Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist

Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration. Overall design: RNAseq was performed on hippocampal tissue of 9.5 month old APOE4-KI mice or PS19/APOE4-KI mice treated with control or GW3965 diet from 6-9.5.months

载脂蛋白E（Apolipoprotein E, APOE）是晚发型阿尔茨海默病（AD）的强遗传风险因子，其中APOE4相较于APOE3会升高患病风险，而APOE2则可降低该风险。在tau蛋白病P301S小鼠模型中，与ApoE3或无ApoE的组别相比，ApoE4可加重tau病理与神经退行性变。但目前学界尚未明确ApoE亚型在tau病变背景下对脂质代谢的调控作用。
本研究采用靶向脂质组学（targeted lipidomics）结合组织学分析手段，证实于P301S tau小鼠中，ApoE4可显著促进神经胶质脂质蓄积，并伴随胆固醇代谢与溶酶体功能的显著紊乱。通过给予肝X受体（liver X receptor, LXR）激动剂GW3965以增强神经胶质脂质外流，可在体外减少原代E4型小胶质细胞内的脂滴蓄积；而GW3965干预或Abca1过表达，可显著减轻P301S/ApoE4小鼠的tau病理、神经退行性变及突触丢失。
通过免疫染色、整体转录组测序与单细胞核RNA测序（single nuclear RNA sequencing, snRNA-seq），本研究证实：在LXR激活的响应下，tau病变小鼠神经胶质中的反应性星形胶质细胞与小胶质细胞比例降低，同时胆固醇生物合成与代谢通路发生显著改变。
上述数据表明，通过Abca1介导促进神经胶质脂质外流，或可作为改善tau及APOE4相关神经退行性变的潜在治疗策略。
总体实验设计：对9.5月龄的APOE4敲入小鼠或PS19/APOE4-KI敲入小鼠开展RNA测序，上述小鼠自6月龄至9.5月龄期间分别饲喂对照饲料或GW3965干预饲料。