Laboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium.
Neurobiol Dis. 2013 Feb;50:21-9. doi: 10.1016/j.nbd.2012.09.003. Epub 2012 Sep 10.
Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aβ(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aβ plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aβ(1-42) production. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是细胞外含有 Aβ（1-42）的斑块和细胞内含有过度磷酸化 tau 蛋白的神经原纤维缠结（NFT）。随着这些标志物影响海马体和前额叶皮层等高度参与记忆的区域，记忆缺陷和认知障碍逐渐开始出现。在 Aβ 斑块和 NFT 附近表达水平较高的结缔组织生长因子（CTGF）被发现会影响 γ-分泌酶活性，这是 Aβ（1-42）产生的分子关键。牛磺熊脱氧胆酸（TUDCA）是一种内源性胆汁酸，可下调肝细胞中的 CTGF 表达，并且已被证明在神经退行性模型中具有治疗功效。为了研究 TUDCA 的可能体内治疗效果，我们向 APP/PS1 小鼠提供了含有 0.4% TUDCA 的补充食物，APP/PS1 小鼠是一种成熟的 AD 小鼠模型。6 个月的 TUDCA 补充预防了在 8 个月大的 APP/PS1 小鼠中观察到的空间、识别和情景记忆缺陷。此外，TUDCA 补充的 APP/PS1 小鼠显示出海马体和前额叶皮层中淀粉样沉积减少。TUDCA 补充的这些效果表明了阿尔茨海默病治疗的一种新的机制途径。
