The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
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DOI：
10.1016/s1474-4422(11)70013-8
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发表时间：
2011-03
期刊：
影响因子：
48
通讯作者：
Zhu, Xiongwei
中科院分区：
文献类型：
--
作者：
Bonda, David J.;Lee, Hyoung-gon;Camins, Antoni;Pallas, Merce;Casadesus, Gemma;Smith, Mark A.;Zhu, Xiongwei
老年学的进步揭示了衰老过程的分子和生物化学方面的关键见解。去乙酰化酶途径，最值得注意的是它与热量限制的抗衰老作用的关联，已经受到特别的关注，去乙酰化酶途径的药理学或转基因上调已经在衰老的实验室模型中证明了一些非常有希望的结果。阿尔茨海默病（AD）是老年性痴呆的主要原因，是一种破坏性的神经退行性疾病，给社会带来越来越大的负担。目前可用于该疾病的治疗剂的缺乏为开发有效的治疗策略提供了强烈的激励，并且有趣的是，研究已经发现了sirtuin途径的新作用机制，其提供了显著的潜力。Sirt 1是NAD+依赖性去乙酰化酶sirtuin家族的7个哺乳动物同源物之一，最近在体外细胞培养研究和AD转基因小鼠模型中被证明可以减弱淀粉样β蛋白前体（AβPP）的淀粉样蛋白形成过程。从机制上讲，Sirt 1通过激活α-分泌酶基因ADAM 10增加α-分泌酶的产生和活性。由于α-分泌酶是负责AβPP非淀粉样蛋白裂解的关键酶，因此α-分泌酶的上调改变了AβPP的加工过程，以减少β-和γ-分泌酶活性导致的推定毒性Aβ物质的病理性蓄积。有趣的是，最近一项关于大脑中Aβ沉积空间模式的研究表明，这些区域中有氧糖酵解的利用率增加与A β沉积的空间模式密切相关。有氧糖酵解消耗细胞内NAD+水平（通过降低NAD+/NADH比值），NAD+依赖性沉默调节蛋白通路的相应下调可能是AβPP淀粉样蛋白形成过程的部分原因。Sirt 1对Aβ生成的特异性抑制，加上有氧糖酵解、NAD+消耗和淀粉样蛋白生成之间的联系（通过sirtuin途径），具有翻译意义。一方面，sirtuin通路在AD发病和发展中可能的潜在作用可能会启发我们对这种破坏性疾病的理解。另一方面，Sirt 1的治疗性上调可以通过抑制淀粉样蛋白生成等（即，调节细胞代谢或抑制tau病理-见下文）。最后，如果要取得任何进展，就必须进一步分析这两个方面。
Advancements in gerontology have revealed key insights into the molecular and biochemical aspects of the aging process. The sirtuin pathway, most notable for its association with the anti-aging effects of calorie restriction, has received particular attention, and pharmacologic or transgenic upregulation of the sirtuin pathway has demonstrated some very promising results in laboratory models of aging. Alzheimer disease (AD), the leading cause of senile dementia, is a devastating neurodegenerative condition that is imposing an increasing burden on society. The lack of therapeutics currently available for the disease provides strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a novel mechanism of action of the sirtuin pathway that offers significant potential as such. Sirt1, one of the seven mammalian homologues of the sirtuin family of NAD+-dependent deacetylases, has recently been demonstrated to attenuate amyloidogenic processing of amyloid-β protein precursor (AβPP) in cell culture studies in vitro and transgenic mouse models of AD. Mechanistically, Sirt1 increases α-secretase production and activity through activation of the α-secretase gene ADAM10. Since α-secretase is the critical enzyme responsible for the non-amyloidogenic cleavage of AβPP, upregulation of α-secretase shifts AβPP processing to reduce the pathological accumulation of the presumptive toxic Aβ species that results from β- and γ-secretase activity. Interestingly, a recent study of the spatial patterns of Aβ deposition in the brain indicates a strong correlation with an increased utilization of aerobic glycolysis in those regions. Aerobic glycolysis depletes cellular levels of NAD+ (via decreased NAD+/NADH ratio), and it is possible that a corresponding downregulation of the NAD+-dependent sirtuin pathway is partly responsible for the amyloidogenic processing of AβPP. The specific inhibition of Aβ generation by Sirt1 coupled with the link between aerobic glycolysis, NAD+ depletion, and amyloidogenesis via the sirtuin pathway has translational implications. On the one hand, the likely underlying role of the sirtuin pathway in AD onset and development may enlighten our understanding of this devastating condition. On the other, therapeutic upregulation of Sirt1 may provide opportunities for the amelioration of AD-type neuropathology through an inhibition of amyloidogenesis, among other things (i.e., regulation of cellular metabolism or inhibition of tau pathology — see below). Ultimately, further analysis into both aspects is necessary if any progress is to be made.