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
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
Sci Transl Med. 2020 Feb 5;12(529). 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.
载脂蛋白E（APOE）ε4等位基因是晚发性阿尔茨海默病最强的遗传风险因素，主要通过驱动β淀粉样蛋白病变起作用。最近，APOE也被发现是路易体痴呆（LBD）的遗传风险因素，LBD包括路易体痴呆和帕金森病痴呆。APOE如何驱动LBD风险以及它是否对α-突触核蛋白病变有直接影响尚不清楚。在此，我们使用腺相关病毒基因递送α-突触核蛋白，在表达APOE2、APOE3或APOE4的人APOE靶向替代小鼠中生成了突触核蛋白病小鼠模型。我们发现，在9个月大时，APOE4而非APOE2或APOE3增加了α-突触核蛋白病变，损害了行为表现，加剧了神经元和突触损失，并增加了星形胶质细胞增生。在表达APOE4的α-突触核蛋白小鼠中的转录组分析突出了脂质和能量代谢以及突触相关途径的改变。我们还在具有LBD且淀粉样蛋白病变轻微的人类尸检大脑中观察到APOE对α-突触核蛋白病变的影响。我们的数据证明了APOE4在加重α-突触核蛋白病变中独立于淀粉样蛋白的致病作用，为APOE如何增加LBD风险提供了机制性见解。
