脂肪酸酰胺水解酶基因失活可诱导 5xFAD 阿尔茨海默病小鼠模型的小胶质细胞功能发生异细胞增效。

IF 5.4 2区 医学 Q1 NEUROSCIENCES
Glia Pub Date : 2025-02-01 Epub Date: 2024-10-30 DOI:10.1002/glia.24638
María Andrea Arnanz, María Ferrer, María Teresa Grande, Samuel Ruiz de Martín Esteban, Gonzalo Ruiz-Pérez, Benjamin F Cravatt, Ricardo Mostany, Víctor Javier Sánchez-Arévalo Lobo, Julián Romero, Ana María Martínez-Relimpio
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引用次数: 0

摘要

最近,神经炎症已成为阿尔茨海默病(AD)发病机制中的一个关键因素。小胶质细胞在炎症反应中发挥着重要的功能;特别是疾病相关小胶质细胞(DAM)的出现为人们提供了新的视角,使人们能够深入了解小胶质细胞是有害还是有益的这一相互矛盾的观点。我们以前的研究表明,通过使脂肪酸酰胺水解酶(FAAH)失活来调节内源性大麻素,可以在淀粉样变性的情况下产生有益的效果,但与之矛盾的是,神经炎症反应会加剧,DAM 的数量也会增加。在这里,我们通过使用 RNA 序列分析、分子测定和体内多光子显微镜的形态学研究,旨在阐明缺乏 FAAH 的小鼠在 5xFAD AD 小鼠模型中的小胶质细胞的作用。缺乏FAAH的AD小鼠显示出炎症基因上调,并表现出DAM遗传特征。相反,与AD相关的基因则下调。使用PLX5622清除小胶质细胞后发现,与对照组小鼠相比,FAAH缺乏的AD小鼠斑块相关的小胶质细胞形态更稳定、更分化,对Aβ的吸收增加,从而减少了斑块的生长。重要的是,FAAH 在小胶质细胞中的表达可以忽略不计,这表明 FAAH 在中枢神经系统的细胞相互作用中发挥作用。我们的研究结果表明,Faah 基因失活会引发小胶质细胞功能的异细胞增强,而与之矛盾的是,炎症反应会加剧。综上所述,本研究数据凸显了 FAAH 是治疗 AD 的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Fatty acid amide hydrolase gene inactivation induces hetero-cellular potentiation of microglial function in the 5xFAD mouse model of Alzheimer's disease.

Neuroinflammation has recently emerged as a crucial factor in Alzheimer's disease (AD) etiopathogenesis. Microglial cells play an important function in the inflammatory response; specifically, the emergence of disease-associated microglia (DAM) has offered new insights into the conflicting perspectives on the detrimental or beneficial roles of microglia. We previously showed that modulating the endocannabinoid tone by fatty acid amide hydrolase (FAAH) inactivation renders beneficial effects in an amyloidosis context, paradoxically accompanied by an exacerbated neuroinflammatory response and the enrichment of DAM population. Here, we aim to elucidate the role of microglial cells in FAAH-lacking mice in the 5xFAD mouse model of AD by using RNA-sequencing analysis, molecular determinations, and morphological studies by using in vivo multiphoton microscopy. FAAH-lacking AD mice displayed upregulated inflammatory genes and exhibited a DAM genetic profile. Conversely, genes linked to AD were downregulated. Depleting microglia using PLX5622 revealed that plaque-associated microglia in FAAH-deficient AD mice had a more stable, ramified morphology and increased Aβ uptake, leading to reduced plaque growth compared to control mice. Importantly, FAAH expression was negligible in microglial cells, thus suggesting a role for FAAH in the cellular interplay in the central nervous system. Our findings show that Faah gene inactivation triggers a hetero-cellular enhancement of microglial function that was paradoxically paralleled by an exacerbated inflammatory response. Taken together, the present data highlight FAAH as a potential therapeutic target in AD.

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来源期刊
Glia
Glia 医学-神经科学
CiteScore
13.10
自引率
4.80%
发文量
162
审稿时长
3-8 weeks
期刊介绍: GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.
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