APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

Joel W Blanchard; Leyla Anne Akay; Jose Davila-Velderrain; Djuna von 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; Li-Huei Tsai

doi:10.1038/s41586-022-05439-w

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

Nature. 2022 Nov;611(7937):769-779. doi: 10.1038/s41586-022-05439-w. Epub 2022 Nov 16.

Authors

Joel W Blanchard^#^{1

2

3}, Leyla Anne Akay^#^{1

2

4}, Jose Davila-Velderrain^#^{4

5}, Djuna von Maydell^#^{1

2

4}, Hansruedi Mathys^{1

2

6}, Shawn M Davidson⁷, Audrey Effenberger^{1

2}, Chih-Yu Chen⁸, Kristal Maner-Smith⁸, Ihab Hajjar⁹, Eric A Ortlund^{8

10}, Michael Bula^{1

2}, Emre Agbas^{1

2}, Ayesha Ng^{1

2}, Xueqiao Jiang^{1

2}, Martin Kahn^{1

2}, Cristina Blanco-Duque^{1

2}, Nicolas Lavoie^{1

2}, Liwang Liu^{1

2}, Ricardo Reyes³, Yuan-Ta Lin^{1

2}, Tak Ko¹, Lea R'Bibo³, William T Ralvenius^{1

2}, David A Bennett¹¹, Hugh P Cam^{1

2}, Manolis Kellis^{12

13}, Li-Huei Tsai^{14

15

16}

Affiliations

¹ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Nash Family Department of Neuroscience, Black Family Stem Cell Institute, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mt Sinai, New York, NY, USA.
⁴ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
⁵ Human Technopole, Milan, Italy.
⁶ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
⁸ Department of Medicine, Emory Integrated Metabolomics and Lipidomics Core, Emory University School of Medicine, Atlanta, GA, USA.
⁹ Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
¹² MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA. manoli@mit.edu.
¹³ Broad Institute of Harvard and MIT, Cambridge, MA, USA. manoli@mit.edu.
¹⁴ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
¹⁵ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
¹⁶ Broad Institute of Harvard and MIT, Cambridge, MA, USA. lhtsai@mit.edu.

^# Contributed equally.

Abstract

APOE4 is the strongest genetic risk factor for Alzheimer's disease^1-3. 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 disease^4-8. 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 APOE^2-6, 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aging / genetics
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Animals
Apolipoprotein E4* / genetics
Apolipoprotein E4* / metabolism
Autopsy
Biological Transport
Brain* / metabolism
Brain* / pathology
Cholesterol* / metabolism
Gene Expression Profiling
Heterozygote
Homeostasis
Humans
Induced Pluripotent Stem Cells
Memory
Mice
Myelin Sheath / metabolism
Myelin Sheath / pathology
Nerve Fibers, Myelinated* / metabolism
Nerve Fibers, Myelinated* / pathology
Neurons / metabolism
Neurons / pathology
Oligodendroglia* / metabolism
Oligodendroglia* / pathology
Single-Cell Analysis

Substances

Apolipoprotein E4
Cholesterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding