Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles.
Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles.
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DOI：
10.1002/ana.24145
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发表时间：
2014-06
影响因子：
11.2
通讯作者：
Pratico, Domenico
中科院分区：
文献类型：
--
作者：
Li, Jian-Guo;Chu, Jin;Barrero, Carlos;Merali, Salim;Pratico, Domenico
高水平的同型半胱氨酸(Hcy)是阿尔茨海默病(AD)的公认危险因素。然而，其中涉及的机制尚不清楚。以往的研究表明，在淀粉样前体蛋白转基因小鼠中，高同型半胱氨酸可增加脑内b-淀粉样蛋白(Ab)的水平，但目前尚无数据表明其对AD的其他主要病理特征如tau的影响。3xTg高同型半胱氨酸小鼠与正常同型半胱氨酸小鼠比较。神经细胞与同型半胱氨酸共同孵育和不与同型半胱氨酸共同孵育。饮食诱导的高Hcy导致3xTg小鼠整个AD样表型的恶化。特别是，我们发现，与对照组相比，高同型半胱氨酸的小鼠出现了显著的记忆和学习障碍，并有升高的抗体水平和沉积，这是通过激活γ-分泌酶途径来调节的。此外，同一组小鼠的tau不溶性部分及其在特定表位的磷酸化显著增加，这是由CDK5途径介导的。体外研究证实了这些观察结果，并提供证据表明，Hcy对抗体和tau的影响是相互独立的。综上所述，我们的发现表明，导致Hcy水平升高的饮食条件会导致AD表型的所有三个主要病理特征的恶化：记忆缺陷，以及Ab和tau神经病理。他们支持这样的概念，即这种饮食生活方式可以作为危险因素，并积极促进疾病的发展。
High level of homocysteine (Hcy) is a recognized risk factor for developing Alzheimer disease (AD). However, the mechanisms involved are unknown. Previously, it was shown that high Hcy increases brain b-amyloid (Ab) levels in amyloid precursor protein transgenic mice, but no data are available on the effect that it may have on the other main pathologic features of AD such as tau. 3xTg mice with diet-induced high Hcy were compared with mice having normal Hcy. Neuronal cells were incubated with and without Hcy. Diet-induced high Hcy resulted in an exacerbation of the entire AD-like phenotype of the 3xTg mice. In particular, we found that compared with controls, mice with high Hcy developed significant memory and learning deficits, and had elevated Ab levels and deposition, which was mediated by an activation of the γ-secretase pathway. In addition, the same mice had a significant increase in the insoluble fraction of tau and its phosphorylation at specific epitopes, which was mediated by the cdk5 pathway. In vitro studies confirmed these observations and provided evidence that the effects of Hcy on Ab and tau are independent from each other. Taken together, our findings demonstrate that a dietary condition that leads to an elevation of Hcy levels results in an exacerbation of all 3 major pathological features of the AD phenotype: memory deficits, and Ab and tau neuropathology. They support the concept that this dietary lifestyle can act as a risk factor and actively contribute to the development of the disease.
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