NLRX1 orchestrates neuronal mitophagy in Alzheimer's Disease: a mechanistic exploration.

IF 1.5 4区医学 Q3 CLINICAL NEUROLOGY

Neurological Research Pub Date : 2025-09-26 DOI:10.1080/01616412.2025.2566230

Baoying Qiu, Jiajun He, Shu Li, Qiaoling Wang, Wenhua Feng, Xiaotong Yu, Yuanyuan Jia, Shuyu Liu, Dijin Jiao, Ling Xie

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引用次数: 0

Abstract

Background: Mitophagy dysfunction in Alzheimer's Disease (AD) accelerates disease progression, highlighting the need for novel therapeutic targets. Although Nucleotide oligomerization domain - like receptor X1 (NLRX1) regulates mitophagy, its role in AD remains unclear. This study aimed to elucidate NLRX1's function in AD - associated mitophagy and its therapeutic potential.

Methods: APP/PS1 transgenic mice and N2A - SW cells were used to establish AD models. Behavioral assays evaluated cognitive function in APP/PS1 mice, while transmission electron microscopy examined mitochondrial morphology. ELISA measured β - amyloid (Aβ)1-42 levels, and RT - qPCR and Western blot analyzed NLRX1 and mitophagy - related proteins after manipulating NLRX1 expression.

Results: APP/PS1 mice had cognitive impairment, elevated Aβ1-42, and abnormal mitochondrial morphology, with reduced NLRX1 expression. NLRX1 - RNAi worsened mitochondrial function, increased Aβ1-42 and mitochondrial ROS, decreased the LC3B - II/I ratio, and upregulated Cyt - C, HSP60, and TIM23, while NLRX1 overexpression alleviated these effects. Co-immunoprecipitation confirmed NLRX1's interaction with key mitophagy protein.

Conclusion: NLRX1 is a key regulator of neuronal mitophagy in AD, and its downregulation impairs mitophagy, suggesting it as a potential therapeutic target.

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NLRX1在阿尔茨海默病中协调神经元自噬：机制探索。

背景：阿尔茨海默病（AD）的线粒体自噬功能障碍加速了疾病进展，突出了对新的治疗靶点的需求。虽然核苷酸寡聚结构域样受体X1 （NLRX1）调节有丝分裂，但其在AD中的作用尚不清楚。本研究旨在阐明NLRX1在阿尔茨海默病相关的有丝分裂中的功能及其治疗潜力。方法：应用APP/PS1转基因小鼠和N2A - SW细胞建立AD模型。行为分析评估APP/PS1小鼠的认知功能，透射电镜检查线粒体形态。ELISA检测β -淀粉样蛋白（Aβ）1-42水平，RT - qPCR和Western blot检测NLRX1和线粒体自噬相关蛋白的表达。结果：APP/PS1小鼠出现认知障碍，a - β1-42升高，线粒体形态异常，NLRX1表达降低。NLRX1 - RNAi使线粒体功能恶化，增加a - β1-42和线粒体ROS，降低LC3B - II/I比值，上调Cyt - C、HSP60和TIM23，而NLRX1过表达可减轻这些影响。共免疫沉淀证实NLRX1与关键的有丝分裂蛋白相互作用。结论：NLRX1在阿尔茨海默病中是神经元自噬的关键调控因子，其下调会损害线粒体自噬，提示其可能是一个潜在的治疗靶点。

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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来源期刊

Neurological Research 医学-临床神经学

CiteScore

3.60

自引率

0.00%

发文量

116

审稿时长

5.3 months

期刊介绍： Neurological Research is an international, peer-reviewed journal for reporting both basic and clinical research in the fields of neurosurgery, neurology, neuroengineering and neurosciences. It provides a medium for those who recognize the wider implications of their work and who wish to be informed of the relevant experience of others in related and more distant fields. The scope of the journal includes: •Stem cell applications •Molecular neuroscience •Neuropharmacology •Neuroradiology •Neurochemistry •Biomathematical models •Endovascular neurosurgery •Innovation in neurosurgery.