Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
J Neurosci. 2010 Aug 25;30(34):11414-25. doi: 10.1523/JNEUROSCI.2127-10.2010.
Overproduction of beta-amyloid (Abeta) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on Abeta-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of Abeta in EC slices. Synaptic depression and LTD impairment induced by Abeta were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1beta (interleukin-1beta) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in Abeta-induced EC synaptic dysfunction.
β-淀粉样蛋白（Abeta）的过度产生是阿尔茨海默病的病理特征，导致认知障碍。在这里，我们研究了晚期糖基化终产物（RAGE）的细胞特异性受体对 Abeta 诱导的内嗅皮层（EC）突触功能障碍的影响。我们发现，Abeta 应用于 EC 切片后，会导致基础突触传递短暂抑制和长时程抑制（LTD）的抑制。Abeta 诱导的突触抑制和 LTD 损伤可通过 RAGE 的功能抑制得到挽救。值得注意的是，这种挽救仅发生在靶向小胶质细胞的有缺陷形式的 RAGE 在表达的小鼠切片中，而不在靶向神经元的有缺陷 RAGE 表达的小鼠切片中。此外，我们发现，炎症细胞因子白细胞介素-1β（IL-1β）和应激激活的激酶[p38 MAPK（p38 丝裂原活化蛋白激酶）和 JNK（c-Jun N 末端激酶）]在神经元或小胶质细胞中根据 RAGE 表达而发生显著改变，并参与 RAGE 信号通路。这些发现表明，小胶质细胞 RAGE 信号在 Abeta 诱导的 EC 突触功能障碍中具有重要作用。
