The role of Abeta in injury-induced cell death

Abeta 在损伤诱导的细胞死亡中的作用

基本信息

批准号：
8126336
负责人：
MARK P BURNS
金额：
$ 7.52万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8126336
关键词：
Acute Alzheimer&apos s Disease American Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Antibodies Apoptosis Apoptotic Behavioral Biochemical Blood flow Brain Cell Count Cell Death Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Cleaved cell Clinical Clinical Trials Data Deposition Elements Exposure to Hippocampus (Brain)Hospitalization Hour Human Impairment Inflammation Inflammatory Injury Knock-out Knockout Mice Learning Length Lesion Life Mechanics Mediating Multiple Trauma Mus Neuroglia Neurons Outcome Passive Immunization Pathway interactions Peptides Pharmaceutical Preparations Process Production Proteins Reporting Role Set protein Site Therapeutic Therapeutic Agents Therapeutic Effect Time Trauma Traumatic Brain Injury Work amyloid precursor protein processing cost design disability experience inhibitor/antagonist mouse model neurotoxic novel novel therapeutics prevent public health relevance research study secretase

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a degenerative process, with an initial primary injury which causes immediate mechanical cell death. This injury also induces biochemical and cellular changes that contribute to continuing neuronal damage and death over time. This continuing damage is known as secondary injury, and multiple apoptotic and inflammatory pathways are activated as part of this process. One of the neurotoxic elements produced following TBI is the Alzheimer's disease-related protein A¿. A¿ deposits, similar to those in Alzheimer's disease, are seen within 24 hours after exposure to TBI. A¿ is produced following sequential cleavage of the amyloid precursor protein (APP) by ¿- and ?-secretase. We have recently reported that A¿ and the APP secretases are elevated in non-transgenic mice following TBI, with protein levels peaking at 3 days post-trauma. We found that immediate treatment with a ?- secretase inhibitor (DAPT) can completely block the learning deficits following TBI, and reduce brain lesion volume by 70%. Thus, we conclude that ?- secretase is a promising target for treatment of TBI. In order to fully exploit this new target, a key set of experiments have been designed. Firstly, the therapeutic window for APP secretase inhibition will be calculated. By narrowing the treatment window (both the start and end points of treatment), we can determine the time at which APP secretases are initiating secondary injury, and determine how long treatment should be maintained. This data will help us identify where in the sequence of secondary injury that APP secretases are important, and help to establish a therapeutic strategy for this class of inhibitors. Secondly, it is unclear from our data what the downstream target of APP secretase inhibitors are. Aim 2 of this application examines APP and A¿ as primary downstream targets of ?-secretase following trauma. While between them ¿- and ?-secretase have multiple downstream targets, there are a limited set of proteins that are cleaved by both ¿- and ?-secretase. Given the excess of data suggesting that A¿ can impair blood flow, induce inflammation and cause apoptosis - all hallmarks of secondary injury - APP/A¿ is the most apparent of these targets. The specific aims are designed to enhance our understanding of ?- secretase inhibitors as a treatment for TBI, and to determine if the continuing cell death following TBI is mediated through APP processing. PUBLIC HEALTH RELEVANCE: This application aims to establish the role of the Alzheimer's disease peptide A¿ after traumatic brain injury (TBI). A¿ levels rapidly increase after TBI in the days following injury. We have previously shown that blocking ¿- and ?- secretase activity after TBI can reduce hippocampal cell death and prevent learning impairments after trauma. Both ¿- and ?- secretase inhibitors are currently in clinical trials for Alzheimer's disease, making these drugs a novel therapeutic strategy for TBI. This application will enhance our understanding of APP-secretase inhibitors as a treatment for TBI, and determine if the continuing cell death following TBI is mediated through cleavage of APP or production of the A¿ peptide.

描述（由申请人提供）：创伤性脑损伤（TBI）是一种退行性过程，最初的原发性损伤会导致立即机械性细胞死亡，这种损伤还会引起生化和细胞变化，随着时间的推移，这些变化会导致持续的神经元损伤和死亡。损伤被称为继发性损伤，作为该过程的一部分，多种细胞凋亡和炎症途径被激活，TBI 后产生的神经毒性元素之一是阿尔茨海默氏病相关蛋白 A¿ 。与阿尔茨海默氏病中的沉积物类似，在接触 TBI 后 24 小时内就会出现沉积物。是在淀粉样前体蛋白 (APP) 被 ¿ 连续裂解后产生的- 和 ?- 分泌酶我们最近报道了 A¿ TBI 后非转基因小鼠的 APP 分泌酶升高，蛋白质水平在创伤后 3 天达到峰值。我们发现立即使用 β-分泌酶抑制剂 (DAPT) 治疗可以完全阻止 TBI 后的学习缺陷，并减少。因此，我们得出结论，β-分泌酶是治疗 TBI 的一个有希望的靶点，为了充分利用这一新靶点，我们设计了一组关键的实验。通过缩小治疗窗口（治疗的起点和终点），我们可以计算 APP 分泌酶抑制作用，我们可以确定 APP 分泌酶开始继发性损伤的时间，并确定治疗应维持多长时间。我们确定了 APP 分泌酶在继发性损伤序列中的重要位置，并有助于制定此类抑制剂的治疗策略。其次，从我们的数据中尚不清楚此类 APP 分泌酶抑制剂的下游靶标是什么。应用检查 APP 和 A¿作为创伤后β-分泌酶的主要下游靶标。 - 和 ?-分泌酶有多个下游靶标，因此 ¿ 和 ? 都切割有限的一组蛋白质- 和 ?- 分泌酶鉴于过量的数据表明 A¿会损害血流、诱发炎症并导致细胞凋亡 - 所有继发性损伤的标志 - APP/A¿是这些目标中最明显的目标，其具体目的是为了增强我们对β-分泌酶抑制剂作为TBI治疗的理解，并确定TBI后的持续细胞死亡是否是通过APP处理介导的。公共健康相关性：本申请旨在确定阿尔茨海默病肽 A 的作用创伤性脑损伤（TBI）后。在受伤后的几天内，TBI 水平迅速升高，我们之前已经证明，阻塞 ¿ TBI 后的 - 和 - 分泌酶活性可以减少海马细胞死亡并预防创伤后的学习障碍。 -和β-分泌酶抑制剂目前正处于阿尔茨海默氏病的临床试验中，使这些药物成为治疗TBI的新策略。该应用将增强我们对APP-分泌酶抑制剂作为TBI治疗的理解，并确定是否会导致持续的细胞死亡。 TBI 通过 APP 的裂解或 A 的产生来介导肽。