硫氧还蛋白-1通过调节AMPK/Sirt1/PGC1α通路促进阿尔茨海默病线粒体生物发生

IF 3.9 4区 医学 Q2 NEUROSCIENCES ASN NEURO Pub Date : 2023-01-01 DOI:10.1177/17590914231159226
Jinjing Jia, Jiayi Yin, Yu Zhang, Guangtao Xu, Min Wang, Haiying Jiang, Li Li, Xiansi Zeng, Dongsheng Zhu
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引用次数: 1

摘要

阿尔茨海默病(AD)是最常见的神经退行性疾病。越来越多的研究表明,线粒体功能障碍与AD的发病密切相关。Thioredoxin-1 (Trx-1)是哺乳动物细胞中主要的氧化还原蛋白之一,在AD中起神经保护作用。然而,Trx-1是否可以调节AD中线粒体的生物发生在很大程度上是未知的。在本研究中,我们发现Aβ25-35处理不仅显著诱导活性氧过量产生和细胞凋亡,而且显著减少线粒体中具有生物活性的线粒体数量和三磷酸腺苷含量,提示AD细胞线粒体生物发生受损。这些变化被慢病毒介导的Trx-1的稳定过表达或外源给药重组人Trx-1逆转。此外,腺相关病毒介导的Trx-1在APP/PS1小鼠海马区特异性过表达可改善学习记忆能力,减轻海马区Aβ沉积。重要的是,APP/PS1小鼠中Trx-1的过表达恢复了线粒体生物发生相关蛋白的减少,包括单磷酸腺苷活化蛋白激酶(AMPK)、沉默信息调节因子2相关酶1 (Sirt1)和过氧化物酶体增殖物激活受体γ辅助激活因子1- α (PGC1α)。此外,慢病毒介导的Trx-1在大鼠肾上腺嗜铬细胞瘤(PC12)细胞中的过表达也恢复了Aβ25-35处理后AMPK、Sirt1和PGC1α的下降。AMPK活性的药理抑制显著消除了Trx-1对线粒体生物发生的影响。综上所述,我们的数据提供了Trx-1通过恢复AD中AMPK/Sirt1/PGC1α通路促进线粒体生物发生的证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

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来源期刊
ASN NEURO
ASN NEURO NEUROSCIENCES-
CiteScore
7.70
自引率
4.30%
发文量
35
审稿时长
>12 weeks
期刊介绍: ASN NEURO is an open access, peer-reviewed journal uniquely positioned to provide investigators with the most recent advances across the breadth of the cellular and molecular neurosciences. The official journal of the American Society for Neurochemistry, ASN NEURO is dedicated to the promotion, support, and facilitation of communication among cellular and molecular neuroscientists of all specializations.
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