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

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.

• Authors: 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 Asmann, Pamela J McLean, Dennis W Dickson, Owen A Ross, Guojun Bu
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 529 (02 05 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32024798 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Amyloid beta-Peptides
• Apolipoprotein E4
• alpha-Synuclein

Topics

• Amyloid beta-Peptides
• Animals
• Apolipoprotein E4 (genetics)
• Lewy Body Disease (genetics)
• Mice
• Mice, Knockout, ApoE
• Synucleinopathies (genetics)
• alpha-Synuclein