Sirtuin3 介导的神经适应性反应在间断禁食延缓阿尔茨海默病中的作用

Intermittent Fasting (IF) has been reported to delay onset and slow the progression of Alzheimer’s Disease (AD) in animal models. One speculative mechanism of action of intermittent fasting is that it may induce mild energetic and metabolic stress, which triggers adaptive cellular stress responses, and then result in an enhanced ability to cope with more severe stress and counteract disease processes. Nevertheless, the exact mechanism is unclear. We have previously reported that mitochondrial Sirtuin3 (SIRT3)mediates the adaptive responses of neurons to excitatory and oxidative stress. Moreover, excitotoxicity and oxidative stress are important pathogenesis of AD. Taken together, does the adaptive response of IF on Alzheimer's disease take through the role of SIRT3? Our previous experiments confirmed that long-term intermittent fasting upregulates the expression of SIRT3 protein, and using gene knockout mice, we found that SIRT3 mediates intermittent fasting-induced adaptation of brain to excitatory stimulation. Therefore, in the future, by means of transgenic animal hybridization, behavior, functional imaging, neuroelectrophysiology, and molecular biology，we will study in animal model of AD to explore whether intermittent fasting regulate the neural adaptation through SIRT3, thereby delaying the occurrence and development of AD. This study aims to reveal the mechanism of long-term intermittent fasting on senile dementia from the perspective of adaptive response and provided the basis and strong evidence for its clinical transformation.

已有研究发现，在阿茨海默病（AD）小鼠发病前给予长期间断禁食（IF）能延缓疾病进程，显示出极大的临床转化潜力。其可能通过引起轻度能量应激，激活自身神经适应性反应，从而增强机体对抗疾病状态的能力，但具体机制不清。我们前期实验显示，长期间断禁食使线粒体Sirtuin3（SIRT3）蛋白表达上调，并在SIRT3敲除小鼠上证实，即SIRT3介导了间断禁食引起神经元应对过兴奋性和氧化性应激的适应性反应。而过兴奋和氧化应激是AD发生发展的重要病理机制，可以推测SIRT3在IF延缓AD中可能起关键性作用，其机制也值得进一步探讨。因此，我们后续将在AD小鼠模型中，通过转基因动物杂交、行为学、功能影像、神经电生理及分子生物学等手段，探讨间断禁食是否通过SITR3调节神经适应性，进而延缓AD发生发展。从神经适应性角度进一步揭示长期间断禁食对老年痴呆的作用机制，为其临床转化提供基础及有力证据。

线粒体去乙酰化酶Sirtuin-3 (SIRT3)已被证明具有调节代谢和抗氧化功能。已有研究报道SIRT3介导神经元兴奋性的改变。然而，其潜在机制尚不清楚。在这里，我们发现SIRT3缺乏导致培养神经元的神经活性亢进、存活率下降和氧化应激增加，而超氧化物歧化酶2模拟物降低氧化应激并抑制神经元活性亢进。在Aβ处理的培养神经元中，SIRT3激活剂降低了活性氧(ROS)水平和神经元的活性，而增加ROS水平则恢复了神经元的活性。利用双光子活体脑成像，我们发现抑制SIRT3导致早期阿尔茨海默病动物模型神经元兴奋性升高，而抑制ROS水平则逆转这一结果。这些发现证明了SIRT3在阿尔茨海默病神经元兴奋性调节中的氧化应激依赖作用。