Type I interferon response-related microglial Mef2c deregulation at the onset of Alzheimer's pathology in 5×FAD mice.
Type I interferon response-related microglial Mef2c deregulation at the onset of Alzheimer's pathology in 5×FAD mice.
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DOI：
10.1016/j.nbd.2021.105272
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发表时间：
2021-05
影响因子：
6.1
通讯作者：
Guo L
中科院分区：
文献类型：
--
作者：
Xue F;Tian J;Yu C;Du H;Guo L
阿尔茨海默病（AD）是一种多因素病因的慢性神经退行性疾病。近年来，人们越来越认识到小胶质细胞在阿尔茨海默病发病机制中的作用；然而，在ad相关病理环境中形成小胶质细胞表型的详细机制在很大程度上仍未解决。肌细胞特异性增强因子2C （Mef2C）是一种具有多种功能的转录因子。最近的研究将衰老相关的小胶质细胞变化归因于I型干扰素（IFN-I）相关的Mef2C失调。鉴于脑老化与AD的密切关系，确定AD相关条件下小胶质细胞Mef2C的变化具有重要意义。在本研究中，我们发现在脑淀粉样变性小鼠模型（5×FAD小鼠）中，Mef2C核易位抑制是一种早期和突出的小胶质表型，随着年龄的增长而加剧。转录数据显示，年轻5×FAD小鼠的小胶质细胞中引发了IFN-I反应，这与早期Mef2C解除管制及其与小胶质细胞激活的关联相呼应。淀粉样蛋白β42 （Aβ42）的低聚形式促进了急性器官型脑切片小胶质细胞中Mef2C的解除，增强了小胶质细胞的激活，并通过小胶质细胞吞噬作用消除突触。重要的是，这些寡聚a β42介导的小胶质细胞变化通过阻断IFN-I信号传导而显著减弱。对结果最简单的解释是，Mef2C与激活的IFN-I信号一起，构成了ad相关疾病的早期小胶质细胞变化。除了Mef2C失调对AD小胶质细胞表型发展的潜在贡献外，Mef2C在小胶质细胞中的抑制可能是连接脑衰老和AD的潜在机制途径。
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with multifactorial etiology. The role of microglia in the pathogenesis of AD has been increasingly recognized in recent years; however, the detailed mechanisms shaping microglial phenotypes in AD-relevant pathological settings remain largely unresolved. Myocyte-specific enhancer factor 2C (Mef2C) is a transcription factor with versatile functions. Recent studies have attributed aging-related microglial changes to type I interferon (IFN-I)-associated Mef2C deregulation. In view of the close relationship between brain aging and AD, it is of great interest to determine microglial Mef2C changes in AD-related conditions. In this study, we have found that suppressed Mef2C nuclear translocation was an early and prominent microglial phenotype in a mouse model of brain amyloidosis (5×FAD mice), which exacerbated with age. Echoing the early Mef2C deregulation and its association with microglial activation, transcriptional data showed elicited IFN-I response in microglia from young 5×FAD mice. Amyloid beta 42 (Aβ42) in its oligomeric forms promoted Mef2C deregulation in microglia on acute organotypic brain slices with augmented microglial activation and synapse elimination via microglial phagocytosis. Importantly, these oligomeric Aβ42-mediated microglial changes were substantially attenuated by blocking IFN-I signaling. The simplest interpretation of the results is that Mef2C, concurring with activated IFN-I signaling, constitutes early microglial changes in AD-related conditions. In addition to the potential contribution of Mef2C deregulation to the development of microglial phenotypes in AD, Mef2C suppression in microglia may serve as a potential mechanistic pathway linking brain aging and AD.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
7.7
作者：
Harrington, Adam J.;Raissi, Aram;Cowan, Christopher W.
通讯作者：
Cowan, Christopher W.
DOI：
10.1073/pnas.0602460103
发表时间：
2006-05-16
影响因子：
11.1
作者：
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通讯作者：
Michiels, Thomas
影响因子：
11
作者：
Ben-Yehuda, Hila;Matcovitch-Natan, Orit;Schwartz, Michal
通讯作者：
Schwartz, Michal
DOI：
10.1007/978-3-030-05542-4_2
发表时间：
2019-01-01
期刊：
REVIEWS ON BIOMARKER STUDIES IN PSYCHIATRIC AND NEURODEGENERATIVE DISORDERS
影响因子：
--
作者：
Cummings, Jeffrey
通讯作者：
Cummings, Jeffrey