Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease

阿尔茨海默氏病 BACE1 升高的分子神经病理学和机制

基本信息

批准号：
7248235
负责人：
ROBERT J VASSAR
金额：
$ 32.17万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2007-09-15 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7248235
关键词：
5&apos Untranslated Regions Acute Address Adverse effects Age Alzheimer&apos s Disease Amyloid Amyloid deposition Antibodies Appendix Attention Biochemical Biological Markers Brain Calcium Calpain Cell Culture System Cells Cellular Stress Cessation of life Characteristics Chronic Cleaved cell Clinical Critical Pathways Cultured Cells Dementia Dependovirus Development Disease Progression Disease regression Dominant-Negative Mutation Elderly Elevation Emotional Emotional Disturbance Enzymes Epidemic Foundations Functional disorder Gene Targeting Generations Human Immunoblotting Immunohistochemistry Impaired cognition In Vitro Incidence Individual Inflammation Injection of therapeutic agent Knockout Mice Lead Luciferases Measures Memory Memory impairment Messenger RNA Modeling Molecular Molecular Profiling Mus Nerve Degeneration Neuroblastoma Neuroglia Neurons Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathway interactions Peptide Initiation Factors Peptides Phosphotransferases Play Process Production Protein Overexpression RNA Interference Religion and Spirituality Reporter Reporting Research Personnel Role Senile Plaques Signal Pathway Signal Transduction Site Stress Structure System Testing Tg2576 Therapeutic Time Tissues Transfection Transgenic Mice Transgenic Organisms Translational Regulation Work aging population amyloid pathology beta-site APP cleaving enzyme 1 biological adaptation to stress brain tissue clinical Diagnosis cognitive function frontal lobe genetic activator genetic analysis immunoreactivity in vivo in vivo Model inhibitor/antagonist insight interest mild neurocognitive impairment morris water maze neuropathology novel therapeutics programs research study response secretase small hairpin RNA therapeutic target

项目摘要

DESCRIPTION (provided by applicant): 3-Secretase BACE1 generates the A¿ peptide involved in Alzheimer's disease (AD). Inhibition of BACE1 for towering A¿ in Alzheimer's disease should be efficacious, however memory and emotional deficits in BACE1 knockout mice suggest that BACE1 inhibition may have side-effects. BACE1 levels are increased in Alzheimer's disease, suggesting that BACE1 elevation may play a role in Alzheimer's disease. We have shown that acute energy inhibition elevates BACE1 and in brains of Tg2576 mice, and our results indicate that chronic energy inhibition increases amyloid in Tg2576. We also observe elevated BACE1 around plaques in Alzheimer's disease, Tg2576, and in our new rapid amyloid model, 5XFAD mice. BACE1 elevation is not the result of increased BACE1 mRNA levels, suggesting a post- transcriptional mechanism. Two important questions arise: 1) Is BACE1 elevation involved in AD progression? 2) What is the molecular mechanism of BACE1 elevation? We will address these questions using a combination of molecular, cellular, and genetic analyses of human Alzheimer's disease, mouse Alzheimer's disease, and cell cultures. First, we will determine the molecular profile of BACE1 elevation in Alzheimer's disease. AD mice will then serve as in vivo models of BACE1 elevation, and cell cultures will be used to dissect molecular mechanism. We will then return to human Alzheimer's disease to verify the mechanism and use AD mice as experimental systems to interfere with the mechanism, block BACE1 elevation, and ameliorate amyloid pathology and memory deficits. Our overall hypothesis is that chronic cellular stress during AD results in sustained low-level increases of BACE1 and A¿ that drive AD pathogenesis. AIM1: Determine the molecular profile of BACE1-positive plaques, and examine their relation to amyloid and to clinical AD and level of cognitive function assessed proximate to death. Aim2: Determine the molecular and cellular characteristics of the BACE1 elevation with age in APR transgenic mice and compare to human Alzheimer's disease. AIM3: Determine the molecular mechanism and pathway of the BACE1 elevation in vitro. Aim4: Validate the BACE1-elevating molecular pathway in Alzheimer's disease and APR transgenic brain and determine whether inhibition of the pathway in APR transgenic mice will slow progression of amyloid pathology. Alzheimer's disease is the leading cause of dementia in the elderly and there is no cure. The incidence of Alzheimer's disease will increase due to the aging population, indicating an impending AD epidemic. Inhibition of BACE1 elevation should reduce A¿ without directly blocking BACE1 and thus may be efficacious without side-effects for Alzheimer's disease.

描述（应用程序提供）：3-分泌酶Bace1产生参与阿尔茨海默氏病（AD）的肽。在阿尔茨海默氏病中抑制BACE1高耸的a资金应有效，但是记忆和情感在BACE1敲除小鼠中定义了Bace1抑制作用可能具有副作用。阿尔茨海默氏病的BACE1水平升高，表明BACE1升高可能在阿尔茨海默氏病中起作用。我们已经表明，急性能量抑制可提高BACE1和TG2576小鼠的大脑，我们的结果表明，慢性能量抑制会增加TG2576中的淀粉样蛋白。我们还观察到阿尔茨海默氏病TG2576的斑块周围的Bace1升高，以及我们新的快速淀粉样蛋白模型5xFAD小鼠。 BACE1升高不是Bace1 mRNA水平升高的结果，这表明转录后机制。出现了两个重要的问题：1）BACE1升高是否参与AD进展？ 2）BACE1升高的分子机制是什么？我们将使用人类阿尔茨海默氏病，小鼠阿尔茨海默氏病和细胞培养的分子，细胞和遗传分析的结合来解决这些问题。首先，我们将确定阿尔茨海默氏病BACE1升高的分子谱。然后，AD小鼠将用作BACE1升高的体内模型，细胞培养物将用于剖析分子机制。然后，我们将回到人类阿尔茨海默氏病以验证机制，并使用AD小鼠作为实验系统来干扰机制，阻断BACE1升高以及改善淀粉样蛋白病理学和记忆缺陷。我们的总体假设是，在AD期间，慢性细胞应激导致持续的Bace1和A。持续的低水平增加，从而驱动AD发病机理。 AIM1：确定BACE1阳性斑块的分子谱，并检查其与淀粉样蛋白的关系以及与临床功能的临床AD和临床水平相关的关系。 AIM2：在APR转基因小鼠中确定BACE1升高的分子和细胞特征，并与人类阿尔茨海默氏病进行比较。 AIM3：在体外确定BACE1升高的分子机制和途径。 AIM4：验证阿尔茨海默氏病和APR转基因大脑中的BACE1升级分子途径，并确定APR转基因小鼠中对途径的抑制是否会降低淀粉样蛋白病理的进展。阿尔茨海默氏病是古老的痴呆症的主要原因，无法治愈。阿尔茨海默氏病的事件将由于人口老龄化而增加，表明即将出现的AD流行。 BACE1升高的抑制作用应减少A?未直接阻止BACE1，因此在没有阿尔茨海默氏病的副作用的情况下可能是有效的。