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.

中文翻译：

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APOE4 加剧 α-突触核蛋白病理学和相关毒性，与淀粉样蛋白无关。

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，主要通过驱动淀粉样蛋白-β 病理学。最近，APOE4还被发现是路易体痴呆（LBD）的遗传危险因素，LBD包括路易体痴呆和帕金森病痴呆。APOE4 如何增加 LBD 风险以及它是否对 α-突触核蛋白病理有直接影响尚不清楚。在这里，我们使用腺相关病毒基因在表达 APOE2、APOE3 或 APOE4 的人类 APOE 靶向替代小鼠中传递 α-突触核蛋白，生成了突触核蛋白病小鼠模型。我们发现，APOE4（而非 APOE2 或 APOE3）会增加 α-突触核蛋白病理，损害行为表现，加重神经元和突触损失，并增加 9 个月龄时的星形胶质细胞增生。表达 APOE4 的 α-突触核蛋白小鼠的转录组分析强调了脂质和能量代谢以及突触相关途径的改变。我们还观察到 APOE4 对具有 LBD 和最小淀粉样蛋白病理的死后大脑中 α-突触核蛋白病理的影响。我们的数据证明了 APOE4 在加剧 α-突触核蛋白病理学方面的致病作用，与淀粉样蛋白无关，为 APOE4 如何增加 LBD 风险提供了机制见解。