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

随着BACE 1作为参与阿尔茨海默病（AD）中β-淀粉样蛋白（Abeta）肽产生的β-分泌酶的发现，我们开始了一系列研究来检查这种跨膜β-淀粉样蛋白酶的功能作用。我们已经提供了证据来支持我们的假设，即BACE 1和BACE 2的分布和水平，沿着APP，是脑对A β淀粉样变性的选择性易感性的关键决定因素。重要的是，BACE 1的缺失消除了Abeta沉积，并防止了突变型APP;PS1小鼠大脑中发生的认知缺陷。虽然BACE 1基因敲除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发生了变化。项目1的目标是评估BACE 1和BACE 2的功能作用，并严格评估BACE 1作为高优先级治疗靶点的作用 治疗AD。因此，目的1中的研究旨在检查BACE 1-/-、BACE 2-/-或BACE 1-/-; BACE 2-/-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，我们计划研究AP swe; PS1 deltaE 9小鼠中Abeta肽异常积累和突触异常之间的联系。这些研究对于目标3至关重要，其旨在评估在A β淀粉样变性的不同阶段BACE 1实验性减少后的可逆性/恢复程度， 退化我们预计，新的机制为基础的治疗，如BACE 1抑制剂将在未来成为可用的，因此，重要的是要前瞻性地解决的问题的可逆性Abeta诱导的异常和大脑的能力，以修复自己。目的3中的研究旨在确定Abeta沉积和相关异常在Abeta沉积开始后不同时间的BACE 1活性降低后可以逆转的程度。总之，这些研究的结果将提供关于BACE 1和BACE 2的生理作用的重要信息，并允许 对BACE 1作为治疗靶点降低AD患者Abeta负荷的关键评价。此外，这些研究提供了关于与抗BACE 1治疗相关的潜在机制毒性的重要信息，未来应在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.