Control of AMPA Receptor Trafficking by Beta Amyloid

描述(由申请人提供)：长时程增强和长时程增强抑制(LTP和LTD)是脊椎动物突触可塑性的有希望和广泛研究的例子。在LTP和LTD，在短暂的突触活动条件期之后，分别有持续性的突触增强或减少。在这两种形式的可塑性中，AMPA受体(-R)在突触处的运输起着关键作用。这项拨款的总体目标是研究控制AMPA-R贩运的亚细胞信号。最近，我们发现β-淀粉样蛋白(A？)，一种与阿尔茨海默病密切相关的多肽，对AMPA-R的转运有显著的影响。 在这一授权期内，我们将如何考察A？可以控制突触AMPA受体的运输。我们最近的研究表明，A？新兵信号用于有限公司移除突触AMPA受体。此外，突触AMPA受体的丧失会导致树突棘和NMDA受体的丧失，也就是突触的丧失。在这里，我们将确定A？导致了这些事件。将使用几种补充方法，包括分子生物学、电生理学、双光子激光扫描显微镜和电子显微镜。这些研究将使用器官型大鼠海马片、分离培养的神经元和转基因小鼠。这些研究的结果将阐明阿尔茨海默病的机制，并提供潜在有效的治疗策略。具体目标是确定：SA1：如果A？变构上调NMDA-R功能；SA2：如何A？与突触可塑性相互作用；SA3：如何A？导致突触AMPA-R的移除；SA4：如何A？会导致突触丢失。越来越多的证据表明，阿尔茨海默病的首批功能障碍靶点之一是突触。我们将研究β淀粉样蛋白导致突触功能障碍的机制，β淀粉样蛋白是一种与疾病病因密切相关的分子。通过阐明这些机制，我们将确定阿尔茨海默病治疗的潜在治疗靶点。

DESCRIPTION (provided by applicant): Long-term potentiation and depression (LTP and LTD) are promising and widely studied examples of vertebrate synaptic plasticity. In LTP and LTD there is a persistent synaptic enhancement or decrement, respectively, seen following brief conditioning periods of synaptic activity. In both these forms of plasticity, which are leading models of memory, the trafficking of AMPA receptors (-Rs) at synapses plays a key role. The general aim of this grant has been to examine the subcellular signaling controlling AMPA-R trafficking. Recently, we have found that beta amyloid (A?), a peptide strongly implicated as a causative agent in Alzheimer's disease, has pronounced effects on AMPA-R trafficking. In this grant period, we will examine how A? can control the trafficking of synaptic AMPA receptors. Our recent studies show that A? recruits signaling used in LTD to remove synaptic AMPA receptors. Furthermore, loss of synaptic AMPA receptors leads to loss of dendritic spines and NMDA receptors; that is, loss of the synapse. Here we will determine the mechanisms by which A? leads to these events. Several complementing methodologies will be used, including molecular biology, electrophysiology, two-photon laser scanning microscopy, and electron microscopy. These studies will use organotypic rat hippocampal slices, dissociated cultured neurons and transgenic mice. The results of these studies will elucidate the mechanisms underlying Alzheimer's disease as well as provide potentially efficacious treatment strategies. The specific aims are to determine: SA1: If A? allosterically up-modulates NMDA-R function; SA2: How A? interacts with synaptic plasticity; SA3: How A? leads to removal of synaptic AMPA-Rs; SA4: How A? leads to loss of synapses. There is growing evidence that one of the first targets of dysfunction in Alzheimer's disease is the synapse. We will examine the mechanisms by which beta amyloid, a molecule strongly implicated in the etiology of the disease, leads to synaptic dysfunction. By elucidating these mechanisms we will identify potentially therapeutic targets in the treatment of Alzheimer's disease.