Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.

中文翻译：

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APOE3-Jacksonville (V236E) 变体可降低自我聚集和痴呆风险

载脂蛋白 E ( APOE ) 基因变异已被证明可以降低阿尔茨海默病 (AD) 的风险。我们之前发现了一种APOE3变体 ( APOE 3-V236E)，命名为APOE3 -Jacksonville ( APOE3 -Jac)，它与健康的大脑老化以及降低 AD 和路易体痴呆 (DLB) 的风险相关。在此，我们解决了 APOE3-Jac 在人脑以及细胞和生化检测中减少 APOE 聚集并增强其脂化的功能机制。与 APOE3 相比，星形胶质细胞中 APOE3-Jac 的表达会增加大脑中几类脂质，包括磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酸和脑硫脂，对突触功能至关重要。表达 APOE3-Jac 的小鼠可以减少淀粉样蛋白病理、斑块相关的免疫反应和神经炎性营养不良。V236E 取代也足以减少 APOE4 的聚集，其基因等位基因是 AD 和 DLB 的主要遗传风险因素。这些发现表明，针对 APOE 聚集可能是治疗 AD 和 DLB 个体亚组的有效策略。