Learning in a Mouse Model of Alzheimer's Disease

阿尔茨海默病小鼠模型的学习

• 批准号: 6932420
• 负责人: CATHERINE COOK KACZOROWSKI
• 金额: $ 4.66万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932420
• 关键词: Alzheimer' s disease; action potentials; amyloid proteins; behavior test; biophysics; calcium; computer program /software; conditioning; disease /disorder model; endopeptidases; enzyme activity; gene expression; gene targeting; genetically modified animals; genome; hippocampus; laboratory mouse; learning; memory; neuritic plaques; predoctoral investigator; protein structure function; reflex; single cell analysis; voltage /patch clamp

DESCRIPTION (provided by applicant): Abeta has emerged as a key molecule in the pathogenesis of Alzheimer's Disease (AD). This proposal will exploit the dependence of Abeta formation on the availability of the beta-site amyloid cleaving enzyme (BACE1) in order to reduce or block production of Abeta. Transgenic mice that express mutated human amyloid precursor protein (APP) show dramatic elevations in Abeta that parallel those seen in sporadic AD cases. Additionally, these mice show learning deficits and alterations in neuronal biophysical properties that underlie learning. This proposal will test the hypothesis that the removal of BACE1 from the genome will rescue the learning abilities and altered biophysical properties from the overexpression of Abeta in the "Westaway" mouse. Eyeblink conditioning, one of the most well characterized neuro-behavioral systems for learning and memory, and alterations in the amplitude of the afterhyperpolarization (AHP) and spike frequency accommodation (Accom) will respectively be used as behavioral and biophysical assays. The progeny of the Westaway and BACE knockout mice will comprise the four geneotypes that are required to test this hypothesis: The results should indicate whether or not a beta-secretase inhibitor will be a viable therapeutic agent for the treatment of AD.

描述（由申请人提供）： Abeta已成为阿尔茨海默氏病（AD）发病机理的关键分子。该建议将利用Abeta形成对β位点淀粉样蛋白切割酶（BACE1）的可用性的依赖性，以减少或阻止Abeta的产生。表达突变的人淀粉样蛋白前体蛋白（APP）的转基因小鼠在Abeta中表现出显着的升高，这些升高与零星AD病例中看到的升高相似。此外，这些小鼠在学习构成的神经元生物物理特性的学习缺陷和改变。该提案将检验以下假设：从基因组中去除BACE1将从“ Westaway”小鼠中Abeta的过表达中挽救学习能力并改变生物物理特性。 Ekeblink调节是用于学习和记忆的最良好特征的神经行为系统之一，以及余余（AHP）和Spike频率适应性（ACCOM）的幅度的改变，将用作行为和生物物理测定法。西部和贝丝敲除小鼠的后代将构成检验该假设所需的四种基因型：结果应表明β-分泌酶抑制剂是否将是用于治疗AD的可行治疗剂。

项目成果

Bidirectional pattern-specific plasticity of the slow afterhyperpolarization in rats: role for high-voltage activated Ca2+ channels and I h.

• DOI: 10.1111/j.1460-9568.2011.07899.x
• 发表时间: 2011-12
• 期刊: The European journal of neuroscience
• 作者: Kaczorowski CC