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Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist
Neuron ( IF 14.7 ) Pub Date : 2023-11-22 , DOI: 10.1016/j.neuron.2023.10.023
Alexandra Litvinchuk 1 , Jung H Suh 2 , Jing L Guo 2 , Karin Lin 2 , Sonnet S Davis 2 , Nga Bien-Ly 2 , Eric Tycksen 3 , G Travis Tabor 1 , Javier Remolina Serrano 1 , Melissa Manis 1 , Xin Bao 1 , Choonghee Lee 1 , Megan Bosch 1 , Enmanuel J Perez 1 , Carla M Yuede 1 , Anil G Cashikar 4 , Jason D Ulrich 1 , Gilbert Di Paolo 2 , David M Holtzman 1
Affiliation  

Apolipoprotein E () is a strong genetic risk factor for late-onset Alzheimer’s disease (LOAD). increases and decreases risk relative to . 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.

中文翻译:


使用 LXR 激动剂改善 Tau 和 ApoE4 连接的胶质脂质积累和神经变性



载脂蛋白 E () 是晚发性阿尔茨海默病 (LOAD) 的强遗传危险因素。相对于 ,风险增加和减少。在 tau 蛋白病的 P301S 小鼠模型中,与 ApoE3 或不存在 ApoE 相比,ApoE4 增加了 tau 病理和神经退化。然而,ApoE 亚型和脂质代谢在促进 tau 介导的变性中的作用尚不清楚。我们证明在 P301S tau 小鼠中,ApoE4 强烈促进神经胶质脂质积累以及胆固醇代谢和溶酶体功能的扰动。通过 LXR 激动剂或 Abca1 过表达增加神经胶质细胞中的脂质外排强烈减轻了 P301S/ApoE4 小鼠的 tau 病理和神经退行性变。我们还证明了反应性星形胶质细胞和小胶质细胞的减少,以及响应 LXR 激活的 tau 病小鼠神经胶质细胞中胆固醇生物合成和代谢的变化。这些数据表明,促进神经胶质脂质外排可能作为改善 tau 和 ApoE4 相关神经变性的治疗方法。
更新日期:2023-11-22
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