APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

Na Zhao, Olivia N. Attrebi, Yingxue Ren, Wenhui Qiao, Berkiye Sonustun, Yuka A. Martens, Axel D. Meneses, Fuyao Li, Francis Shue, Jiaying Zheng, Alexandra J. van Ingelgom, Mary D. Davis, Aishe Kurti, Joshua A. Knight, Cynthia Linares, Yixing Chen, Marion Delenclos, Chia Chen Liu, John D. Fryer, Yan W. AsmannPamela J. McLean, Dennis W. Dickson, Owen A. Ross, Guojun Bu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.

Original languageEnglish (US)
Article numbereaay1809
JournalScience translational medicine
Volume12
Issue number529
DOIs
StatePublished - Feb 5 2020

ASJC Scopus subject areas

  • Medicine(all)

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    Zhao, N., Attrebi, O. N., Ren, Y., Qiao, W., Sonustun, B., Martens, Y. A., Meneses, A. D., Li, F., Shue, F., Zheng, J., van Ingelgom, A. J., Davis, M. D., Kurti, A., Knight, J. A., Linares, C., Chen, Y., Delenclos, M., Liu, C. C., Fryer, J. D., ... Bu, G. (2020). APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Science translational medicine, 12(529), [eaay1809]. https://doi.org/10.1126/scitranslmed.aay1809