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

阿尔茨海默病转基因模型记忆丧失的分子机制

基本信息

批准号：
7917249
负责人：
Salvatore Oddo
金额：
$ 24.65万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917249
关键词：
Accounting Address Affect Age Alleles Alzheimer&apos s Disease Amygdaloid structure Amyloid Antibodies Behavioral Brain Brain region Breeding CREB1 gene Chronic Cognition Cognitive deficits Confounding Factors (Epidemiology)Data Deposition Deterioration Development Double Effect Event Gender Gene Expression Genetic Genotype Goals Harvest Hippocampus (Brain)Human Immunization Immunotherapy Impaired cognition Impairment In Vitro Lead Learning Lesion Link Memory Memory Loss Mentors Molecular Mus Mutation Nature Neurofibrillary Tangles Outcome Pathology Pathway interactions Patients Phase Positioning Attribute Production Proto-Oncogene Proteins c-akt Regulatory Element Role Senile Plaques Severities Signal Transduction Signal Transduction Pathway Tauopathies Testing Tg2576 Training Transgenes Transgenic Mice Transgenic Organisms cognitive function embryo cell follow-up hyperphosphorylated tau men morris water maze mouse model mutant neurofibrillary tangle formation new therapeutic target overexpression presenilin prevent protein aggregate research study tau Proteins tau aggregation transgenic model of alzheimer disease

项目摘要

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.

阿尔茨海默病的特点是淀粉样斑块和神经原纤维缠结（NFT）的积累。临床上，AD患者表现出记忆力和其他认知功能逐渐恶化。最近的有证据表明可溶性 A 是引发记忆丧失的绝佳候选者。这其中的一个焦点该提案旨在阐明 A¿ 和 tau 相互作用的途径。我们拥有独特的优势来解决这个问题问题，因为我们已经生成了 AD 转基因模型 (3xTg-AD)，该模型既发育斑块又纠结。指导阶段提出的研究目标是阐明时间关系 3xTg-AD 小鼠中的 A¿ 和 tau 之间。提出了两个具体目标：目标 1 将确定 A¿ 免疫可以阻止或延迟 NFT 的发展。我们早期的结果表明被动 A¿ 免疫疗法足以去除早期但不能去除晚期过度磷酸化的 tau 病变。在此我们建议确定 tau 病理学的时间发展是否会通过积极免疫年轻的、病理前的动物而改变 3xTg-AD 小鼠。目标 2 将确定是否通过基因改变 Ap 的产生 A¿42 至 A¿40 影响斑块负荷和 tau 负荷以及认知缺陷。为了这个目标，我们将使用一个降低 A¿42 产量的遗传方法，以确定减少 A¿42 产量的后果 3xTg-AD 小鼠中 AP 和 tau 病理学以及认知缺陷的发生和进展。主要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。特别提出了两个额外目标：目标 3 将阐明 AKT/CREB 的作用在A¿引起的学习缺陷中。这一目标是根据我们的初步数据得出的，该数据显示 4 个月大的婴儿与年龄和性别匹配的 NonTg 小鼠相比，3xTg-AD 小鼠的 CREB 激活显着降低接受 MWM 训练的小鼠。因此，我们假设 A¿42 通过直接或间接干扰 AKT 活性。为了检验这个假设，我们将使用遗传和免疫学方法阻止 A¿ 积累并确定 CREB 和 AKT 激活缺陷是否在以下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改善认知缺陷在 A¿ 存在的情况下恢复。目标 4 使用候选方法来确定其他分子途径潜在的 A¿ 引起的认知能力下降，并且是我们努力定义链接的分子途径的一部分 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连接 A¿ 与认知的途径。识别导致认知能力下降的途径可能表明新的治疗靶点。