SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10.
SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10.
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DOI：
10.1016/j.cell.2010.06.020
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发表时间：
2010-07-23
期刊：
影响因子：
64.5
通讯作者：
Guarente L
中科院分区：
文献类型：
--
作者：
Donmez G;Wang D;Cohen DE;Guarente L
阿尔茨海默病(AD)的一个特征是Aβ1-40和1-42肽斑块的聚集，这是β和γ-分泌酶对APP顺序切割的结果。Aβ多肽的产生是通过α和γ-分泌酶交替切割APP来避免的。在这里，我们证明了在AD小鼠模型中，β-淀粉样蛋白和斑块的产生通过在脑中过度表达依赖于NAD的脱乙酰酶SIRT1而减少，而通过在脑中敲除SIRT1而增加。SIRT1直接激活编码α分泌酶的基因ADAM10的转录。SIRT1去乙酰化并共激活维甲酸受体β，这是一种已知的ADAM10转录调节因子。由SIRT1激活的ADAM10还诱导Notch通路，该通路被认为是修复大脑中神经元损伤的途径。我们的发现表明，激活SIRT1是对抗AD，或许还有其他神经退行性疾病的可行策略。
A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Aβ 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the β and γ-secretases. The production of Aβ peptides is avoided by alternate cleavage of APP by the α and γ-secretases. Here we show that production of β-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the α-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor β, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD, and perhaps other neurodegenerative diseases.
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