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

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 ReyesYuan Ta Lin, Tak Ko, Lea R’Bibo, William T. Ralvenius, David A. Bennett, Hugh P. Cam, Manolis Kellis^*, Li Huei Tsai^*

^*Corresponding author for this work

Medicine, Pulmonary Division

Research output: Contribution to journal › Article › peer-review

149 Scopus citations

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.

Original language	English (US)
Pages (from-to)	769-779
Number of pages	11
Journal	Nature
Volume	611
Issue number	7937
DOIs	https://doi.org/10.1038/s41586-022-05439-w
State	Published - Nov 24 2022

Funding

We thank the individuals who donated post-mortem brain samples, and their families, for enabling this research; Y. Zhou, E. McNamara and T. Garvey for administrative support and animal care; and J. M. Bonner for input on the lipidomic analyses. We acknowledge support from the Robert A. and Renee E. Belfer Family, The JPB Foundation, The Carol and Gene Ludwig Family Foundation, the Cure Alzheimer’s Fund and the National Institutes of Health (RF1 AG062377, RF1 AG054012-01, U54HG008097 and 747UG3NS115064). J.W.B. was supported by the NIH grant UG3-NS115064, R01NS114239-01A1, Cure Alzheimer’s Fund; L.A.A. was supported by NIH grant RF1-AG0540124 and the MIT BCS Henry E. Singleton Graduate Student Fellowship; D.v.M. was supported by the MIT BCS Broshy Graduate Student Fellowship and the MIT BCS Halis Graduate Student Fellowship; X.J. was supported by NIH grant U01-NS110453; Y.-T.L. was supported by NIH grant R01-AG058002; W.T.R. was supported by an Alzheimer’s Association Research Fellowship; H.P.C. was supported by NIH grants RF1-AG054012 and RF1-AG062377. ROSMAP is supported by NIA grants P30AG20262, R01AG15819, R01AG17917, U01AG46152, U01AG 61356 and P30AG72975. RF1AG057470, RF1AG051633, K24AG062786 from NIA to I.H. ROSMAP resources can be requested at https://www.radc.rush.edu . Graphic illustrations were generated using BioRender under agreements VI24HP0GQM and NE24HPHF0X. We thank the individuals who donated post-mortem brain samples, and their families, for enabling this research; Y. Zhou, E. McNamara and T. Garvey for administrative support and animal care; and J. M. Bonner for input on the lipidomic analyses. We acknowledge support from the Robert A. and Renee E. Belfer Family, The JPB Foundation, The Carol and Gene Ludwig Family Foundation, the Cure Alzheimer’s Fund and the National Institutes of Health (RF1 AG062377, RF1 AG054012-01, U54HG008097 and 747UG3NS115064). J.W.B. was supported by the NIH grant UG3-NS115064, R01NS114239-01A1, Cure Alzheimer’s Fund; L.A.A. was supported by NIH grant RF1-AG0540124 and the MIT BCS Henry E. Singleton Graduate Student Fellowship; D.v.M. was supported by the MIT BCS Broshy Graduate Student Fellowship and the MIT BCS Halis Graduate Student Fellowship; X.J. was supported by NIH grant U01-NS110453; Y.-T.L. was supported by NIH grant R01-AG058002; W.T.R. was supported by an Alzheimer’s Association Research Fellowship; H.P.C. was supported by NIH grants RF1-AG054012 and RF1-AG062377. ROSMAP is supported by NIA grants P30AG20262, R01AG15819, R01AG17917, U01AG46152, U01AG 61356 and P30AG72975. RF1AG057470, RF1AG051633, K24AG062786 from NIA to I.H. ROSMAP resources can be requested at https://www.radc.rush.edu. Graphic illustrations were generated using BioRender under agreements VI24HP0GQM and NE24HPHF0X.

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Blanchard, J. W., Akay, L. A., Davila-Velderrain, J., von Maydell, D., Mathys, H., Davidson, S. M., Effenberger, A., Chen, C. Y., Maner-Smith, K., Hajjar, I., Ortlund, E. A., Bula, M., Agbas, E., Ng, A., Jiang, X., Kahn, M., Blanco-Duque, C., Lavoie, N., Liu, L., ... Tsai, L. H. (2022). APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature, 611(7937), 769-779. https://doi.org/10.1038/s41586-022-05439-w

@article{71fd1265d2c1494086ec27b4e3852b86,

title = "APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes",

abstract = "APOE4 is the strongest genetic risk factor for Alzheimer{\textquoteright}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{\textquoteright}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{\textquoteright}s disease.",

author = "Blanchard, {Joel W.} and Akay, {Leyla Anne} and Jose Davila-Velderrain and {von Maydell}, Djuna and Hansruedi Mathys and Davidson, {Shawn M.} and Audrey Effenberger and Chen, {Chih Yu} and Kristal Maner-Smith and Ihab Hajjar and Ortlund, {Eric A.} and Michael Bula and Emre Agbas and Ayesha Ng and Xueqiao Jiang and Martin Kahn and Cristina Blanco-Duque and Nicolas Lavoie and Liwang Liu and Ricardo Reyes and Lin, {Yuan Ta} and Tak Ko and Lea R{\textquoteright}Bibo and Ralvenius, {William T.} and Bennett, {David A.} and Cam, {Hugh P.} and Manolis Kellis and Tsai, {Li Huei}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = nov,

day = "24",

doi = "10.1038/s41586-022-05439-w",

language = "English (US)",

volume = "611",

pages = "769--779",

journal = "Nature",

issn = "0028-0836",

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Blanchard, JW, Akay, LA, Davila-Velderrain, J, von Maydell, D, Mathys, H, Davidson, SM, Effenberger, A, Chen, CY, Maner-Smith, K, Hajjar, I, Ortlund, EA, Bula, M, Agbas, E, Ng, A, Jiang, X, Kahn, M, Blanco-Duque, C, Lavoie, N, Liu, L, Reyes, R, Lin, YT, Ko, T, R’Bibo, L, Ralvenius, WT, Bennett, DA, Cam, HP, Kellis, M & Tsai, LH 2022, 'APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes', Nature, vol. 611, no. 7937, pp. 769-779. https://doi.org/10.1038/s41586-022-05439-w

TY - JOUR

T1 - APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

AU - Blanchard, Joel W.

AU - Akay, Leyla Anne

AU - Davila-Velderrain, Jose

AU - von Maydell, Djuna

AU - Mathys, Hansruedi

AU - Davidson, Shawn M.

AU - Effenberger, Audrey

AU - Chen, Chih Yu

AU - Maner-Smith, Kristal

AU - Hajjar, Ihab

AU - Ortlund, Eric A.

AU - Bula, Michael

AU - Agbas, Emre

AU - Ng, Ayesha

AU - Jiang, Xueqiao

AU - Kahn, Martin

AU - Blanco-Duque, Cristina

AU - Lavoie, Nicolas

AU - Liu, Liwang

AU - Reyes, Ricardo

AU - Lin, Yuan Ta

AU - Ko, Tak

AU - R’Bibo, Lea

AU - Ralvenius, William T.

AU - Bennett, David A.

AU - Cam, Hugh P.

AU - Kellis, Manolis

AU - Tsai, Li Huei

PY - 2022/11/24

Y1 - 2022/11/24

N2 - 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.

AB - 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.

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ER -

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes

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