Paul F. Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2010 Jul 23;142(2):320-32. doi: 10.1016/j.cell.2010.06.020.
A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Abeta 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the beta and gamma-secretases. The production of Abeta peptides is avoided by alternate cleavage of APP by the alpha and gamma-secretases. Here we show that production of beta-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 alpha-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor beta, 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.
阿尔茨海默病（AD）的一个标志是 Abeta 1-40 和 1-42 肽的斑块积累，这是由 APP 通过β和γ-分泌酶的顺序切割产生的。APP 通过α和γ-分泌酶的交替切割可以避免 Abeta 肽的产生。在这里，我们表明，通过在大脑中过度表达 NAD 依赖性去乙酰化酶 SIRT1，AD 小鼠模型中的β-淀粉样蛋白和斑块的产生减少，而通过在大脑中敲除 SIRT1 则增加。SIRT1 直接激活编码α-分泌酶 ADAM10 的基因的转录。SIRT1 去乙酰化并共激活视黄酸受体β，视黄酸受体β是 ADAM10 转录的已知调节剂。SIRT1 通过 ADAM10 的激活还诱导 Notch 途径，该途径已知可修复大脑中的神经元损伤。我们的发现表明，SIRT1 的激活是对抗 AD 甚至其他神经退行性疾病的可行策略。
