The role of Abeta in injury-induced cell death

Abeta 在损伤诱导的细胞死亡中的作用

• 批准号: 8044951
• 负责人: MARK P BURNS
• 金额: $ 7.68万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044951
• 关键词: Acute; Alzheimer' 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; Transgenic Mice; 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

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(申请人提供)：创伤性脑损伤(TBI)是一个退行性的过程，最初的原发损伤会导致立即的机械性细胞死亡。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。这种持续的损伤被称为继发性损伤，作为这一过程的一部分，多个凋亡和炎症通路被激活。脑外伤后产生的神经毒性成分之一是阿尔茨海默病相关蛋白A？类似于阿尔茨海默氏症的沉积，在暴露于脑外伤后24小时内可见。在淀粉样前体蛋白(APP)被？和？-分泌酶连续切割后产生A。我们最近报道，在非转基因小鼠脑损伤后，A？和APP分泌增加，蛋白水平在创伤后3天达到峰值。我们发现，立即使用β-分泌酶抑制剂(DAPT)可以完全阻断脑损伤后的学习障碍，并使脑损伤体积减少70%。因此，我们认为β-分泌酶是治疗脑外伤的一个有前景的靶点。为了充分利用这一新的目标，设计了一系列关键的实验。首先，计算APP分泌抑制的治疗窗。通过缩小治疗窗口(治疗的开始和结束点)，我们可以确定APP分泌启动继发性损伤的时间，并确定应该维持治疗多久。这些数据将帮助我们确定APP分泌在继发性损伤序列中的哪些方面是重要的，并有助于建立针对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。本申请的目的2研究创伤后β-分泌酶的主要下游靶点APP和A。虽然在它们之间，？和？分泌酶有多个下游靶点，但有一组有限的蛋白质同时被？和？分泌酶切割。鉴于过多的数据表明A？会损害血流、引发炎症和导致细胞凋亡--这些都是继发性损伤的特征--APP/A？是这些靶点中最明显的。这些特定的目的是为了加强我们对β-分泌酶抑制剂作为脑外伤治疗方法的理解，并确定脑外伤后持续的细胞死亡是否通过APP处理而介导。 公共卫生相关性：这项申请旨在确定阿尔茨海默病A肽在创伤性脑损伤(TBI)后的作用。颅脑损伤后，A？水平在伤后数天迅速升高。我们先前已经证明，阻断脑损伤后的分泌酶活性可以减少海马细胞死亡，防止创伤后的学习障碍。分泌酶抑制剂和分泌酶抑制剂目前都在治疗阿尔茨海默病的临床试验中，这使这些药物成为治疗脑损伤的新策略。这一应用将加深我们对APP-分泌酶抑制剂作为治疗脑损伤的理解，并确定脑损伤后持续的细胞死亡是通过APP的裂解还是A？肽的产生而介导的。