Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease.
Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease.
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DOI：
10.1523/jneurosci.2481-08.2008
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发表时间：
2008-12-31
期刊：
影响因子：
--
通讯作者：
Südhof TC
中科院分区：
文献类型：
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作者：
Ho A;Liu X;Südhof TC
Mint/X11是与淀粉样蛋白-β前体蛋白（APP）结合的神经元衔接蛋白。先前的研究表明，Mint/X11蛋白影响APP切割，并影响阿尔茨海默病中致病性Aβ肽的产生;然而，Mint/X11与APP结合的生物学意义及其在Aβ产生中的可能作用仍不清楚。在这里，我们将条件性和组成性Mint 1、Mint 2和Mint 3基因敲除小鼠与阿尔茨海默病过度产生人类Aβ肽的转基因小鼠模型杂交。我们发现，删除所有三种单独的Mint蛋白会延迟淀粉样斑块数量和Aβ40-和Aβ42-水平的年龄依赖性产生，其中Mint 2的缺失影响最大。在培养的神经元中急性条件性缺失所有三种Mint通过减少β-裂解抑制APP C-末端片段的积累和胞外域APP的分泌，但不损害随后的γ-裂解。这些结果表明，三种Mint/X11蛋白通过一种新的机制调节Aβ的产生，这可能对改变阿尔茨海默病中APP裂解的治疗方法产生影响。
Mints/X11s are neuronal adaptor proteins that bind to amyloid-β precursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage, and affect production of pathogenic Aβ-peptides in Alzheimer’s disease; however, the biological significance of Mint/X11-binding to APP and their possible role in Aβ-production remain unclear. Here, we crossed conditional and constitutive Mint1, Mint2, and Mint3 knockout mice with transgenic mouse models of Alzheimer’s disease overproducing human Aβ-peptides. We show that deletion of all three individual Mint proteins delays the age-dependent production of amyloid plaque numbers and Aβ40- and Aβ42-levels with loss of Mint2 having the largest effect. Acute conditional deletion of all three Mints in cultured neurons suppresses the accumulation of APP C-terminal fragments and the secretion of ectodomain APP by decreasing β-cleavage, but does not impair subsequent γ-cleavage. These results suggest that the three Mint/X11 proteins regulate Aβ-production by a novel mechanism that may have implications for therapeutic approaches to altering APP cleavage in Alzheimer’s disease.