Interaction of ABeta & the alpha7 AChR in mouse AD model

Aβ的相互作用

• 批准号: 6952289
• 负责人: JOANNA L JANKOWSKY
• 金额: $ 12.45万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952289
• 关键词: Alzheimer' s disease; Xenopus oocyte; acetylcholine; amyloid proteins; amyloidosis; binding sites; calcium flux; cognition; disease /disorder model; electrophysiology; genetically modified animals; hippocampus; laboratory mouse; neural transmission; neuritic plaques; neurons; neuropathology; neurotransmitter antagonist; nicotinic receptors; pathologic process; protein protein interaction; protein structure function; receptor binding; synapses; tissue /cell preparation

DESCRIPTION (provided by applicant): Although our understanding of the pathogenesis of Alzheimer's disease (AD) has advanced enormously over the past decade, the link between the pathology of the disease and its devastating cognitive symptoms remains unclear. An exciting possibility for this connection recently came to light in the discovery of a direct interaction between the Abeta peptide found in amyloid lesions of AD and a neurotransmitter receptor that modulates synaptic function in parts of the brain most afflicted by the disease. Not only does the alpha7 acetylcholine receptor bind strongly and specifically to Abeta, but in so doing, its response to stimulation by acetylcholine is significantly altered. This interaction could substantially affect cholinergic transmission in areas of the brain rich in both Abeta and alpha7, including the cortex and the hippocampus. However, most of the research to characterize this interaction to date has focused the peptide's acute effects in preparations often quite unrelated to the adult brain. Our proposed experiments will extend these earlier findings in several important ways. First, we will address the functional consequences of Abeta exposure by examining alpha7-mediated neurotransmitter release and calcium homeostasis in hippocampal neurons. Second, we will use an acute slice preparation from postnatal animals that retains much of the normal neuronal connectivity found in vivo. Third, we will explore how prolonged exposure to Abeta influences alpha7-mediated synaptic function, and how this compares to the peptide's acute effects. Fourth, we will examine whether binding to alpha7 later promotes aggregation of Aa and the formation of amyloid plaques. Finally, we will determine the binding site for Abeta on the alpha7 receptor. Thus our proposed research will assess the functional and pathological changes caused by the binding of Abeta to alpha7, and determine the site on the receptor where this interaction takes place with the long term prospect of pharmaceutical intervention.

描述（由申请人提供）：尽管我们对阿尔茨海默病（AD）发病机制的理解在过去十年中取得了巨大进展，但该疾病的病理学与其破坏性认知症状之间的联系仍不清楚。最近发现，AD 淀粉样蛋白病变中发现的 Abeta 肽与调节受该疾病影响最严重的大脑部分突触功能的神经递质受体之间存在直接相互作用，这种联系的一个令人兴奋的可能性被揭示。 α7 乙酰胆碱受体不仅与 Abeta 强烈且特异性地结合，而且这样做时，其对乙酰胆碱刺激的反应也显着改变。这种相互作用可能会极大地影响富含 Abeta 和 α7 的大脑区域（包括皮层和海马体）的胆碱能传递。然而，迄今为止，大多数表征这种相互作用的研究都集中在通常与成人大脑无关的制剂中肽的急性作用。我们提出的实验将以几个重要的方式扩展这些早期发现。首先，我们将通过检查海马神经元中 α7 介导的神经递质释放和钙稳态来解决 Abeta 暴露的功能后果。其次，我们将使用产后动物的急性切片制剂，保留体内发现的大部分正常神经元连接。第三，我们将探讨长期暴露于 Abeta 如何影响 alpha7 介导的突触功能，以及如何将其与肽的急性作用进行比较。第四，我们将检查与 alpha7 的结合是否会促进 Aa 的聚集和淀粉样蛋白斑的形成。最后，我们将确定 Abeta 在 α7 受体上的结合位点。因此，我们提出的研究将评估 Abeta 与 α7 结合引起的功能和病理变化，并确定受体上发生这种相互作用的位点，并从药物干预的长期前景出发。