Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
Brain Res Bull. 2022 Jan;178:57-68. doi: 10.1016/j.brainresbull.2021.11.004. Epub 2021 Nov 18.
Alzheimer's disease (AD) is the major cause of neurodegeneration worldwide and is characterized by the accumulation of amyloid beta (Aβ) in the brain, which is associated with neuronal loss and cognitive impairment. Liver X receptor (LXR), a critical nuclear receptor, and major regulator in lipid metabolism and inflammation, is suggested to play a protective role against the mitochondrial dysfunction noted in AD. In our study, our established 3D gelatin scaffold model and a well characterized in vivo (APP/PS1) murine model of AD were used to directly investigate the molecular, biochemical and behavioral effects of neuronal stem cell exposure to Aβ to improve understanding of the in vivo etiology of AD. Herein, human neural stem cells (hNSCs) in our 3D model were exposed to Aβ, and had significantly decreased cell viability, which correlated with decreased mRNA and protein expression of LXR, Bcl-2, CREB, PGC1α, NRF-1, and Tfam, and increased caspase 3 and 9 activities. Cotreatment with a synthetic agonist of LXR (TO901317) significantly abrogated these Aβ-mediated effects in hNSCs. Moreover, TO901317 cotreatment both significantly rescues hNSCs from Aβ-mediated decreases in ATP levels and mitochondrial mass, and significantly restores Aβ-induced fragmented mitochondria to almost normal morphology. TO901317 cotreatment also decreases tau aggregates in Aβ-treated hNSCs. Importantly, TO901317 treatment significantly alleviates the impairment of memory, decreases Aβ aggregates and increases proteasome activity in APP/PS1 mice; whereas, these effects were blocked by cotreatment with an LXR antagonist (GSK2033). Together, these novel results improve our mechanistic understanding of the central role of LXR in Aβ-mediated hNSC dysfunction. We also provide preclinical data unveiling the protective effects of using an LXR-dependent agonist, TO901317, to block the toxicity observed in Aβ-exposed hNSCs, which may guide future treatment strategies to slow or prevent neurodegeneration in some AD patients.
阿尔茨海默病（AD）是全球神经退行性疾病的主要原因，其特征是大脑中β淀粉样蛋白（Aβ）的积累，这与神经元丧失和认知障碍有关。肝 X 受体（LXR）是一种关键的核受体，也是脂质代谢和炎症的主要调节剂，被认为对 AD 中观察到的线粒体功能障碍具有保护作用。在我们的研究中，我们使用了已建立的 3D 明胶支架模型和经过充分表征的 AD 体内（APP/PS1）小鼠模型，直接研究神经元干细胞暴露于 Aβ的分子、生化和行为影响，以更好地理解 AD 的体内病因。在此，我们的 3D 模型中的人神经干细胞（hNSC）暴露于 Aβ后，细胞活力显著降低，这与 LXR、Bcl-2、CREB、PGC1α、NRF-1 和 Tfam 的 mRNA 和蛋白表达降低以及 caspase 3 和 9 活性增加有关。用 LXR 的合成激动剂（TO901317）共同处理显著消除了这些 hNSC 中 Aβ介导的作用。此外，TO901317 共同处理可显著挽救 hNSC 免受 Aβ介导的 ATP 水平和线粒体质量降低的影响，并使 Aβ诱导的碎片化线粒体恢复到几乎正常的形态。TO901317 共同处理还可减少 Aβ 处理的 hNSC 中的 tau 聚集体。重要的是，TO901317 治疗可显著减轻 APP/PS1 小鼠记忆损伤，减少 Aβ 聚集体并增加蛋白酶体活性；而用 LXR 拮抗剂（GSK2033）共同处理则阻断了这些作用。总之，这些新结果提高了我们对 LXR 在 Aβ 介导的 hNSC 功能障碍中的核心作用的机制理解。我们还提供了临床前数据，揭示了使用 LXR 依赖性激动剂 TO901317 来阻断 Aβ 暴露的 hNSC 中观察到的毒性的保护作用，这可能为某些 AD 患者的减缓或预防神经退行性变的未来治疗策略提供指导。
