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斑块和神经原纤维缠结(NFT)的积累。 临床上，阿尔茨海默病患者的记忆和其他认知功能呈进行性下降。近期 有证据表明，可溶性Aé是最初引发记忆丧失的极佳候选者。这其中的一个焦点 建议阐明A？和tau相互作用的途径。我们处于解决这一问题的独特地位 问题，因为我们已经生成了AD(3xTg-AD)的转基因模型，该模型同时出现斑块和 唐格斯。为指导阶段提出的研究的目标是阐明时间关系 在3xTg-AD小鼠中，Aβ和tau之间的差异。提出了两个具体目标：目标1将决定是否主动A？ 免疫接种可防止或延缓NFTs的发展。我们早先的结果表明，被动的A？ 免疫治疗可以早期去除过度磷酸化的tau病变，但不能消除晚期。在此，我们建议 确定是否通过主动免疫准备阶段的年轻患者来改变tau病理的时间发展。 3xTg-AD小鼠。目标2将确定是否从基因上转移AP的产量 A？42到A？40影响斑块负荷、tau负荷和认知缺陷。在这个目标中，我们将使用 降低A？42产量的遗传方法，以确定A？42减产的后果 3xTg-AD小鼠AP和tau病理及认知功能障碍的发生发展。主 独立阶段的重点将是确定A？诱导的分子机制 认知能力下降。特别是，提出了另外两个目标：目标3将阐明AKT/CREB的作用 A？诱发的学习缺陷。这个目标是根据我们的初步数据显示的，4个月大的 与年龄和性别匹配的非Tg相比，3xTg-AD小鼠的CREB活性显著降低 小鼠，在MWM训练后。因此，我们假设A？42通过直接或 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 阻断A？蓄积并确定CREB和AKT激活缺陷是否在下列情况下恢复的方法 学习。此外，我们将直接增加CREB功能，以确定是否可以认知障碍 在Aé在场的情况下恢复。目标4使用候选方法来确定其他分子途径 潜在的A？诱导的认知功能下降，这是我们努力定义与 AP导致认知能力下降。结合所提出的目标将有助于阐明潜在的分子 将A与认知联系起来的途径。识别出导致认知能力下降的途径可能指向 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.