APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Neurons
Heterozygote Aging Multidisciplinary Gene Expression Profiling Apolipoprotein E4 Induced Pluripotent Stem Cells Brain Biological Transport Nerve Fibers Myelinated Article Mice Oligodendroglia Cholesterol Alzheimer Disease Memory Animals Humans Homeostasis Autopsy Single-Cell Analysis Myelin Sheath |
| Zdroj: | Nature |
| Popis: | APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD)(1–3). Yet, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for APOE4 and other AD risk factors(4–8). To gain more comprehensive insight into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4-carriers compared to non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with APOE’s biological function(2–6), APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, iPSC-derived cells, and targeted-replacement mice, we further discovered that cholesterol is aberrantly deposited in oligodendrocytes, myelinating cells responsible for insulating and promoting electrical activity of neurons. We discovered 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. Our study delivers a single-cell atlas detailing the transcriptional effects of APOE4 on the aged human brain and establishes a functional link between APOE4, cholesterol, myelination, and memory; opening paths to new therapeutic opportunities for AD. |
| Databáze: | OpenAIRE |
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