美国研究人员7月11日公布研究成果称，他们在动物实验中发现，一种与长寿相关的基因似乎也与实验鼠记忆及学习能力密切相关。

这一基因名为SIRT1，在此前的研究中，它编码的蛋白酶Sirtuin1已被证明可以通过限制热量消耗来延缓啮齿类动物的衰老进程。

在最新研究中，由麻省理工学院大脑和认知科学系教授蔡立慧领导的研究小组利用转基因工程剔除了实验鼠的SIRT1基因。在与正常实验鼠对比时，研究人员发现，体内缺乏SIRT1基因的实验鼠大脑海马区对电流刺激反应很差，而海马区是大脑学习和长期记忆的关键区域，在阿尔茨海默氏症患者中，海马区是首先受损的大脑区域之一。研究人员还发现，转基因实验鼠神经元密度也有所下降，后者是衡量大脑活性的重要指标。此外，它们在记忆测试中，对新旧物体的区分也不及正常实验鼠。

蔡立慧说：“这一结果显示了SIRT1在大脑中扮演的多重作用，同时表明它在治疗认知障碍疾病时具有作为靶向的潜力。”

蔡立慧表示，这一成果仅是初步性的，现在利用该成果设计临床试验为时尚早，但它的确为开发治疗阿尔茨海默氏症及其他神经退行性疾病的药物提供了方向。

这项研究成果11日发表在英国《自然》（Nature）杂志上。

原文出处：

Nature doi:10.1038/nature09271

A novel pathway regulates memory and plasticity via SIRT1 and miR-134
Jun Gao1,2,3,5, Wen-Yuan Wang1,2,5, Ying-Wei Mao1,2, Johannes Gr?ff1,4, Ji-Song Guan1,2, Ling Pan1,2, Gloria Mak1,2, Dohoon Kim1,2,6, Susan C. Su1,2 & Li-Huei Tsai1,2,4

Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts 02142, USA
These authors contributed equally to this work.
Present address: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
 
The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1, 2. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.