BACKGROUND The neurodegenerative disorder Alzheimer's disease is caused by the accumulation of toxic aggregates of β-amyloid in the human brain. On the one hand, hyperhomocysteinemia has been shown to be a risk factor for cognitive decline in Alzheimer's disease. On the other hand, betaine has been demonstrated to attenuate Alzheimer-like pathological changes induced by homocysteine. It is reasonable to conclude that this is due to triggering the remethylation pathway mediated by betaine-homocysteine-methyltransferase. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, to test whether betaine is able to reduce β-amyloid-induced paralysis in C. elegans. This model expresses human β-amyloid 1-42 under control of a muscle-specific promoter that leads to progressive, age-dependent paralysis in the nematodes. RESULTS Betaine at a concentration of 100 μM was able to reduce homocysteine levels in the presence and absence of 1 mM homocysteine. Simultaneously, betaine both reduced normal paralysis rates in the absence of homocysteine and increased paralysis rates triggered by addition of homocysteine. Knockdown of cystathionine-β-synthase using RNA interference both increased homocysteine levels and paralysis. Additionally, it prevented the reducing effects of betaine on homocysteine levels and paralysis. CONCLUSION Our studies show that betaine is able to reduce homocysteine levels and β-amyloid-induced toxicity in a C. elegans model for Alzheimer's disease. This effect is independent of the remethylation pathway but requires the transsulfuration pathway mediated by cystathionine-β-synthase.

中文翻译：

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甜菜碱通过激活秀丽隐杆线虫阿尔茨海默病模型中的胱硫醚-β-合酶来减少 β-淀粉样蛋白诱导的麻痹。


背景技术神经退行性疾病阿尔茨海默氏病是由人脑中有毒的β-淀粉样蛋白聚集物的积累引起的。一方面，高同型半胱氨酸血症已被证明是阿尔茨海默病认知能力下降的危险因素。另一方面，甜菜碱已被证明可以减轻同型半胱氨酸引起的阿尔茨海默样病理变化。可以合理地得出结论，这是由于触发了甜菜碱-同型半胱氨酸-甲基转移酶介导的再甲基化途径。在本研究中，我们使用转基因秀丽隐杆线虫菌株CL2006来测试甜菜碱是否能够减少β-淀粉样蛋白诱导的秀丽隐杆线虫麻痹。该模型在肌肉特异性启动子的控制下表达人类 β-淀粉样蛋白 1-42，导致线虫进行性、年龄依赖性麻痹。结果 在存在和不存在 1 mM 同型半胱氨酸的情况下，浓度为 100 μM 的甜菜碱能够降低同型半胱氨酸水平。同时，甜菜碱既降低了不存在同型半胱氨酸的情况下的正常麻痹率，又增加了添加同型半胱氨酸引发的麻痹率。使用 RNA 干扰敲低胱硫醚-β-合酶会增加同型半胱氨酸水平并导致麻痹。此外，它还可以防止甜菜碱对同型半胱氨酸水平的降低作用和麻痹作用。结论 我们的研究表明，甜菜碱能够降低阿尔茨海默氏病模型中的同型半胱氨酸水平和 β-淀粉样蛋白诱导的毒性。这种作用与再甲基化途径无关，但需要由胱硫醚-β-合酶介导的转硫途径。