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

随着BACE1作为参与阿尔茨海默病(AD)中β-淀粉样多肽(Abeta)生成的β-分泌酶的发现，我们开始了一系列的研究，以探讨这种跨膜天冬氨酸蛋白酶的功能作用。我们提供的证据支持了我们的假设，即BACE1和BACE2以及APP的分布和水平是大脑选择性易患Abeta淀粉样变性的关键决定因素。重要的是，BACE1的缺失消除了Abeta的沉积，并防止了突变型APP；PS1小鼠大脑中发生认知障碍。虽然BACE1基因缺失的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绪测试中的表现确实发生了变化。项目1的目标是评估BACE1和BACE2的功能作用，并严格评估BACE1作为高优先级治疗靶点 治疗阿尔茨海默病。因此，目标1中的研究旨在检查BACET1-/-、BACE2-/-或BACE1-/-；BACE2-/-小鼠是否存在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多肽的异常积累和突触异常之间的联系。这些研究对AIM 3至关重要，该研究旨在评估Abeta淀粉样变性不同阶段BACE1实验降低后的可逆性/恢复程度。 退化。我们预计未来将有新的基于机制的治疗方法，如BACE1抑制剂，因此，前瞻性地解决Abeta诱导的异常的可逆性和大脑自我修复能力的问题是重要的。AIM 3中的研究旨在确定在Abeta沉积开始后不同时间BACE1活性降低后，Abeta沉积及其相关异常可以在多大程度上逆转。总之，这些研究的结果将提供关于BACE1和BACE2的生理作用的重要信息，并允许 对BACE1作为治疗靶点在努力减少AD患者的Abeta负担方面的关键评估。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，这些毒性应在未来的临床试验中仔细监测。

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.