APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

• Type of Material: Article
• Authors: Joel W Blanchard, Massachusetts Institute of Technology; Leyla A Akay, Massachusetts Institute of Technology; Jose Davila-Velderrain, Massachusetts Institute of Technology; Djuna von Maydell, Massachusetts Institute of Technology; Hansruedi Mathys, Massachusetts Institute of Technology; Shawn M Davidson, Princeton University; Audrey Effenberger, Massachusetts Institute of Technology; Chin-Yu Chen, Emory University; Kristal Maner-Smith, Emory University; Ihab Hajjar, Emory University; Eric Ortlund, Emory University; Michael Bula, Massachusetts Institute of Technology; Emre Agbas, Massachusetts Institute of Technology; Ayesha Ng, Massachusetts Institute of Technology; Xueqiao Jiang, Massachusetts Institute of Technology; Martin Kahn, Massachusetts Institute of Technology; Cristina Blanco-Duque, Massachusetts Institute of Technology; Nicolas Lavoie, Massachusetts Institute of Technology; Liwang Liu, Massachusetts Institute of Technology; Ricardo Reyes, Icahn School of Medicine at Mt. Sinai; Yuan-Ta Lin, Massachusetts Institute of Technology; Tak Ko, Massachusetts Institute of Technology; Lea R'Bibo, Icahn Sch Med Mt Sinai; William T Ralvenius, Massachusetts Institute of Technology; David A Bennett, Rush University; Hugh P Cam, Massachusetts Institute of Technology; Manolis Kellis, Massachusetts Institute of Technology; Li-Huei Tsai, Massachusetts Institute of Technology
• Language: English
• Date: 2022-11-10
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05439-w
• Title of Journal or Parent Work: NATURE
• Volume: 611
• Issue: 7935
• Start Page: 769
• End Page: +
• Keywords: ALZHEIMERS-DISEASE; STRESS; CELLS; TYPE-4 ALLELE; Science & Technology - Other Topics; GENE; MODEL; APOLIPOPROTEIN-E; Multidisciplinary Sciences; RISK; Science & Technology

Abstract

APOE4 is the strongest genetic risk factor for Alzheimer’s disease1–3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer’s disease4–8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2–6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes—myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer’s disease.