Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia

TCW, J.; Liang, S. A.; Qian, L.; Pipalia, N. H.; Chao, M. J.; Shi, Y.; Bertelsen, S. E.; Kapoor, M.; Marcora, E.; Sikora, E.; Holtzman, D. M.; Maxfield, F. R.; Zhang, B.; Wang, M.; Poon, W. W.; Goate, A. M.

doi:10.1101/713362

bioRxiv · 10.1101/713362

Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia

TCW, J.·Liang, S. A.·Qian, L.·Pipalia, N. H.·Chao, M. J.·Shi, Y.·Bertelsen, S. E.·Kapoor, M.·Marcora, E.·Sikora, E.·Holtzman, D. M.·Maxfield, F. R.·Zhang, B.·Wang, M.·Poon, W. W.·Goate, A. M.

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Abstract

Apolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for Alzheimers disease (AD). Although its association with AD is well-established, the impact of APOE {varepsilon}4 on human brain cell function remains unclear. Here we investigated the effects of APOE {varepsilon}4 on several brain cell types derived from human induced pluripotent stem cells and human APOE targeted replacement mice. Gene set enrichment and pathway analyses of whole transcriptome profiles showed that APOE {varepsilon}4 is associated with dysregulation of cholesterol homeostasis in human but not mouse astrocytes and microglia. Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE {varepsilon}4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell-type deconvoluted transcriptomic data from APOE {varepsilon}4 glia and AD post-mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE {varepsilon}4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE {varepsilon}4 glia also secrete higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation. Thus, APOE {varepsilon}4 induces human glia-specific dysregulation that may initiate AD risk.

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TCW, J., Liang, S. A., Qian, L., Pipalia, N. H., Chao, M. J., Shi, Y., Bertelsen, S. E., Kapoor, M., Marcora, E., Sikora, E., Holtzman, D. M., Maxfield, F. R., Zhang, B., Wang, M., Poon, W. W., Goate, A. M.. 2019-07-25. Cholesterol and matrisome pathways dysregulated in human APOE ε4 glia. https://doi.org/10.1101/713362

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