SECOND MESSENGER SYSTEMS ON THE ACTIONS OF A-BETA ON HIPPOCAMPAL NEURONS

A-β 对海马神经元作用的第二信使系统

• 批准号: 6578754
• 负责人: ISTVAN MODY
• 金额: $ 22.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6578754
• 关键词: Alzheimer's disease; G protein; amyloid proteins; calcium binding protein; calcium flux; cell age; cyclic GMP; electrophysiology; enzyme activity; hippocampus; intracellular transport; laboratory rat; microelectrodes; neural conduction; neural degeneration; phosphoprotein phosphatase; protein kinase; second messengers

Deposition of fibrillary beta-amyloid peptide (Abeta), the main component of amyloid plaques, is considered by most uccrent theories on Alzheimer's disease (AD) to be a key factor in the selective neuritic dystrophy and neuronal degeneration. Extracellular deposition of Abeta is thought to be one of the causes of AD pathology. The neural fibrillary tangles, cell loss, vascular damage, and dementia are presumed to follow as a direct result of this deposition. Accordingly, much of AD research focuses on understanding the molecular pathways for Abeta generation, on discovering factors affecting Abeta aggregation and deposition and on identifying the effects of Abeta at the cellular level. Most of our understanding concerning the effects of Abeta on cellular events is derived from research on cultured embryonic nerve cells, a preparation in an early stage of its maturation that cannot adequately resemble mature neurons that usually succumb to AD. In contrast, the preliminary experiments which will constitute the basis of the proposed studies, were obtained in acutely dissociated adult or aged hippocampal neurons. In these cells, intracellular second messenger- related pathways appear to mediate rapid cellular effects of Ab that may underlie some of the pathological consequences of the aggregated peptide. Acute exposure of the neurons to Abetas dramatically enhanced NMDA channel function through a modulatory pathway distinct from known effects of Abetas including elevated Ca2+ influx, liberation of free radicals, or activation of tachykinin receptors. Based on these findings, the present proposal will address the following hypothesis: intracellular second messenger pathways, including protein kinases or phosphatases, are activated by Abeta in adult or aged neurons. This project has four specific aims: 1) to identify protein kinases and phosphoprotein phosphatases activated or inhibited by Abeta; 2) to ascertain whether Abeta activates 2nd messenger systems common to other peptide receptors; 3) to determine the role and contribution of Ca2+ in the cellular and toxic actions of Abeta; and 4) to reveal the possible involvement of G-proteins and cyclic GMP in the cellular actions of Abeta. The study will use high resolution electrophysiological recordings in vitro in adult rodent CNS neurons, and in collaboration with Dr. Frautschy, it will assess the cellular damage produced by Abeta administration in vivo into the brains of mice null mutant for the intracellular Ca2+-binding proteins calbindin (CB) and parvalbumin (PV). By addressing the effects of Abeta on cellular second messenger functions in adult and aged nerve cells of the hippocampus and studying these novel actions of Abeta on cellular second messenger functions in adult and aged nerve cells of the hippocampus, and studying these novel actions on Abeta on NMDA channel activity in fully developed and aged neurons this proposal will identify intracellular second messenger pathways possibly involved in the actions of Abeta. An activation of second messenger cascades by Abeta may cause may lead, in the long run, to the neuronal dysfunction and the eventual degeneration associated with AD.

β-淀粉样肽（Abeta）的沉积， 淀粉样蛋白斑块的组成部分，被认为是大多数现有的理论， 阿尔茨海默病（AD）是选择性神经炎的关键因素， 营养不良和神经元变性。Abeta的细胞外沉积 被认为是AD病理学的原因之一。神经 神经纤维缠结、细胞丢失、血管损伤和痴呆是 被认为是这份证词的直接结果因此，委员会认为， 许多AD研究集中在了解AD的分子途径， Abeta生成，发现影响Abeta聚集的因素， 沉积和确定Abeta在细胞中的作用 水平我们对Abeta影响的大多数理解是 细胞事件来自于对培养的胚胎神经的研究 细胞，一种处于成熟早期阶段的制剂， 充分类似于通常屈服于AD的成熟神经元。在 对比，初步实验将构成的基础， 建议的研究，获得急性分离的成人或老年人 海马神经元在这些细胞中，细胞内第二信使- 相关途径似乎介导Ab的快速细胞效应， 造成了一些病理性后果， 肽。急性暴露于阿贝塔的神经元显著增强了 NMDA通道通过不同于已知的调节途径发挥功能 Abetas的作用，包括升高的Ca 2+内流，游离 自由基或速激肽受体的激活。基于这些 根据调查结果，本提案将处理以下假设： 细胞内第二信使途径，包括蛋白激酶或 在成年或老化的神经元中，磷酸酶被Abeta激活。这 该项目有四个具体目标：1）鉴定蛋白激酶， 磷蛋白磷酸酶被Abeta激活或抑制; 2） 确定Abeta是否激活与其他人共同的第二信使系统 肽受体; 3）确定Ca 2+在 Abeta的细胞和毒性作用;和4）揭示可能的 G-蛋白和环GMP参与的细胞活动 Abeta该研究将使用高分辨率电生理 成年啮齿动物CNS神经元的体外记录，并与 它将评估Abeta产生的细胞损伤， 体内给药到小鼠的脑中， 细胞内钙结合蛋白（CB）和小清蛋白（PV）。 通过研究Abeta对细胞第二信使的影响， 成年和老年海马神经细胞的功能和研究 Abeta对细胞第二信使功能的这些新作用， 成年和老年海马神经细胞，并研究这些新的 Abeta对完全发育和老年大鼠NMDA通道活性的作用 神经元这一建议将确定细胞内的第二信使 可能参与Abeta作用的途径。的激活 从长远来看， 神经元功能障碍和最终的退化 与AD