APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes

S.M. de Leeuw, A.W.T. Kirschner, K. Lindner, R. Rust, V. Budny, W.E. Wolski, A.-C. Gavin, R.M. Nitsch, C. Tackenberg

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

© 2021 The Author(s)The apolipoprotein E4 (APOE4) variant is the strongest genetic risk factor for Alzheimer disease (AD), while the APOE2 allele is protective. A major question is how different APOE genotypes affect the physiology of astrocytes, the main APOE-producing brain cells. Here, we differentiated human APOE-isogenic induced pluripotent stem cells (iPSCs) (APOE4, E3, E2, and APOE knockout [APOE-KO]) to functional “iAstrocytes”. Mass-spectrometry-based proteomic analysis showed genotype-dependent reductions of cholesterol and lipid metabolic and biosynthetic pathways (reduction: APOE4 > E3 > E2). Cholesterol efflux and biosynthesis were reduced in APOE4 iAstrocytes, while subcellular localization of cholesterol in lysosomes was elevated. An increase in immunoregulatory proteomic pathways (APOE4 > E3 > E2) was accompanied by elevated cytokine release in APOE4 cells (APOE4 > E3 > E2 > KO). Activation of iAstrocytes exacerbated proteomic changes and cytokine secretion mostly in APOE4 iAstrocytes, while APOE2 and APOE-KO iAstrocytes were least affected. Taken together, APOE4 iAstrocytes reveal a disease-relevant phenotype, causing dysregulated cholesterol/lipid homeostasis, increased inflammatory signaling, and reduced β-amyloid uptake, while APOE2 iAstrocytes show opposing effects.
Original languageEnglish
Pages (from-to)110-126
JournalStem cell reports
Volume17
Issue number1
DOIs
Publication statusPublished - 11 Jan 2022
Externally publishedYes

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