Role of BACE stabilization in Alzheimer's Disease (AD)

BACE 稳定性在阿尔茨海默病 (AD) 中的作用

基本信息

批准号：
7568266
负责人：
GIUSEPPINA TESCO
金额：
$ 1.03万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568266
关键词：
AP40 Adaptor Signaling Protein Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amino Acids Amyloid Amyloid beta-Protein Precursor Animal Model Apoptosis Apoptotic Applications Grants Aspartic Endopeptidases BACE stabilization Brain Hypoxia-Ischemia Caspase Caspase Inhibitor Cell Culture Techniques Cell Death Cells Cerebral Ischemia Cerebrovascular Disorders Cerebrum Chemicals Chemosensitization Cleaved cell Complex Craniocerebral Trauma Cytochromes Data Dementia Deposition Development Dominant-Negative Mutation Down-Regulation Etoposide Event Fostering Generations Genetic Glucose Goals Human In Vitro Induction of Apoptosis Injection of therapeutic agent Ischemia Knowledge Lead Lysosomes Mediating Membrane Memory Loss Messenger RNA Modeling Molecular Molecular Chaperones Mus Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neurons Oxygen Pathogenesis Pathway interactions Peptides Plasmids Play Process Production Proteins Proteolysis RNA Interference Rattus Receptor Activation Research Personnel Research Proposals Resistance Risk Risk Factors Rodent Model Role Senile Plaques Site Site-Directed Mutagenesis Small Interfering RNA Sorting - Cell Movement Staurosporine Stroke Synapses System Techniques Testing Tg2576 Therapeutic Intervention Toxic effect Traumatic Brain Injury age effect amyloid precursor protein processing base beta-site APP cleaving enzyme 1 caspase-3 caspase-8 caspase-9 cell type cognitive function deprivation extracellular human PEN-2 protein in vitro Model in vivo member mouse model mutant nicastrin protein novel novel therapeutics overexpression presenilin prevent programs receptor secretase trafficking

项目摘要

Description (provided by the applicant): Aging, genetic factors and head trauma are major risk factors for Alzheimer's disease (AD). Additionally, stroke significantly increases the risk of Alzheimer's disease, operating as either a precipitating or "triggering" event. Apoptosis and increased Aa42 production have both been associated with stroke and head trauma. While there is an increasing body of knowledge indicating a strong association between cerebrovascular disease and Alzheimer's disease, the role of apoptosis and cerebral ischemia in Alzheimer's disease remains unclear. The central hypothesis of this research proposal is that conditions associated with apoptosis/caspase activation (e.g cerebral ischemia) increase BACE protein levels and a-secretase activity resulting in a potentiation of the amyloidogenic processing of APP leading to a vicious cycle of Aa toxicity/production. This hypothesis is strongly supported by our in vivo and in vitro preliminary data showing that a-secretase levels and activity are increased during apoptosis, leading to elevated total Aa and Aa42 levels in a variety of cell types (including primary neurons), and cerebral ischemia models in rats and mice. We have also discovered that the elevated activity of a-secretase during apoptosis is the result of increased protein stability of BACE following caspase activation. Caspase inhibition by treatment with zVAD, a broad spectrum caspase inhibitor is able to prevent the stabilization of BACE and the increase in Aa production. Regarding mechanism of stabilization, we have also discovered that BACE is degraded by the lysosomes and that GGA3, an adaptor protein involved in BACE intracellular trafficking, is a novel caspase substrate that it is cleaved during apoptosis. The latter was observed both in in vitro cell cultures and in vivo in rodent models of cerebral ischemia. The objective of this grant proposal is to determine the molecular mechanisms that regulate the activity and stability of a-secretase associated with apoptosis/caspase activation both in vitro and in animal models of ischemia. Specifically, we propose: 1: To determine the extent to which GGA3 affects BACE stability under normal conditions and during apoptosis; 2: To determine which caspase(s) play a role in BACE stabilization (and increased Aa generation) during apoptosis; 3: To determine the extent to which caspase-mediated increase in BACE protein levels and a-secretases activity contributes to increased Aa production in vivo.

描述（由申请人提供）：衰老，遗传因素和头部创伤是阿尔茨海默氏病（AD）的主要危险因素。此外，中风大大增加了阿尔茨海默氏病的风险，作为促成或“触发”事件的运行。凋亡和AA42产量增加都与中风和头部创伤有关。尽管知识的越来越多，表明脑血管疾病与阿尔茨海默氏病之间存在密切的联系，但凋亡和脑缺血在阿尔茨海默氏病中的作用尚不清楚。该研究提案的中心假设是，与凋亡/caspase激活（例如脑缺血）相关的条件会增加BACE蛋白水平和A-凝聚酶的活性，从而增强了应用程序的淀粉样蛋白源性处理，从而导致AA毒性/产生的恶性循环。该假设得到了我们的体内和体外初步数据的强烈支持，表明在凋亡过程中A-分泌酶的水平和活性增加，导致多种细胞类型（包括原发性神经元）和大鼠和小鼠的多种细胞类型（包括原发性神经元）的总AA和AA42水平升高。我们还发现，凋亡过程中A分泌酶的活性升高是胱天蛋白酶激活后贝叶蛋白质稳定性提高的结果。通过用ZVAD处理caspase抑制作用，广谱caspase抑制剂能够防止贝丝的稳定和AA产生的增加。关于稳定机制，我们还发现，贝丝被溶酶体降解，而GGA3是一种参与乳胶细胞内运输的衔接蛋白，是一种新型的caspase底物，其在凋亡过程中被裂解。在体外细胞培养物和脑缺血模型中都观察到后者。该赠款提案的目的是确定调节与凋亡/caspase激活A-分泌酶的活性和稳定性的分子机制，无论是在体外和缺血模型中。具体而言，我们提出：1：确定GGA3在正常条件下和凋亡期间影响BACE稳定性的程度； 2：确定哪些胱天蛋白酶在凋亡过程中在贝斯稳定（和AA产生增加）中起作用； 3：确定caspase介导的乳液蛋白水平和A-分泌酶活性的升高程度有助于体内的AA产生。