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.

阿尔茨海默氏病的标志是淀粉样蛋白斑块和神经原纤维缠结（NFTS）的积累。在临床上，AD患者表现出对记忆和其他认知功能的逐步确定。最近的证据表明固体A赛是最初触发记忆力损失的绝佳候选者。重点建议是阐明A和Tau相互作用的途径。我们是解决这个问题的独特位置问题，因为我们已经生成了一个AD的转基因模型（3XTG-AD），该模型既开发斑块又有斑块缠结。针对修订阶段提出的研究的目的是阐明临时关系在3XTG-AD小鼠中的A和Tau之间。提出了两个具体的目标：AIM 1将确定是否有效a？免疫阻止或延迟NFT的发展。我们的较早结果表明被动a。免疫疗法足以清除早期但不是晚期的磷酸化tau病变。在这里我们建议确定通过主动免疫年轻，前病理学来改变tau病理的临时发育是否会改变 3XTG-AD小鼠。 AIM 2将确定基因将AP产生主要从主要因素转移 42至40影响斑块Burnen和Tau负载和认知缺陷。在此目标中，我们将使用降低A a a a的遗传方法，以确定减少A a 42生产的后果 3XTG-AD小鼠的AP和TAU病理学以及认知缺陷的开始和进展。主独立阶段的重点将是识别a检测的分子机制认知能力下降。特别是提出了两个其他目标：AIM 3将阐明AKT/CREB的作用在A诱导的学习缺陷中。此目标遵循我们的初步数据，显示了4个月大的与年龄和性别匹配的NONTG相比，3XTG-AD小鼠的CREB激活显着降低在MWM训练后，老鼠。那就是我们假设A€42通过直接阻止CREB激活或间接干扰AKT活动。为了检验这一假设，我们将使用遗传和免疫学阻止A积累并确定CREB和AKT激活是否恢复的方法学习。此外，我们将直接提高CREB功能，以确定认知定义是否可以在a面前恢复。 AIM 4使用候选方法来确定其他分子途径基础A诱导的认知能力下降，这是我们定义连接的分子途径的努力的一部分 AP到认知能力下降。提出的目标将有助于阐明基础分子将A与认知联系起来的途径。导致认知下降的途径的识别可能指向新的治疗靶标。