Effect of Human AD Brain-Derived Abeta Species on Synaptic Function

描述（由申请人提供）：突触传递中断是阿尔茨海默病患者症状的基础，即记忆和认知缺陷。神经元细胞死亡和突触功能障碍，独立于细胞死亡，似乎是负责这些赤字。淀粉样蛋白-p（A3）肽，神经炎斑的主要成分，已被证明在几种疾病模型中抑制突触传递。本申请的目的是确定介导神经传递中这些改变的A？的精确类型和构象，以及它们起作用的机制。将从细胞系以及人类AD脑组织中分离天然产生的A？的特定构象，因为这最接近地模拟了疾病状态中存在的A？类型。这一提议的基本原理是，了解A？如何导致神经元功能障碍，可以找到更好的诊断方法，并找到治疗干预的潜在靶点。在初步的数据中，我们证明A？可以改变突触传递，可能是通过突触前和突触后机制。我们还表明，突触活动可以调节A从神经元释放到细胞外空间。总之，这表明突触释放的A？可能会反馈抑制神经元功能。我们建议使用电生理学和活细胞成像在原代神经元培养物和急性脑切片中研究A？对突触活动的影响和机制，以及有限的一系列体内研究。电生理学和成像方面的拟议培训将极大地促进申请人的职业发展，使他能够从多个角度研究突触传递。重要的是，在这些研究过程中获得的科学和技术专业知识将使候选人能够实现在神经科学领域建立独立研究生涯的长期目标。简短的描述。突触传递的中断是阿尔茨海默病患者许多症状的基础。这项提案将确定自然产生的A？，阿尔茨海默病发病机制和进展的关键因素，如何影响突触传递。了解突触功能障碍的原因可能为疾病的诊断和治疗提供新的途径。

DESCRIPTION (provided by applicant): Disruptions in synaptic transmission underlie the symptoms of Alzheimer's disease patients, namely memory and cognitive deficits. Both neuronal cell death and synaptic dysfunction, independent of cell death, appear to be responsible for these deficits. Amyloid-p (A3) peptide, the primary constituent of neuritic plaques, has been shown to depress synaptic transmission in several models of disease. The objective of this application is to determine the precise types and conformations of A¿ that mediate these alterations in neurotransmission, as well as mechanisms by which they act. Specific conformations of naturally-produced A¿ will be isolated from cell lines, as well as from human AD brain tissue since this most closely mimics the types of A¿ that are present within the disease state. The rationale for this proposal is that an understanding of how A¿ contributes to neuronal dysfunction could lead to identification of better ways to diagnose the disease, as well as lead to potential targets for therapeutic intervention. In preliminary data, we demonstrate that A¿ can alter synaptic transmission, likely through both presynaptic and postsynaptic mechanisms. We also show that synaptic activity can regulate release of A¿ from neurons into the extracellular space. Together, this suggests that synaptically-released A¿ may feedback to depress neuronal function. We propose to study the effect and mechanisms of A¿ on synaptic activity using electrophysiology and live-cell imaging in primary neuronal cultures and acute brain slices, as well as a limited series of studies in vivo. The proposed training in electrophysiology and imaging will greatly enhance the career development of the applicant, allowing him to study synaptic transmission from many perspectives. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain his long-term goal of establishing an independent research career in neuroscience. Short description. Disruptions in synaptic transmission underlie many of the symptoms of Alzheimer's disease patients. This proposal will determine how naturally-produced A¿, a key factor in Alzheimer's disease pathogenesis and progression, affects synaptic transmission. Understanding the causes of synaptic dysfunction may provide new avenues for diagnosis and treatment of the disease.