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

描述(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，即记忆和认知障碍。神经细胞死亡和突触功能障碍，与细胞死亡无关，似乎都是造成这些缺陷的原因。淀粉样蛋白-P(A3)是神经炎斑块的主要成分，已被证明在几种疾病模型中抑制突触传递。这项应用的目的是确定在神经传递中介导这些变化的A？的确切类型和构象，以及它们的作用机制。自然产生的A？的特定构象将从细胞系以及人类AD脑组织中分离出来，因为这最接近于疾病状态中存在的A？的类型。这一建议的基本原理是，了解A？如何导致神经元功能障碍可以导致确定诊断这种疾病的更好方法，并导致潜在的治疗干预目标。在初步数据中，我们证明A？可以改变突触传递，可能通过突触前和突触后机制。我们还表明，突触活动可以调节神经元向细胞外间隙释放Aβ。综上所述，这表明突触释放的A？可能反馈抑制神经元功能。我们建议通过原代神经元培养和急性脑片的电生理学和活细胞成像以及体内有限的一系列研究来研究Aβ对突触活性的影响和机制。拟议的电生理学和成像方面的培训将极大地促进申请者的职业发展，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他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的许多症状的基础。这项提议将确定自然产生的A？如何影响突触传递。A？是阿尔茨海默病发病和发展的关键因素。了解突触功能障碍的原因可能为该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.