RAGE Inhibition in Microglia Prevents Ischemia-Dependent Synaptic Dysfunction in an Amyloid-Enriched Environment
RAGE Inhibition in Microglia Prevents Ischemia-Dependent Synaptic Dysfunction in an Amyloid-Enriched Environment
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DOI：
10.1523/jneurosci.0141-14.2014
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发表时间：
2014-06-25
影响因子：
5.3
通讯作者：
Domenici, Luciano
中科院分区：
文献类型：
--
作者：
Origlia, Nicola;Criscuolo, Chiara;Domenici, Luciano
已知缺血会增加β-淀粉样蛋白（A β）的有害作用，导致阿尔茨海默病的早期认知障碍。在这里，我们研究了短暂性缺血是否可以作为内嗅皮层（EC）中A β依赖性突触损伤的触发器，通过特定的细胞信号传导起作用。我们发现，无论是在合成寡聚体A β的存在下，还是在突变型人淀粉样前体蛋白转基因小鼠（mhAPP J20）的切片中，由氧葡萄糖剥夺（OGD）诱导的突触抑制在EC切片中增强。OGD诱导的突触抑制可通过功能性抑制突触抑制来改善。特别是，在富含淀粉样蛋白的环境中，针对小胶质细胞的显性负性形式的DNMSR的过表达保护OGD诱导的突触损伤，减少应激相关激酶（p38 MAPK和JNK）的激活和IL-1 β的释放。我们的研究结果表明，RAGE依赖性神经炎症通路在A β诱导的突触失败和短暂缺血触发的突出作用。
Ischemia is known to increase the deleterious effect of beta-amyloid (A beta), contributing to early cognitive impairment in Alzheimer's disease. Here, we investigated whether transient ischemia may function as a trigger for A beta-dependent synaptic impairment in the entorhinal cortex (EC), acting through specific cellular signaling. We found that synaptic depression induced by oxygen glucose deprivation (OGD) was enhanced in EC slices either in presence of synthetic oligomeric A beta or in slices from mutant human amyloid precursor protein transgenic mice (mhAPP J20). OGD-induced synaptic depression was ameliorated by functional suppression of RAGE. In particular, overexpression of the dominant-negative form of RAGE targeted to microglia (DNMSR) protects against OGD-induced synaptic impairment in an amyloid-enriched environment, reducing the activation of stress-related kinases (p38MAPK and JNK) and the release of IL-1 beta. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by A beta and triggered by transient ischemia.