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褪黑素通过诱导 TFEB 核易位、促进线粒体自噬和调节 NLRP3 炎症小体活性来改善阿尔茨海默病的进展。

Melatonin Ameliorates the Progression of Alzheimer's Disease by Inducing TFEB Nuclear Translocation, Promoting Mitophagy, and Regulating NLRP3 Inflammasome Activity.

机构信息

Department of Neurology, The Second Hospital of Shandong University, Shandong University, Jinan 250033, China.

出版信息

Biomed Res Int. 2022 Aug 9;2022:8099459. doi: 10.1155/2022/8099459. eCollection 2022.

DOI:10.1155/2022/8099459
PMID:35983247
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9381268/
Abstract

BACKGROUND

The NLRP3 inflammasome is overactivated in the brains of APP/PS1 transgenic mice and AD patients, and mitophagy has an obvious negative regulatory role on NLRP3 inflammasome activation. The protective effect of melatonin in AD may be related to the regulation of mitophagy and NLRP3 inflammasome activity. TFEB plays a critical role in maintaining autophagy/mitophagy. Studies have found that TFEB plays a protective role in AD.

METHODS

APP/PS1 transgenic mice were given melatonin in their drinking water for 3 months. Compared with mice without melatonin treatment, the mice given melatonin showed changes in the following features: (1) cognitive function, (2) mitophagy-related proteins in the brain, (3) ROS, (4) NLRP3 inflammasome and related proteins and the concentrations of inflammatory cytokines, and (5) A deposition. In experiments, effects of melatonin on mitophagy, NLRP3 inflammasome activity, and TFEB in SH-SY5Y cells with A were observed. TFEB knockdown was implemented in combination with A and melatonin treatment, and the expressions of TFEB, Parkin, p62, IL-1, caspase-1, ROS, and IL-18 were explored.

RESULTS

Melatonin improved cognitive function in APP/PS1 transgenic mice and decreased ROS and senile plaques. Melatonin promoted mitophagy in SH-SY5Y cells with A and APP/PS1 transgenic mice. NLRP3 inflammasome activity was inhibited, and the concentrations of IL-18 and IL-1were clearly reduced. Compared with C57/BL6J mice, the amount of TFEB in the brain nucleus of APP/PS1 transgenic mice was decreased. Melatonin treatment increased the nuclear translocation of TFEB in SH-SY5Y cells. TFEB knockout was implemented in combination with A and MT treatment; the expressions of Parkin, p62, caspase-1, IL-1, IL-18, and ROS were accelerated.

CONCLUSIONS

Melatonin promotes mitophagy by inducing TFEB nuclear translocation, downregulates NLRP3 inflammasome activation, and exerts protective effects in SH-SY5Y cells and APP/PS1 transgenic mice.

摘要

背景

NLRP3 炎性小体在 APP/PS1 转基因小鼠和 AD 患者的大脑中过度激活，而细胞自噬对 NLRP3 炎性小体的激活具有明显的负调控作用。褪黑素对 AD 的保护作用可能与调控细胞自噬/线粒体自噬和 NLRP3 炎性小体活性有关。TFEB 在维持自噬/线粒体自噬中起关键作用。研究发现 TFEB 在 AD 中起保护作用。

方法

APP/PS1 转基因小鼠饮用含褪黑素的水 3 个月。与未给予褪黑素治疗的小鼠相比，给予褪黑素的小鼠表现出以下特征的变化：（1）认知功能，（2）大脑中的线粒体自噬相关蛋白，（3）ROS，（4）NLRP3 炎性小体及相关蛋白和炎症细胞因子的浓度，以及（5）Aβ沉积。在实验中，观察了褪黑素对 Aβ 诱导的 SH-SY5Y 细胞中线粒体自噬、NLRP3 炎性小体活性和 TFEB 的影响。TFEB 敲低与 Aβ 和褪黑素治疗相结合，研究了 TFEB、Parkin、p62、IL-1、caspase-1、ROS 和 IL-18 的表达。

结果

褪黑素改善了 APP/PS1 转基因小鼠的认知功能，降低了 ROS 和老年斑。褪黑素促进了 Aβ 诱导的 SH-SY5Y 细胞和 APP/PS1 转基因小鼠的线粒体自噬。NLRP3 炎性小体活性受到抑制，IL-18 和 IL-1 的浓度明显降低。与 C57/BL6J 小鼠相比，APP/PS1 转基因小鼠大脑核中的 TFEB 量减少。褪黑素治疗增加了 SH-SY5Y 细胞中 TFEB 的核转位。TFEB 敲除与 Aβ 和 MT 治疗相结合；Parkin、p62、caspase-1、IL-1、IL-18 和 ROS 的表达加快。

结论

褪黑素通过诱导 TFEB 核转位促进线粒体自噬，下调 NLRP3 炎性小体的激活，在 SH-SY5Y 细胞和 APP/PS1 转基因小鼠中发挥保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/0af63175d645/BMRI2022-8099459.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/6d9db60b4bd6/BMRI2022-8099459.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/14d29097692c/BMRI2022-8099459.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/112712edff4d/BMRI2022-8099459.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/e6138e39df49/BMRI2022-8099459.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/0af63175d645/BMRI2022-8099459.005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/6d9db60b4bd6/BMRI2022-8099459.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/14d29097692c/BMRI2022-8099459.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/112712edff4d/BMRI2022-8099459.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/e6138e39df49/BMRI2022-8099459.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ef5/9381268/0af63175d645/BMRI2022-8099459.005.jpg

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