Neuroscience Institute, Italian National Research Council, Pisa 56100, Italy,
Neuroscience Institute, Italian National Research Council, Pisa 56100, Italy, Departments of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67010 L'Aquila, Italy.
J Neurosci. 2014 Jun 25;34(26):8749-60. doi: 10.1523/JNEUROSCI.0141-14.2014.
Ischemia is known to increase the deleterious effect of β-amyloid (Aβ), contributing to early cognitive impairment in Alzheimer's disease. Here, we investigated whether transient ischemia may function as a trigger for Aβ-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 Aβ 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-1β. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia.
缺血已知会增加β-淀粉样蛋白（Aβ）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触发物，通过特定的细胞信号传导，导致内侧隔核（EC）中 Aβ依赖性的突触损伤。我们发现，在存在合成寡聚体 Aβ或来自突变型人淀粉样前体蛋白转基因小鼠（mhAPP J20）的切片中，氧葡萄糖剥夺（OGD）诱导的突触抑制增强。RAGE 的功能抑制可改善 OGD 诱导的突触抑制。具体而言，针对小胶质细胞的 RAGE 显性负形式（DNMSR）的过表达可防止富含淀粉样蛋白的环境中 OGD 诱导的突触损伤，减少应激相关激酶（p38MAPK 和 JNK）的激活和 IL-1β的释放。我们的结果表明，RAGE 依赖性神经炎症途径在 Aβ诱导和短暂性缺血触发的突触功能障碍中起重要作用。
