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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的机械性细胞死亡。这种损伤还诱导生物化学和细胞变化，随着时间的推移导致持续的神经元损伤和死亡。这种持续的损伤被称为继发性损伤，并且作为该过程的一部分，多种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病相关蛋白A？。与阿尔茨海默病相似的A？沉积物在暴露于TBI后24小时内可见。淀粉样前体蛋白（APP）被<$-和？-连续切割后产生A <$-。分泌酶我们最近报道，在非转基因小鼠TBI后，A？和APP分泌酶升高，蛋白水平在创伤后3天达到峰值。我们发现，立即治疗与？-分泌酶抑制剂（secretase inhibitor，DAPT）可完全阻断TBI后的学习障碍，并使脑损伤体积减少70%。因此，我们的结论是？分泌酶是治疗TBI的一个有前途的靶点。为了充分利用这一新目标，设计了一系列关键实验。首先，计算APP分泌酶抑制的治疗窗。通过缩小治疗窗口（治疗的开始和结束点），我们可以确定APP分泌酶开始继发性损伤的时间，并确定治疗应该维持多久。这些数据将帮助我们确定APP分泌酶在继发性损伤序列中的重要位置，并帮助建立这类抑制剂的治疗策略。其次，从我们的数据中还不清楚APP分泌酶抑制剂的下游靶点是什么。本申请的目标2将APP和A？作为？的主要下游靶标进行检查。创伤后分泌酶而在他们之间呢？分泌酶有多个下游靶点，有一组有限的蛋白质被两种酶切割，分泌酶鉴于大量数据表明A <$可以损害血流，诱导炎症和引起细胞凋亡-所有继发性损伤的标志- APP/A <$是这些靶点中最明显的。具体目标是为了加强我们对？分泌酶抑制剂作为TBI的治疗，并确定TBI后的持续细胞死亡是否通过APP加工介导。公共卫生相关性：本申请旨在确定阿尔茨海默病肽A在创伤性脑损伤（TBI）后的作用。在TBI后的几天内，A水平迅速增加。我们以前已经表明，阻塞？-和？-脑外伤后分泌酶活性的变化可以减少海马细胞的死亡，防止脑外伤后的学习障碍。两个-还有呢？分泌酶抑制剂目前正在进行阿尔茨海默病的临床试验，使这些药物成为TBI的新治疗策略。本申请将增强我们对APP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通过APP的切割或A肽的产生介导。