Litvinchuk Alexandra, Suh Jung H, Guo Jing L, Lin Karin, Davis Sonnet S, Bien-Ly Nga, Tycksen Eric, Tabor G Travis, Remolina Serrano Javier, Manis Melissa, Bao Xin, Lee Choonghee, Bosch Megan, Perez Enmanuel J, Yuede Carla M, Cashikar Anil G, Ulrich Jason D, Di Paolo Gilbert, Holtzman David M
Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63108, USA.
Denali Therapeutics Inc., South San Francisco, CA 94080, USA.
Neuron. 2024 Feb 7;112(3):384-403.e8. doi: 10.1016/j.neuron.2023.10.023. Epub 2023 Nov 22.
Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as 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 may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
载脂蛋白E（APOE）是晚发性阿尔茨海默病（LOAD）的一个强大遗传风险因素。与APOE3相比，APOE4会增加风险，而APOE2会降低风险。在tau蛋白病的P301S小鼠模型中，与APOE3或缺乏APOE相比，ApoE4会增加tau病理变化和神经退行性变。然而，ApoE亚型和脂质代谢在导致tau介导的神经退行性变中的作用尚不清楚。我们证明，在P301S tau小鼠中，ApoE4强烈促进神经胶质细胞脂质积累以及胆固醇代谢和溶酶体功能的紊乱。通过LXR激动剂或Abca1过表达增加神经胶质细胞中的脂质流出，可强烈减轻P301S/ApoE4小鼠的tau病理变化和神经退行性变。我们还证明，反应性星形胶质细胞和小胶质细胞减少，以及tau蛋白病小鼠神经胶质细胞中胆固醇生物合成和代谢因LXR激活而发生变化。这些数据表明，促进神经胶质细胞脂质流出可能是改善tau和ApoE4相关神经退行性变的一种治疗方法。
