APOE4 Impairs Myelination Via Cholesterol Dysregulation in Oligodendrocytes

Overview

Journal Nature

Specialty Science

Date 2022 Nov 17

PMID 36385529

Authors

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 RBibo

William T Ralvenius

David A Bennett

Hugh P Cam

Manolis Kellis

Li-Huei Tsai

Affiliations

Soon will be listed here.

Abstract

APOE4 is the strongest genetic risk factor for Alzheimer's disease. 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. 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, 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.

Citing Articles

A single-cell atlas to map sex-specific gene-expression changes in blood upon neurodegeneration.

Grandke F, Fehlmann T, Kern F, Gate D, Wolff T, Leventhal O Nat Commun. 2025; 16(1):1965.

PMID: 40000636 PMC: 11862118. DOI: 10.1038/s41467-025-56833-7.

pTDP-43 levels correlate with cell type-specific molecular alterations in the prefrontal cortex of ALS/FTD patients.

Wang H, Xiang J, Yuan C, Veire A, Gendron T, Murray M Proc Natl Acad Sci U S A. 2025; 122(9):e2419818122.

PMID: 39999167 PMC: 11892677. DOI: 10.1073/pnas.2419818122.

From Genetics to Neuroinflammation: The Impact of ApoE4 on Microglial Function in Alzheimer's Disease.

Dias D, Portugal C, Relvas J, Socodato R Cells. 2025; 14(4).

PMID: 39996715 PMC: 11853365. DOI: 10.3390/cells14040243.

Lipid metabolism, remodelling and intercellular transfer in the CNS.

Vanherle S, Loix M, Miron V, Hendriks J, Bogie J Nat Rev Neurosci. 2025; .

PMID: 39972160 DOI: 10.1038/s41583-025-00908-3.

Swimming exercise induces redox-lipid crosstalk to ameliorate osteoarthritis progression.

Wu Y, Hou M, Deng Y, Xia X, Liu Y, Yu J Redox Biol. 2025; 81:103535.

PMID: 39952199 PMC: 11875157. DOI: 10.1016/j.redox.2025.103535.

References

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G . Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993; 261(5123):921-3. DOI: 10.1126/science.8346443. View

Strittmatter W, Saunders A, Schmechel D, Pericak-Vance M, Enghild J, Salvesen G . Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90(5):1977-81. PMC: 46003. DOI: 10.1073/pnas.90.5.1977. View

Liu C, Zhao N, Fu Y, Wang N, Linares C, Tsai C . ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron. 2017; 96(5):1024-1032.e3. PMC: 5948105. DOI: 10.1016/j.neuron.2017.11.013. View

Shi Y, Yamada K, Liddelow S, Smith S, Zhao L, Luo W . ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017; 549(7673):523-527. PMC: 5641217. DOI: 10.1038/nature24016. View

Castellano J, Kim J, Stewart F, Jiang H, DeMattos R, Patterson B . Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011; 3(89):89ra57. PMC: 3192364. DOI: 10.1126/scitranslmed.3002156. View

Yamazaki Y, Zhao N, Caulfield T, Liu C, Bu G . Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019; 15(9):501-518. PMC: 7055192. DOI: 10.1038/s41582-019-0228-7. View

Crean S, Ward A, Mercaldi C, Collins J, Cook M, Baker N . Apolipoprotein E ε4 prevalence in Alzheimer's disease patients varies across global populations: a systematic literature review and meta-analysis. Dement Geriatr Cogn Disord. 2010; 31(1):20-30. DOI: 10.1159/000321984. View

Foley P . Lipids in Alzheimer's disease: A century-old story. Biochim Biophys Acta. 2010; 1801(8):750-3. DOI: 10.1016/j.bbalip.2010.05.004. View

10.

Tcw J, Qian L, Pipalia N, Chao M, Liang S, Shi Y . Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. 2022; 185(13):2213-2233.e25. PMC: 9340815. DOI: 10.1016/j.cell.2022.05.017. View

11.

Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young J . Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019; 570(7761):332-337. PMC: 6865822. DOI: 10.1038/s41586-019-1195-2. View

12.

Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley R, Huang Y . Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci. 2006; 26(19):4985-94. PMC: 6674234. DOI: 10.1523/JNEUROSCI.5476-05.2006. View

13.

Lin Y, Seo J, Gao F, Feldman H, Wen H, Penney J . APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018; 98(6):1141-1154.e7. PMC: 6023751. DOI: 10.1016/j.neuron.2018.05.008. View

14.

Bennett D, Buchman A, Boyle P, Barnes L, Wilson R, Schneider J . Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis. 2018; 64(s1):S161-S189. PMC: 6380522. DOI: 10.3233/JAD-179939. View

15.

Wang D, Liu S, Warrell J, Won H, Shi X, Navarro F . Comprehensive functional genomic resource and integrative model for the human brain. Science. 2018; 362(6420). PMC: 6413328. DOI: 10.1126/science.aat8464. View

16.

Huang Y, Zhou B, Wernig M, Sudhof T . ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell. 2017; 168(3):427-441.e21. PMC: 5310835. DOI: 10.1016/j.cell.2016.12.044. View

17.

Zalocusky K, Najm R, Taubes A, Hao Y, Yoon S, Koutsodendris N . Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease. Nat Neurosci. 2021; 24(6):786-798. PMC: 9145692. DOI: 10.1038/s41593-021-00851-3. View

18.

Thadathil N, Delotterie D, Xiao J, Hori R, McDonald M, Khan M . DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains. Mol Neurobiol. 2020; 58(1):118-131. DOI: 10.1007/s12035-020-02109-8. View

19.

Ye S, Huang Y, Mullendorff K, Dong L, Giedt G, Meng E . Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proc Natl Acad Sci U S A. 2005; 102(51):18700-5. PMC: 1311738. DOI: 10.1073/pnas.0508693102. View

20.

Hatters D, Peters-Libeu C, Weisgraber K . Apolipoprotein E structure: insights into function. Trends Biochem Sci. 2006; 31(8):445-54. DOI: 10.1016/j.tibs.2006.06.008. View