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

阿尔茨海默病的特征是淀粉样蛋白斑块和神经纤维缠结（NFT）的积累。 临床上，AD患者表现出记忆和其他认知功能的进行性恶化。最近 有证据表明可溶性A是引发记忆丧失的最佳候选人。其中一个焦点是 该提案旨在阐明A？和tau相互作用的途径。我们处于独特的地位来解决这个问题 问题，因为我们已经产生了AD的转基因模型（3xTg-AD），其发展斑块和 缠结。为指导阶段提出的研究目标是阐明时间关系 在3xTg-AD小鼠中A？和tau之间的关系。提出了两个具体目标：目标1将决定是否积极A？ 免疫接种可以预防或延迟NFT的发展。我们先前的研究结果表明，被动A？ 免疫疗法足以去除早期而非晚期的过度磷酸化tau病变。在此，我们建议 确定tau病理的时间发展是否通过主动免疫年轻的、病理前的 3xTg-AD小鼠。目标2将确定是否通过基因转移将Ap生产从主要 A <$42至A <$40影响斑块负荷和tau负荷以及认知缺陷。为此，我们将使用 遗传方法降低A <$42产量，以确定减少A <$42产量对 3xTg-AD小鼠中AP和tau病理学以及认知缺陷的发作和进展。主要 独立阶段的重点将是确定A？诱导的 认知能力下降特别是提出了两个额外的目标：目标3将阐明AKT/CREB的作用 在A诱导的学习缺陷中。这一目标是根据我们的初步数据得出的， 与年龄和性别匹配的NonTg小鼠相比，3xTg-AD小鼠的CREB活化显著降低 小鼠，在MWM中训练后。因此，我们假设A 42通过直接或间接阻断CREB激活， 间接干扰AKT活性。为了验证这一假设，我们将使用遗传学和免疫学方法。 阻断A？积聚的方法，并确定CREB和AKT激活缺陷是否在以下恢复 学习此外，我们将直接增加CREB功能，以确定认知缺陷是否可以 在A的存在下恢复。AIM4使用候选方法来确定其他分子途径 潜在的A？诱导的认知能力下降，这是我们努力确定连接 认知能力下降。结合提出的目标将有助于阐明潜在的分子 连接A <$和认知的途径导致认知能力下降的途径的确定可能表明 新的治疗靶点。

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 A¿ as an excellent candidate for the initial trigger of memory loss. A focus of this proposal is to elucidate the pathways by which A¿ 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 A¿ 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, prepathological 3xTg-AD mice. Aim 2 will determine if genetically shifting Ap production from predominantly A¿42 to A¿40 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 AP 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 A¿ 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 Ap 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.