BACE1 as a Therapeutic Target for Alzheimer's Disease

描述（由申请人提供）：BACE1是阿尔茨海默病（AD）中Abeta生成的限速酶，是主要的药物靶点。BACE1抑制剂药物近期已进入临床试验阶段。然而，这些药物的安全性和有效性尚不清楚。BACE1缺陷（BACE1-/-）小鼠表现出神经表型，表明BACE1抑制剂可能引起基于机制的毒性。然而，BACE1-/-表型可能反映了发育过程中BACE1缺乏的后果，在这种情况下，BACE1抑制剂可能没有副作用。更不确定的是，在AD的哪个阶段，BACE1抑制将是最有效的。本R01将解决三个对开发安全有效的BACE1 AD抑制剂至关重要的问题：1)BACE1在成人中是必需的，还是开发后可有可无？2)发育代偿是否发生在BACE1-/-小鼠中，从而防止BACE1无表型在成年小鼠中出现？3)在AD的哪个阶段，BACE1抑制剂药物最有效：在（预防）症状出现之前还是在（治疗）症状出现之后？为了解决这些问题，我们产生了条件BACE1敲除（BACE1fl/fl）小鼠。在Aim 1中，我们将确定成人BACE1基因失活是否会导致在BACE1-/-小鼠中观察到的神经表型。将BACE1fl/fl小鼠与CamKII¿-iCre小鼠杂交，灭活成年前脑兴奋性神经元中的BACE1。在Aim 2中，我们将确定成人BACE1基因失活是否会在神经系统和外周产生新的BACE1空表型。BACE1fl/fl小鼠将与R26-cre-ERT2小鼠杂交，在给予他莫昔芬后，在全球范围内灭活BACE1。在Aim 3中，我们将确定成人BACE1基因失活是否会在斑块沉积开始后减少淀粉样蛋白负担。BACE1fl / fl;R26-cre-ERT2小鼠将与APPswe/PS1deltaE9淀粉样斑块模型小鼠杂交，在给予他莫昔芬后全面灭活BACE1。对于所有Aims，小鼠将被老化并分析其行为，电生理，组织学和生物化学。此外，将分析Aim 3小鼠的淀粉样斑块负荷和β水平。总之，这些目标将确定BACE1抑制作为一种阿尔茨海默病治疗策略在其潜在副作用和疗效方面的总体效用。

DESCRIPTION (provided by applicant): BACE1 is the rate-limiting enzyme for Abeta generation in Alzheimer's disease (AD) and is a prime drug target. BACE1 inhibitor drugs have recently entered into clinical trials. However, the safety and efficacy of these agents are unknown. BACE1 deficient (BACE1-/-) mice exhibit neurological phenotypes, suggesting BACE1 inhibitors may incur mechanism-based toxicities. However, BACE1-/- phenotypes may reflect consequences of BACE1 deficiency during development, in which case BACE1 inhibitors may be free of side effects. Even more uncertain is the stage of AD at which BACE1 inhibition would be most efficacious. This R01 will address three questions that are critical for the development of safe, effective BACE1 inhibitors for AD: 1) Is BACE1 required in the adult, or dispensable after development? 2) Does developmental compensation occur in BACE1-/- mice, preventing BACE1 null phenotypes that would otherwise appear in the adult? 3) At what stage of AD will BACE1 inhibitor drugs be most effective: before (prevention) or after (treatment) symptom onset? To address these questions, we have generated conditional BACE1 knockout (BACE1fl/fl) mice. In Aim 1, we will determine whether BACE1 gene inactivation in the adult causes neurological phenotypes that are observed in BACE1-/- mice. BACE1fl/fl mice will be bred with CamKII¿-iCre mice to inactivate BACE1 in excitatory neurons of the adult forebrain. In Aim 2, we will determine whether BACE1 gene inactivation in the adult produces novel BACE1 null phenotypes in the nervous system and periphery. BACE1fl/fl mice will be bred with R26-cre-ERT2 mice to inactivate BACE1 globally following administration of tamoxifen. In Aim 3, we will determine whether BACE1 gene inactivation in the adult will reduce amyloid burden after the start of plaque deposition. BACE1fl/fl; R26-cre-ERT2 mice will be bred with APPswe/PS1deltaE9 amyloid plaque model mice to inactivate BACE1 globally following administration of tamoxifen. For all Aims, mice will be aged and analyzed for behavior, electrophysiology, histology, and biochemistry. In addition, Aim 3 mice will be analyzed for amyloid plaque load and Abeta levels. Together, these Aims will determine the overall utility of BACE1 inhibition as an AD therapeutic strategy in terms of its potential side effect profile and efficacy.