Molecular Mechanisms of Memory Loss in a Transgenic Model of Alzheimer Disease

描述（由申请人提供）：阿尔茨海默病的特征是淀粉样斑块和神经原纤维缠结（nft）的积累。在临床上，AD患者表现为记忆力和其他认知功能的进行性恶化。最近的证据表明，可溶性Ap是记忆丧失的一个极好的初始触发因素。本建议的重点是阐明Ap和tau相互作用的途径。我们在解决这个问题上处于独特的位置，因为我们已经产生了一种AD的转基因模型（3xTg-AD），它既能产生斑块，也能产生缠结。在指导阶段提出的研究目标是阐明3xTg-AD小鼠中Aft和tau之间的时间关系。提出了两个具体目标：目标1将确定主动免疫是否可以预防或延迟nft的发展。我们早期的研究结果表明，被动A¿免疫疗法足以消除早期而不是晚期过度磷酸化的tau病变。在这里，我们建议通过主动免疫年轻的病理前3xTg-AD小鼠来确定tau病理的时间发展是否被改变。目的2将确定A¿的产生从A¿42为主转向Ap40是否会影响斑块负担、tau负荷和认知缺陷。为此，我们将采用遗传方法降低a¿42的产生，以确定减少a¿42的产生对3xTg-AD小鼠a¿和tau病理的发生和进展以及认知缺陷的影响。独立阶段的主要焦点将是确定A¿诱导的认知衰退的分子机制。特别提出了两个额外的目标：目标3将阐明AKT/CREB在A¿诱导的学习缺陷中的作用。我们的初步数据显示，在MWM训练后，4个月大的3xTg-AD小鼠与年龄和性别匹配的非tg小鼠相比，CREB激活显著降低。因此，我们假设A¿42通过直接或间接干扰AKT活性来阻断CREB的激活。为了验证这一假设，我们将使用遗传和免疫学方法来阻止AP积累，并确定CREB和AKT激活缺陷是否在学习后恢复。此外，我们将直接增加CREB功能，以确定认知缺陷是否可以在A¿存在下恢复。Aim 4使用一种候选方法来确定a¿诱导认知能力下降的其他分子途径，这是我们努力定义a¿与认知能力下降联系的分子途径的一部分。结合提出的目标将有助于阐明将A¿与认知联系起来的潜在分子途径。识别导致认知能力下降的途径可能会指向新的治疗靶点。

DESCRIPTION (provided by applicant): Alzheimer disease is marked by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Clinically, AD patients show a progressive deterioration of memory and other cognitive functions. Recent evidence points to soluble Ap as an excellent candidate for the initial trigger of memory loss. A focus of this proposal is to elucidate the pathways by which Ap and tau interact. We are uniquely position to address this question, as we have generated a transgenic model of AD (3xTg-AD) that develops both plaques and tangles. The goal of the studies proposed for the mentored phase is to elucidate the temporal relationship between Aft and tau in the 3xTg-AD mice. Two specific aims are proposed: Aim 1 will determine if active A¿ immunization prevents or delays the development of NFTs. Our earlier results indicate that passive A¿ immunotherapy suffices to remove early but not late hyperphosphorylated tau lesions. Here we propose to determine if the temporal development of the tau pathology is altered by actively immunizing young, pre- pathological 3xTg-AD mice. Aim 2 will determine if genetically shifting A¿ production from predominantly A¿ 42 to Ap40 impacts the plaque burden and tau load and cognitive deficits. In this aim, we will use a genetic approach to lower A¿ 42 production to determine the consequences of reducing A¿ 42 production on the onset and progression of A¿ and tau pathology and cognitive deficits in the 3xTg-AD mice. The main focus of the independent phase will be to identify molecular mechanisms underlying the A¿ -induced cognitive decline. In particular two additional aims are proposed: Aim 3 will elucidate the role of AKT/CREB in the A¿-induced learning deficits. This aim follows up on our preliminary data showing that 4-month old 3xTg-AD mice have significantly reduced CREB activation compared to age- and gender-matched NonTg mice, following training in the MWM. Thus, we hypothesize that A¿ 42 blocks CREB activation by directly or indirectly interfering with AKT activity. To test this hypothesis, we will use a genetic and immunological approach to block AP accumulation and determine if CREB and AKT activation deficits are restored following learning. In addition, we will directly increase CREB function to determine if cognitive deficits can be restored in the presence of A¿. Aim 4 uses a candidate approach to determine other molecular pathways underlying A¿-induced cognitive decline, and is part of our efforts to define the molecular pathways that link A¿ to cognitive decline. Combined the proposed aims will help to elucidate the underlying molecular pathways linking A¿ to cognition. The identification of pathways leading to cognitive decline may point to new therapeutic targets.