BACE1 and BACE2 in Cognition and Models of A-beta Amyloidosis

BACE1 和 BACE2 在 A-β 淀粉样变性认知和模型中的作用

• 批准号: 6968993
• 负责人: DONALD L PRICE
• 金额: $ 31.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968993
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; aspartic endopeptidases; behavior test; cognition disorders; disease /disorder model; enzyme activity; enzyme mechanism; genetically modified animals; laboratory mouse; protease inhibitor; protein degradation; protein localization

With the discovery of BACE1 as the beta-secretase involved in the generation of beta-amyloid (Abeta) peptides in Alzheimer's disease (AD), we embarked on a series of studies to examine the functional roles of this transmembrane aspartyl protease. We have provided evidence to support our hypothesis that the distributions and levels of BACE1 and BACE2, along with APP, are key determinants of selective vulnerability of brain to Abeta amyloidosis. Importantly, deletion of BACE1 abolished Abeta deposition and prevented cognitive deficits occurring in brains of mutant APP;PS1 mice. Although BACE1 null mice do not exhibit overt developmental abnormalities, our recent studies show that these animals do manifest alterations in performance on tests of cognition and emotion. The goal of Project 1 is to assess the functional roles of BACE1 and BACE2 and to evaluate critically BACE1 as a high priority therapeutic target for treatment of AD. Thus, studies in Aim 1 are designed to examine whether deficits in synaptic functions or cognitive/behavioral abnormalities occur in BACET1-/-, BACE2-/-, or BACE1-/-;BACE2-/- mice. In Aim 2, we plan to examine the link between abnormal accumulations of Abeta peptides and synaptic abnormalities occurring in APPswe;PS1deltaE9 mice. These studies are critical for Aim 3, which are designed to assess the degree of reversibility/recovery following experimental reductions of BACE1 at different stages of Abeta amyloidosis and degeneration. We anticipate that novel mechanism-based treatments such as BACE1 inhibitors will become available in the future, and it is therefore important to prospectively address the issues of the reversibility of Abeta induced abnormalities and the capacity of the brain to repair itself. Investigations in Aim 3 are designed to determine to what extent Abeta deposition and associated abnormalities can be reversed following reduction of BACE1 activity at various times after the initiation of Abeta deposition. Taken together, results from these studies will provide important information regarding the physiological roles of BACE1 and BACE2 and allow a critical evaluation of BACE1 as a therapeutic target in efforts to reduce Abeta burden in individuals with AD. Furthermore, these studies provide important information regarding potential mechanism based toxicities associated with anti-BACE1 therapy in humans that should be carefully monitored in clinical trials in the future.

随着发现 BACE1 作为参与阿尔茨海默病 (AD) 中 β-淀粉样蛋白 (Abeta) 肽生成的 β 分泌酶，我们开展了一系列研究来检验这种跨膜天冬氨酰蛋白酶的功能作用。我们提供了证据来支持我们的假设，即 BACE1 和 BACE2 以及 APP 的分布和水平是大脑选择性易受 Abeta 淀粉样变性影响的关键决定因素。重要的是，BACE1 的缺失消除了 Abeta 沉积，并防止了突变 APP;PS1 小鼠大脑中发生的认知缺陷。尽管 BACE1 缺失小鼠没有表现出明显的发育异常，但我们最近的研究表明，这些动物在认知和情感测试中的表现确实出现了变化。项目 1 的目标是评估 BACE1 和 BACE2 的功能作用，并严格评估 BACE1 作为高度优先的治疗靶点 用于治疗AD。因此，目标 1 中的研究旨在检查 BACET1-/-、BACE2-/- 或 BACE1-/-;BACE2-/- 小鼠中是否发生突触功能缺陷或认知/行为异常。在目标 2 中，我们计划检查 APPswe;PS1deltaE9 小鼠中 Abeta 肽的异常积累与突触异常之间的联系。这些研究对于目标 3 至关重要，旨在评估 Abeta 淀粉样变性不同阶段实验性减少 BACE1 后的可逆性/恢复程度 退化。我们预计未来将出现基于机制的新型治疗方法，例如 BACE1 抑制剂，因此前瞻性地解决 Abeta 诱导异常的可逆性和大脑自我修复能力的问题非常重要。目标 3 的研究旨在确定在 Abeta 沉积开始后的不同时间 BACE1 活性降低后，Abeta 沉积和相关异常可以在多大程度上逆转。总而言之，这些研究的结果将提供有关 BACE1 和 BACE2 生理作用的重要信息，并允许 对 BACE1 作为减少 AD 患者 Abeta 负担的治疗靶点进行了严格评估。此外，这些研究提供了与人类抗 BACE1 治疗相关的潜在机制毒性的重要信息，应在未来的临床试验中仔细监测。