Mechanism of Abeta Sequestration

Abeta 封存机制

基本信息

批准号：
7212981
负责人：
YASUJI MATSUOKA
金额：
$ 29.1万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7212981
关键词：
Active Immunization Acute Address Adverse effects Affect Affinity Aftercare Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acid Sequence Amyloid Amyloid beta-Protein Amyloidosis Animal Tarsus Antibodies Antibody Affinity Autologous Binding Binding Sites Biological Assay Biological Markers Biological Process Blood Blood - brain barrier anatomy Brain Brain region Cavia Cerebral Ventricles Clinical Clinical Trials Cognition Collection Complex Condition Consult Data Dementia Deposition Detection Detergents Development Disease District of Columbia Dose Early Diagnosis Elevation Encephalitis Enoxaparin Environment Enzyme-Linked Immunosorbent Assay Equilibrium Extracellular Space Failure Fc Receptor Feasibility Studies Figs - dietary Functional disorder Future Gel Gelsolin Gene Expression Generations Genes Glycosaminoglycans Half-Life Heparin Hour Human Immune Immune response Immunization Immunoglobulin G Immunoglobulins Immunohistochemistry Impaired cognition Inflammatory Infusion procedures Injection of therapeutic agent International Intervention Investigation Kidney Kinetics Knockout Mice Laboratories Lactate Dehydrogenase Length Letters Liver Long-Term Effects Long-Term Potentiation Low-Molecular-Weight Heparin Mass Spectrum Analysis Measurable Measures Mediating Membrane Memory Metabolism Methodology Methods Microdialysis Microglia Molecular Molecular Weight Monitor Mus Mutation Nerve Degeneration Neuraxis New York None or Not Applicable Numbers Organ Outcome Passive Immunization Pathological Staging Pathology Pathway interactions Patients Penetration Peptides Peripheral Permeability Phagocytosis Pharmaceutical Preparations Physiological Plasma Plasma Proteins Pliability Polysaccharides Prealbumin Prevention Principal Investigator Prions Property Protein Overexpression Proteins Radioactivity Radiolabeled Range Rate Rattus Reaction Reducing Agents Reporting Research Research Personnel Research Proposals Running Senile Plaques Site Source Specificity Specimen Spleen Staging Standards of Weights and Measures Synthetic Genes System Techniques Testing Therapeutic Therapeutic Agents Time Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Translating Universities Urine Vaccine Clinical Trial Vaccine Therapy Vaccines Week Western Blotting Withdrawal Work abeta accumulation aged alzhemed amyloid peptide amyloidogenesis base beta-site APP cleaving enzyme 1 brain tissue cognitive function concept day design desire drug development experience extracellular familial Alzheimer disease fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether follow-up glycosylation homotaurine immunoregulation indexing intraneuronal beta amyloid intravenous administration lateral ventricle mimetics monomer mouse model novel passive antibodies peripheral blood programs promoter radiotracer receptor binding research study response small molecule symposium theories therapy development time interval tool treatment duration vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Pathological mutations in familial AD patients have been identified in several genes, and transgenic mice carrying pathological genes have been generated. The generation of transgenic models of amyloidosis has significantly aided progress in the development of therapeutic approaches designed to lower brain amyloid beta (Abeta) load. One of these approaches is called "immunization". Immunologically provoked (or passively administered) antibodies against Abeta have been shown to enhance microglial phagocytosis and reduce Abeta load in the brains of transgenic mice. Significantly, immunization also reversed Abeta associated memory dysfunction. Concomitant with reduced CNS Abeta is the simultaneous observation by us and others that plasma Abeta levels are significantly elevated following immunization. As a result of this observation, we have devised a new methodology to alter brain Abeta load, which has proved to be effective in preliminary studies. In the human active immunization clinical trial, Abeta vaccine approach was terminated after severe brain inflammation was found approximately in 6% of patients. The cause of brain inflammatory side effects is not clear yet, but it is most likely due to immune modulation. Although the first clinical trial of vaccine therapy was terminated, follow up reports are encouraging. Sequestration approach does not modulate immune reaction; therefore, it therapy has higher flexibility in drug development, and drugs based on sequestration approaches have less side effects. In addition, plasma Abeta elevation is a possible biomarker when this approach translates to clinical use. In this study, we will investigate the mechanism of Abeta sequestration mechanism and identify optimal molecular property and drugable target for future development of pharmacological therapy.

描述（由申请人提供）：阿尔茨海默氏病（AD）是与记忆功能障碍相关的神经退行性痛苦。在几种基因中已经鉴定出家族性AD患者的病理突变，并且已经产生了携带病理基因的转基因小鼠。淀粉样变性的转基因模型的产生在旨在降低脑淀粉样β（ABETA）负荷的治疗方法的发展方面具有显着帮助。这些方法之一称为“免疫”。已证明对ABETA的免疫学起（或被动施用）抗体可增强小胶质细胞增多症并减少转基因小鼠大脑中的Abeta负荷。值得注意的是，免疫也逆转了Abeta相关的内存功能障碍。与CNS Abeta降低的同时，我们和其他人同时观察到免疫后血浆Abeta水平显着升高。由于这一观察结果，我们设计了一种新方法来改变脑Abeta负载，事实证明，该方法在初步研究中有效。在人类主动免疫临床试验中，在6％的患者中发现严重的脑部炎症后，ABETA疫苗方法被终止。脑部炎症性副作用的原因尚不清楚，但很可能是由于免疫调节所致。尽管终止了疫苗治疗的第一次临床试验，但后续报告令人鼓舞。隔离方法不会调节免疫反应。因此，IT治疗在药物开发方面具有较高的灵活性，并且基于隔离方法的药物具有较小的副作用。此外，当这种方法转化为临床用途时，血浆Abeta升高是可能的生物标志物。在这项研究中，我们将研究ABETA固存机制的机制，并确定最佳的分子特性和可药物疗法的可药物靶标。