Synapse function in a mouse model of Alzheimer's disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，可导致进行性认知障碍，最显著的是记忆丧失。AD的特征在于神经元损失和蛋白质沉积物（斑块）的积累以及许多脑区域（包括海马体，海马体是许多形式的学习和记忆的关键区域）中的神经元缠结。β-淀粉样蛋白肽（斑块的主要成分）的积聚被认为是与AD相关的认知障碍的因果因素，但对β-淀粉样蛋白积聚的生理效应（导致这些障碍）知之甚少。我们的长期目标是确定β-淀粉样蛋白损害认知的生理机制，以便开发治疗方法来保护这些机制，从而限制AD引起的损害。近年来，已经开发出几种AD的转基因小鼠模型。其中一个模型，即淀粉样前体蛋白（APR）和早老素-1（PS-1）均发生突变的小鼠系，其β-淀粉样蛋白水平显著快速增加，而不形成缠结或神经元丢失。APP/PS-1小鼠海马突触功能受损，早期长期突触可塑性缺陷，后期基础突触功能缺陷。然而，这些缺陷背后的机制仍然未知。在拟议的研究中，我们将确定APP/PS-1小鼠突触功能缺陷的潜在机制。将使用场电位记录和全细胞膜片钳记录在来自APP/PS-1小鼠和野生型同窝仔的海马切片中比较突触特性。将讨论两个具体目标。首先，我们将确定这些小鼠在长期可塑性的早期缺陷和基础突触传递的晚期缺陷中受损的突触机制。其次，我们将确定这些缺陷是否由β-淀粉样蛋白的积累引起。这项拟议中的研究将确定APP/PS-1突变导致海马突触功能受损的机制。项目相关性：拟议的研究将确定由β-淀粉样蛋白积累引起的突触缺陷的潜在机制，β-淀粉样蛋白被认为是AD认知障碍的主要因素。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive cognitive impairments, most notably memory loss. AD is characterized by neuronal loss and by accumulation of protein deposits (plaques) and neurofibrillary tangles in many brain regions including the hippocampus, a region critical for many forms of learning and memory. The build-up of beta-amyloid peptides, a major component of plaques, is thought to be a causal factor in the cognitive impairments associated with AD, but the physiological effects of beta-amyloid accumulation that would cause these impairments are poorly understood. Our long-term objective is to define physiological mechanisms by which beta-amyloids impair cognition, so that therapies may be developed to protect these mechanisms and thereby limit the damage caused by AD. Recently, several transgenic mouse models for AD have been developed. One of these models, a mouse line with mutations in both amyloid precursor protein (APR) and presenilin-1 (PS-1), has a robust and rapid increase in the levels of beta-amyloids, without formation of tangles or neuronal loss. Hippocampal synaptic function in APP/PS-1 mice is impaired, with early defects in long-term synaptic plasticity and later defects in basal synaptic function. However, the mechanisms underlying these defects remain unknown. In the proposed research, we will identify mechanisms underlying the defects in synaptic function in APP/PS-1 mice. Synaptic properties will be compared in hippocampal slices from APP/PS-1 mice and wild- type littermates, using field potential recordings and whole-cell patch clamp recordings. Two specific aims will be addressed. First, we will identify the synaptic mechanisms that are impaired in these mice during early defects in long-term plasticity, and during late defects in basal synaptic transmission. Second, we will determine whether these defects are caused by the accumulation of beta-amyloids. The proposed research will identify the mechanisms by which APP/PS-1 mutations lead to impaired synaptic function in the hippocampus. Project relevance: The proposed research will identify mechanisms underlying synaptic defects caused by accumulation of beta-amyloids, which is thought to be a major factor in the cognitive impairments in AD.