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

• Published in: Science translational medicine Vol. 12; no. 529
• Main Authors: Zhao, Na, Attrebi, Olivia N, Ren, Yingxue, Qiao, Wenhui, Sonustun, Berkiye, Martens, Yuka A, Meneses, Axel D, Li, Fuyao, Shue, Francis, Zheng, Jiaying, Van Ingelgom, Alexandra J, Davis, Mary D, Kurti, Aishe, Knight, Joshua A, Linares, Cynthia, Chen, Yixing, Delenclos, Marion, Liu, Chia-Chen, Fryer, John D, Asmann, Yan W, McLean, Pamela J, Dickson, Dennis W, Ross, Owen A, Bu, Guojun
• Format: Journal Article
• Language: English
• Published: United States 05.02.2020
• Subjects: alpha-Synuclein; Amyloid beta-Peptides; Animals; Apolipoprotein E4 - genetics; Lewy Body Disease - genetics; Mice; Mice, Knockout, ApoE; Synucleinopathies - genetics
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aay1809

The apolipoprotein E ( ) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by driving amyloid-β pathology. Recently, 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 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 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 increases the risk of LBD.