Dionísio Pedro A, Amaral Joana D, Ribeiro Maria F, Lo Adrian C, D'Hooge Rudi, Rodrigues Cecília M P
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Neurobiol Aging. 2015 Jan;36(1):228-40. doi: 10.1016/j.neurobiolaging.2014.08.034. Epub 2014 Sep 28.
Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ₁₋₄₀ and Aβ₁₋₄₂ levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为细胞外淀粉样β（Aβ）肽的积累、神经元内tau蛋白的过度磷酸化以及慢性神经炎症。牛磺熊去氧胆酸（TUDCA）是一种内源性抗凋亡胆汁酸，在AD的多个实验模型中具有强大的神经保护特性。我们之前报道了在APP/PS1双转基因小鼠淀粉样斑块沉积之前进行TUDCA治疗的疗效。在本研究中，我们评估了在淀粉样病理发生后给予TUDCA的保护作用。对7月龄的APP/PS1转基因小鼠每3天腹腔注射一次TUDCA（500 mg/kg），持续3个月。TUDCA治疗显著减轻了大脑中的Aβ沉积，同时Aβ₁₋₄₀和Aβ₁₋₄₂水平降低。淀粉样前体蛋白的淀粉样生成过程也减少了，这表明TUDCA干扰了Aβ的产生。此外，TUDCA消除了GSK3β的过度活性，而GSK3β的过度活性与tau蛋白过度磷酸化和胶质细胞活化密切相关。这种作用可能依赖于上游激酶Akt的特异性激活。最后，TUDCA治疗减少了胶质细胞活化，降低了促炎细胞因子信使RNA的表达，同时部分挽救了突触丢失。总体而言，我们的结果表明，TUDCA不仅是预防AD的一种有前景的治疗策略，而且在疾病发作后治疗AD方面也具有潜力。
