APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

Joel W. Blanchard, Leyla Anne Akay, Jose Davila-Velderrain, Djuna Maydell, Hansruedi Mathys, Shawn M. Davidson, Audrey Effenberger, Chih-Yu Chen, Kristal Maner-Smith, Ihab Hajjar, Eric A. Ortlund, Michael Bula, Emre Agbas, Ayesha Ng, Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta Lin, Tak Ko, Lea R’Bibo, William T. Ralvenius, David A. Bennett, Hugh P. Cam, Manolis Kellis () and Li-Huei Tsai ()
Additional contact information
Joel W. Blanchard: Massachusetts Institute of Technology
Leyla Anne Akay: Massachusetts Institute of Technology
Jose Davila-Velderrain: MIT Computer Science and Artificial Intelligence Laboratory
Djuna Maydell: Massachusetts Institute of Technology
Hansruedi Mathys: Massachusetts Institute of Technology
Shawn M. Davidson: Princeton University
Audrey Effenberger: Massachusetts Institute of Technology
Chih-Yu Chen: Emory University School of Medicine
Kristal Maner-Smith: Emory University School of Medicine
Ihab Hajjar: Emory University School of Medicine
Eric A. Ortlund: Emory University School of Medicine
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 School of Medicine at Mt Sinai
William T. Ralvenius: Massachusetts Institute of Technology
David A. Bennett: Rush University Medical Center
Hugh P. Cam: Massachusetts Institute of Technology
Manolis Kellis: MIT Computer Science and Artificial Intelligence Laboratory
Li-Huei Tsai: Massachusetts Institute of Technology

Nature, 2022, vol. 611, issue 7937, 769-779

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05439-w

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