Neurotropin alleviates Alzheimer's disease pathology by inhibiting FUS-mediated Calhm2 transcription, blocking the Calhm2/EFhd2 interaction, to improve mitochondrial dysfunction-associated microglia polarization.

IF 5 4区 生物学 Q1 BIOLOGY
Yuanlu Huang, Fusheng Wei, Xiaoe Cheng, Yinqi Shi, Ziye Liu, Lingling Ye
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Abstract

Neurotropin, a non-protein extract widely used for the treatment of neuropathic pain, has recently been reported to protect against ischemic brain injury, enhance remyelination in demyelinating diseases, and ameliorate neuroinflammation and memory deficits. However, its role in microglial polarization and mitochondrial dysfunction in Alzheimer's disease (AD) remains poorly understood. In this study, we investigated the therapeutic potential of Neurotropin in the 5xFAD mouse model of AD. Neurotropin administration alleviated cognitive decline, reduced amyloid-β (Aβ) deposition, suppressed neuroinflammation, and preserved neuronal density. Mechanistically, Neurotropin improved mitochondrial morphology, restored ATP production, increased mitochondrial DNA copy number, and reduced oxidative stress while promoting a shift in microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic and molecular analyses revealed that calcium homeostasis modulator family member 2 (Calhm2) was markedly upregulated in 5xFAD mice, colocalized with microglia, and transcriptionally regulated by fused in sarcoma (FUS), while Calhm2 interacted with EF-hand domain containing protein D2 (EFhd2). Neurotropin suppressed FUS-mediated Calhm2 transcription and attenuated Calhm2-EFhd2 interaction. Importantly, overexpression of Calhm2 in both microglial cells and 5xFAD mice abolished the beneficial effects of Neurotropin, leading to exacerbated mitochondrial dysfunction, oxidative stress, and inflammatory cytokine release. Together, these findings identify Calhm2 as a critical mediator of Neurotropin's neuroprotective effects and demonstrate that Neurotropin alleviates AD pathology by suppressing FUS-dependent Calhm2 transcription and blocking the Calhm2/EFhd2 interaction. This study provides new insights into the mechanism of Neurotropin action and highlights its therapeutic potential for AD.

Neurotropin通过抑制fus介导的Calhm2转录,阻断Calhm2/EFhd2相互作用,改善线粒体功能障碍相关的小胶质细胞极化,从而减轻阿尔茨海默病的病理。
神经tropin是一种非蛋白质提取物,广泛用于神经性疼痛的治疗,最近有报道称它可以预防缺血性脑损伤,促进脱髓鞘疾病的再髓鞘生长,改善神经炎症和记忆缺陷。然而,它在阿尔茨海默病(AD)的小胶质细胞极化和线粒体功能障碍中的作用仍然知之甚少。在本研究中,我们研究了Neurotropin在5xFAD小鼠AD模型中的治疗潜力。神经妥乐平可减轻认知能力下降,减少淀粉样蛋白-β (Aβ)沉积,抑制神经炎症,并保持神经元密度。在机制上,Neurotropin改善线粒体形态,恢复ATP的产生,增加线粒体DNA拷贝数,减少氧化应激,同时促进小胶质细胞极化从促炎M1表型向抗炎M2表型转变。转录组学和分子分析显示,钙稳态调节剂家族成员2 (Calhm2)在5xFAD小鼠中显著上调,与小胶质细胞共定位,并通过融合肉瘤(FUS)进行转录调节,同时Calhm2与含EF-hand结构域的蛋白D2 (EFhd2)相互作用。Neurotropin抑制fus介导的Calhm2转录并减弱Calhm2- efhd2相互作用。重要的是,在小胶质细胞和5xFAD小鼠中,Calhm2的过度表达消除了Neurotropin的有益作用,导致线粒体功能障碍、氧化应激和炎症细胞因子释放加剧。总之,这些发现确定Calhm2是Neurotropin神经保护作用的关键介质,并证明Neurotropin通过抑制fus依赖性Calhm2转录和阻断Calhm2/EFhd2相互作用来减轻AD病理。这项研究为神经妥乐平的作用机制提供了新的见解,并强调了其治疗AD的潜力。
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来源期刊
CiteScore
13.60
自引率
1.80%
发文量
47
审稿时长
>12 weeks
期刊介绍: BioScience Trends (Print ISSN 1881-7815, Online ISSN 1881-7823) is an international peer-reviewed journal. BioScience Trends devotes to publishing the latest and most exciting advances in scientific research. Articles cover fields of life science such as biochemistry, molecular biology, clinical research, public health, medical care system, and social science in order to encourage cooperation and exchange among scientists and clinical researchers.
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