APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD

转基因小鼠、家族性和散发性 AD 中的 APP/AB/Tau 生物化学

基本信息

批准号：
8279286
负责人：
ALEX E ROHER
金额：
$ 34.09万
依托单位：
BANNER SUN HEALTH RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279286
关键词：
AD transgenic mice Accounting Active Immunization Affect Affinity Age Age of Onset Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease model American Amino Acids Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animal Model Asses Biochemical Biochemistry Bioinformatics Biological Models Brain Cerebrum Chemicals Chemistry Cleaved cell Clinical Clinical Trials Databases Dementia Deposition Detection Development Diagnostic Disease Elderly Employee Strikes Engineering Enzymes Evaluation Exhibits Functional disorder Future Genes Genetic Goals Histology Human Human Characteristics Immunization Immunoassay Immunotherapy Individual Intervention Knowledge Mass Spectrum Analysis Membrane Membrane Microdomains Metabolic Microtubule Proteins Mitochondria Molecular Mouse Protein Mus Mutation Nature Neurodegenerative Disorders Neuroglia Neurons Organelles Outcome Passive Immunization Pathogenesis Pathologic Patients Peptides Pharmaceutical Preparations Plasma Presenile Alzheimer Dementia Process Protein Precursors Protein Sequence Analysis Protocols documentation Quality of life Role Route Senile Plaques Techniques Testing Tg2576 Therapeutic Therapeutic Agents Therapeutic Intervention Transgenes Transgenic Mice Transgenic Organisms Treatment Efficacy Western Blotting alpha synuclein base beta-site APP cleaving enzyme 1 case control cost density design efficacy testing familial Alzheimer disease gray matter mitochondrial membrane molecular phenotype mouse model next generation novel presenilin presenilin-1 presenilin-2 prevent public health relevance response secretase success synuclein tau Proteins tau mutation tool white matter

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA and this number is projected to quadruple by 2050. This neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of over $100 billion annually. There is an urgent need for effective therapeutic interventions that may prevent, delay the age of onset or relent the course of this dementia. Transgenic (Tg) mice expressing human AD genes such as amyloid-¿ precursor protein (APP), presenilin (PS), the microtubule protein tau, ¿-amyloid cleaving enzyme-1 (BACE-1), and a-synuclein have provided tools to investigate both the pathogenesis and the efficacy of treatments for these neuropathological disorders. Our goal, in Specific Aim 1, is to better understand the strengths and limitations of several Tg mice models by establishing the degree of biochemical similarities and differences between these paradigms and human AD subjects. In Specific Aim 2, soluble and deposited A¿ remaining after anti- A¿ active and passive immunizations of AD patients will be quantitatively and qualitatively assessed in gray and white matter and cerebral vasculature to evaluate the effects of immunization on A¿ dynamics and its clinical impact on the course of AD. In Specific Aim 3, the APP and A¿ peptides retained in the brain microsomal, mitochondrial and lipid raft brain fractions in AD and non-demented controls will be determined to better understand the role of neuronal and glial participation in the pathophysiology of AD. To achieve these three objectives physicochemical techniques involving the use of density and affinity gradients, chaotropic agents, multiple chromatographic separations, amino acid analysis, peptide sequencing, mass spectrometry, bioinformatics data bases, immunoassays and Western blotting will be implemented. The proposed studies will: 1) aid in the accurate interpretation of Tg mouse experimental responses, 2) help to elucidate at the molecular level the direct and indirect effects of anti- A¿ immunization and 3) discover the pathological consequences, beyond soluble A¿ and deposited amyloid, of membrane-retained APP/ A¿ peptides. A more complete understanding of AD molecular phenotypes and their clinical responses will aid in the discovery and application of efficacious treatments that will prevent AD or enhance the quality of life of AD patients. PUBLIC HEALTH RELEVANCE: More than 5 million Americans already suffer from Alzheimer's disease and this number is expected to quadruple by the year 2050, making the development of effective remedial interventions to prevent, delay the onset or slow the progression of this devastating dementia a national imperative. We know neither the cause nor posses a means to cure AD today, but meticulous chemical studies of human brains and animal models will help to elucidate the fundamental molecular basis of Alzheimer's disease and reveal the precise pathological changes that occur in the human brain during the development of this disease. This knowledge will provide the essential bases for the development of the next generation of medicinal interventions that will prevent Alzheimer's disease or enhance the quality of life of individuals with this dementia.

描述（由适用提供）：阿尔茨海默氏病（AD）是一种痴呆症，影响了美国的400万个个人，该数字预计到2050年。到2050年。这一神经退行性疾病罢工在65岁时的4％的人罢工4％，其中多达85岁的年龄超过100亿美元。迫切需要进行有效的治疗干预措施，这可能会阻止，延迟发病年龄或不放松这种痴呆症的过程。表达人AD基因的转基因（TG）小鼠，例如淀粉样蛋白 - 前体蛋白（APP），Presenilin（PS），微管蛋白tau， - - 氨基蛋白裂解酶-1（BACE-1）和A-突触核蛋白提供了用于调查这些Neuropathoction and Neuropation的工具。在特定目标1中，我们的目标是通过建立这些范式和人类广告主体之间的生化相似性和差异的程度来更好地了解几种TG小鼠模型的优势和局限性。在特定的目标2中，在抗A主动和被动免疫抑制后，将在灰色和白质以及脑脉管系统中进行定量评估，并定性地评估AD患者的主动和被动免疫抑制后，并保留了脑抑制对AD的影响，以评估免疫抑制对A动力学对AD动力学的影响及其对广告的临床影响。在特定的目标3中，将确定在AD和非痴呆对照中保留的APP和A肽保留在AD和非痴呆对照中的APPIDE和脂质筏级分数，以更好地了解神经元和神经胶质参与AD的病理生理学的作用。为了实现这三种目标的物理技术，将实施参与使用密度和亲和力梯度的使用，交际剂，多种色谱分离，氨基酸分析，肽测序，质谱，生物信息图数据盆，免疫测定和蛋白质印迹。拟议的研究将：1）有助于对TG小鼠实验反应的准确解释，2）有助于在分子水平上阐明抗Am抗免疫的直接和间接作用，以及3）发现固体A检验的病理后果，超越固体A和沉积的淀粉样蛋白，对膜上固定的应用程序App/ A apeptides。对AD分子表型及其临床反应的更全面了解将有助于发现和应用有效的治疗，从而阻止AD或增强AD患者的生活质量。公共卫生相关性：超过500万美国人已经患有阿尔茨海默氏病，预计到2050年，这一数字有望达到四倍，从而发展有效的补救干预措施，以防止，延迟或减缓这种毁灭性痴呆症的发展或减缓国家势力。我们不知道原因也不构成今天治愈AD的手段，但是对人的大脑和动物模型的细致化学研究将有助于阐明阿尔茨海默氏病的基本分子基础，并揭示该疾病发展过程中人脑中发生的精确病理变化。这些知识将为开发下一代医疗干预措施的发展提供基本基础，从而预防阿尔茨海默氏病或提高这种痴呆症患者的生活质量。