 0.0005). Conclusion:Characteristics of the CSF CEC metrics suggest a potential for independent association with AD and provision of fresh insight into the role of cholesterol in AD pathogenesis.

Keywords: ABCA1, ABCG1, Alzheimer’s disease biomarkers, apolipoprotein A-I, apolipoprotein E, cell cholesterol efflux, clusterin (apolipoprotein J), SR-BI

DOI: 10.3233/JAD-191246

Journal: Journal of Alzheimer's Disease, vol. 74, no. 2, pp. 563-578, 2020