A study of a role for inducible GLP-1 in brain disfunctions

诱导型 GLP-1 在脑功能障碍中的作用研究

基本信息

批准号：
12672131
负责人：
JUN-LCHIRO Oka
金额：
$ 2.18万
依托单位：
Tokyo University of Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672131/
关键词：
β-Amyloid orotein GLP-1 Long-term potentiation(LTP)Hippocampus cAMP MAP kinase Primary culture Neurite elongation GA1 β-amyloid protein CA1 神経細胞死

项目摘要

The final goal of the present study is to examine intracellular mechanisms of interaction between β-amyloid protein and glucagon-like peptide-1 (GLP-1) in progression of the brain dysfunction, and to examine a physiological role of GLP-1 in the brain development. First, we found that progression of apoptosis is an important factor for NFikB activation by p-amyloid protein, and that NFicB activation might not play a functional role in the interaction between p-amyloid protein and GLP-1.Next, we demonstrated that endogenous GLP-1 exacerbates p-amyloid protein-induced impairment of long-term potentiation in the hippocampal CA1 through CAMP-independent mechanism, and that activation of p38 MAP kinase may be involved in p-amyloid protein-induced dysfunction of synaptic plasticity and the interaction with GLP-1.Furthermore, we found that the presence of constitutive GLP-1 in the embryonic but not postnatal rat's hippocampus, where synthesis of GLP-1 is usually suppressed but is stimulated by treatment with p-amyloid protein. Cultured hippocampal neurons had GLP-1 receptors, and an antagonist of GLP-1 receptors inhibited neurite elongation without any effect on cell viability. Our results demonstrated that an increase in CAMP concentration and activation of MAP kinase pathways are involved in the effects of endogenous GLP-1.The same effects were also observed in cultured cerebrocortical neurons and cultured spinal neurons. These results suggest that endogenous GLP-1 acts as a neurotrophic factor in the brain of rat embryos, and that GLP-1 might show a therapeutic effect on the damaged brain by facilitating neurite elongation and re-organizing neuronal networks.

本研究的最终目标是检查 β-淀粉样蛋白和胰高血糖素样肽-1 (GLP-1) 在脑功能障碍进展中相互作用的细胞内机制，并检查 GLP-1 在脑功能障碍中的生理作用。首先，我们发现细胞凋亡的进展是 p-淀粉样蛋白激活 NFikB 的重要因素，并且 NFicB 激活可能在 p-淀粉样蛋白与大脑发育之间的相互作用中不起功能作用。 GLP-1。接下来，我们证明内源性 GLP-1 通过 CAMP 独立机制加剧 p-淀粉样蛋白诱导的海马 CA1 长时程增强损伤，并且 p38 MAP 激酶的激活可能与 p-淀粉样蛋白有关蛋白质诱导的突触可塑性功能障碍以及与 GLP-1 的相互作用。此外，我们发现在胚胎中而非出生后存在组成型 GLP-1培养的海马神经元具有 GLP-1 受体，GLP-1 的合成通常受到抑制，但经过 p-淀粉样蛋白处理后会受到刺激，GLP-1 受体的拮抗剂可抑制神经突伸长，但对细胞活力没有任何影响。我们的结果表明，CAMP 浓度的增加和 MAP 激酶途径的激活与内源性 GLP-1 的作用有关。在培养的脑皮质中也观察到了相同的作用这些结果表明，内源性 GLP-1 在大鼠胚胎大脑中充当神经营养因子，并且 GLP-1 可能通过促进神经突伸长和重组神经网络对受损大脑发挥治疗作用。。