Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer's disease with metabolic syndrome.
Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer's disease with metabolic syndrome.
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DOI：
10.1038/s41598-022-23652-5
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发表时间：
2022-11-17
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
SIRT 3使线粒体蛋白脱乙酰基，从而增强其功能。我们以前已经证明，Sirt 3基因缺失导致脑线粒体功能障碍和神经炎症。我们还报道了Sirt 3基因沉默导致APP/PS1小鼠胰岛素抵抗加重、神经炎症和β淀粉样斑块沉积。为了进一步了解代谢综合征和淀粉样蛋白病理学如何相互作用，我们对APP/PS1/Sirt 3-/-小鼠的大脑样本进行了RNA-seq分析。通过Sirt 3基因缺失、淀粉样蛋白病理学以及两者的结合，在代谢和炎症途径中调节基因表达模式。Sirt 3基因缺失后，一个关键发现是胰岛素降解酶（IDE）的表达降低，IDE是一种调节胰岛素和Aβ肽水平的酶。Sirt 3-/-和APP/PS1小鼠的西方饮食喂养导致IDE蛋白的减少，与Sirt 3下调平行。相反，烟酰胺核苷在体内和体外激活SIRT 3导致IDE上调。SIRT 3在体内的激活也增加了另一种Aβ降解酶脑啡肽酶的水平，并降低了产生Aβ肽的BACE 1的水平，表明SIRT 3在淀粉样斑块减少中的作用。我们的研究结果提供了一个合理的机制联系代谢综合征和淀粉样病变。SIRT 3可能是治疗AD的一个潜在靶点。
SIRT3 deacetylates mitochondrial proteins, thereby enhancing their function. We have previously demonstrated that Sirt3 gene deletion leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and β amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples of APP/PS1/Sirt3-/- mice. Gene expression patterns were modulated in metabolic and inflammatory pathways by Sirt3 gene deletion, amyloid pathology, and the combination. Following Sirt3 gene deletion, a key finding was the decreased expression of insulin-degrading enzyme (IDE), an enzyme that regulates the levels of insulin and Aβ peptides. Western diet feeding of Sirt3-/- and APP/PS1 mice resulted in decrease of IDE protein, parallel to Sirt3 downregulation. Conversely, activation of SIRT3 by nicotinamide riboside in vivo and in vitro resulted in IDE upregulation. SIRT3 activation in vivo also increased the levels of neprilysin, another Aβ degrading enzyme and decreased the levels of BACE1 which generates Aβ peptide suggesting SIRT3’s role in amyloid plaque reduction. Our findings provide a plausible mechanism linking metabolic syndrome and amyloid pathology. SIRT3 may be a potential therapeutic target to treat AD.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
DOI：
10.1523/jneurosci.0295-20.2020
发表时间：
2021-01-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Fracassi A;Marcatti M;Zolochevska O;Tabor N;Woltjer R;Moreno S;Taglialatela G
通讯作者：
Taglialatela G
小分子对胰岛素降解酶的催化位点诱导小鼠葡萄糖不耐症。
影响因子：
16.6
作者：
Deprez-Poulain R;Hennuyer N;Bosc D;Liang WG;Enée E;Marechal X;Charton J;Totobenazara J;Berte G;Jahklal J;Verdelet T;Dumont J;Dassonneville S;Woitrain E;Gauriot M;Paquet C;Duplan I;Hermant P;Cantrelle FX;Sevin E;Culot M;Landry V;Herledan A;Piveteau C;Lippens G;Leroux F;Tang WJ;van Endert P;Staels B;Deprez B
通讯作者：
Deprez B
影响因子：
6
作者：
González-Casimiro CM;Cámara-Torres P;Merino B;Diez-Hermano S;Postigo-Casado T;Leissring MA;Cózar-Castellano I;Perdomo G
通讯作者：
Perdomo G
影响因子：
4.2
作者：
Gong B;Pan Y;Vempati P;Zhao W;Knable L;Ho L;Wang J;Sastre M;Ono K;Sauve AA;Pasinetti GM
通讯作者：
Pasinetti GM