Vasopeptidases and Beta Amyloid Accumulation

说明(申请人提供)：血管肽酶是负责产生或失活血管活性多肽的酶。因此，血管肽酶抑制是治疗心血管疾病的一种重要方法。例如，血管紧张素转换酶(ACE)抑制剂是FDA批准的，并被广泛用于治疗高血压和心力衰竭。此外，另外两种血管肽酶的抑制剂，奈普利辛(NEP)和内皮素转换酶(ECEs)，以及这些酶的联合抑制剂，目前正处于临床前和临床开发阶段。最近，大量数据表明，血管肽酶ECEs和NEP，也许还有ACE，在阿尔茨海默氏症淀粉样β-肽(ABeta)的降解中发挥了作用。由于ABeta的异常积聚在AD的发病机制中起着关键作用，因此对这些血管肽酶的药物抑制非常令人担忧，因为它们可能会增加ABeta的水平，从而增加患阿尔茨海默病的风险。在这项应用中，我们建议通过检测这些酶基因缺陷的小鼠和接受临床相关血管肽酶抑制剂治疗的小鼠的影响，直接评估这一假说，该假说认为慢性减少ECA、NEP和ACE将导致ABeta积聚和AD样病理。这些研究的结果将进一步加深我们对NEP、ECA和ACE在确定脑内ABeta浓度方面的作用的理解，同时有助于评估临床使用血管肽酶抑制剂的潜在风险。

DESCRIPTION (provided by applicant): Vasopeptidases are enzymes responsible for the generation or inactivation of vasoactive peptides. As such, vasopeptidase inhibition represents a significant approach for the treatment of cardiovascular disease. For example, angiotensin-converting enzyme (ACE) inhibitors are FDA approved and widely used to treat hypertension and heart failure. In addition, inhibitors of two other vasopeptidases, neprilysin (NEP) and endothelin-converting enzyme (ECE), are currently in preclinical and clinical development as are combined inhibitors of these enzymes. Recently, considerable data has emerged indicating a role for the vasopeptidases ECE and NEP, and perhaps also ACE, in the degradation of the Alzheimer's amyloid beta-peptide (ABeta). As the abnormal accumulation of ABeta plays a pivotal role in AD pathogenesis, pharmacological inhibition of these vasopeptidases is of considerable concern as they may increase ABeta levels in a manner that increases risk of developing Alzheimer's disease. In this application we propose to directly evaluate the hypothesis that chronic reductions in ECE, NEP, and ACE will result in enhanced ABeta accumulation and AD-like pathology by examining the effects of mice genetically deficient in these enzymes and mice treated with clinically relevant vasopeptidase inhibitors. The results of these studies will further our understanding of the role of NEP, ECE, and ACE in determining ABeta concentration in the brain, while helping to assess the potential risk of the clinical use of vasopeptidase inhibitors.