Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

家族性阿尔茨海默病遗传忠实大鼠模型痴呆发病机制的研究

• 批准号: 9899817
• 负责人: LUCIANO D'ADAMIO
• 金额: $ 78.7万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899817
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Brain; Brain Pathology; Brain imaging; C-terminal; Cannulas; Cerebrospinal Fluid; Cerebrum; Cleaved cell; Code; Cognition; Cognitive; Data; Dementia; Deposition; Disease; Early Onset Familial Alzheimer' s Disease; Electrophysiology (science); Familial Dementias; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Polymorphism; Genetic Techniques; Genomics; Human; Human Amyloid Precursor Protein; Human Genetics; Imaging Techniques; Impaired cognition; Intelligence; Knock-in; Learning; Link; Mainstreaming; Memory; Microdialysis; Modeling; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Organism; Pathogenesis; Pathogenicity; Patients; Peptides; Pharmaceutical Preparations; Physiological Processes; Positron-Emission Tomography; Presenile Alzheimer Dementia; Procedures; Process; Protein Isoforms; Protein Precursors; Proteins; Rattus; Regulation; Research; Rodent; Rodent Model; Role; Sampling; Senile Plaques; Signal Transduction; Synaptic Transmission; Tauopathies; Testing; Transgenic Mice; Transgenic Model; Transgenic Organisms; Treatment Efficacy; Variant; Virulence Factors; alpha secretase; amyloid precursor protein processing; autosomal dominant mutation; base; behavior test; beta secretase; beta-site APP cleaving enzyme 1; cognitive function; design; drug efficacy; experimental study; extracellular; familial Alzheimer disease; gamma secretase; genetic approach; genetic manipulation; human disease; hyperphosphorylated tau; implantation; in vivo; insight; loss of function mutation; mouse model; mutant; neuroinflammation; normal aging; overexpression; presenilin-1; presenilin-2; secretase; tau Proteins; therapeutic evaluation; therapeutic target

Project Summary/Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aβ region: given that aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ to form yet-to-be-identified toxic forms of Aβ, together with the Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of A and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic A have a central pathogenic role. We propose to dissect pathogenic mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.

项目摘要/摘要 阿尔茨海默氏病（AD）是世界上依赖老年痴呆症的最常见原因，是 与脑淀粉样斑块有关，主要由AβPepperides组成。这些辣椒是由 淀粉样前体蛋白（APP）的双重切割。 BACE1裂解产生C末端 片段，β-CTF，然后通过γ-分泌酶处理成几种Aβ。遗传数据表明 应用程序处理的监管有助于AD。此外，APP的多态性可减少处理 BACE1的APP可保护偶发的AD，并免受正常衰老依赖性认知能力下降。那， 人类遗传证据表明，应用程序和应用程序处理对于正常的认知功能很重要。 为了洞悉AD的致病机制，我们引入了一个家庭应用突变（瑞典语 K670N/M671L突变，Apps大鼠）和一个家庭PSEN1突变（L435F，PSEN1LF大鼠）进入基因组应用 和PSEN1大鼠基因座。大鼠和人类应用程序的差异在Aβ区域在3个氨基中差异：鉴于这一点 大多数AD中的主要致病因素都认为Aβ的汇总形式，并且鉴于人Aβ 可能比啮齿动物Aβ具有更高的诺言，以形成尚未确定的Aβ的毒性形式 瑞典突变我们引入了突变以“人性化”大鼠Aβ序列。作为控件，我们产生了 仅携带人源化Aβ序列（APPH大鼠）的大鼠。我们选择敲门方法，而不是 更常见的转基因过表达方法，因为Ki模型没有先入为主 关于致病机制的假设，除了公正的遗传机制。相反，转基因模型， 产生高水平的A并容易沉积淀粉样蛋白斑块的基于以下假设： 斑块和/或其他形式的有毒A具有中心的致病作用。我们建议剖析病原 使用这些FAD的这些Ki大鼠模型的神经退行性的机理。我们将研究应用程序的影响 PSEN1 FAD关于应用程序处理，脑病理学，神经炎症和神经变性的突变， 突触传播/可塑性，学习和记忆。此外，我们将评估独特的应用程序衍生的作用 突变APP和PSEN1触发的神经退行性过程中的代谢产物。这些研究将测试 主流假设，但也考虑了替代性致病机制，包括 FAD发病机理可能取决于APP和PSEN1在大脑中的正常功能的改变。