Study on Thalidomide as BACE1 inhibitor in Alzhiemer's disease

描述(由申请人提供)：考虑到阿尔茨海默病(AD)病例的数量和不断增加的数量以及该病毁灭性的病程，迫切需要开发针对AD关键病理机制的药物。持续的研究揭示了对AD背后的发病机制和分子机制的更多见解，并为疾病修改疗法创造了更多希望，而不仅仅是对症治疗。因为β-分泌酶(BACE1)是处理A代淀粉样前体蛋白(APP)的两个关键酶之一，A？代淀粉样前体蛋白被认为是AD的病理标志。最近的研究表明，脑和脑脊液中BACE1活性显著升高，影响AD轻度认知损害(MCI)。因此，BACE1抑制剂以及潜在的临床试验先导研究对于AD的早期检测至关重要。最近，我们和其他人发现，在AD转基因小鼠中，阻断肿瘤坏死因子信号可以通过抑制BACE1来减少淀粉样斑块和A？的产生。临床研究还表明，使用肿瘤坏死因子融合蛋白拮抗剂Enteracept对1例AD患者有利。然而，Enteracept是一种融合蛋白药物，不能穿透脑血屏障(BBB)，颈部周围注射可能会给患者带来潜在风险。因此，我们决定使用肿瘤坏死因子抑制剂沙利度胺来测试这一概念。我们的新方法是基于开发针对BACE1的TNF1抑制剂药物，从而提供影响特定下游途径的能力。作为这一概念的证明，我们将在AD受试者中应用沙利度胺合乎逻辑地追求这种药物。我们认为沙利度胺可能是BACE1的一种抑制剂。公共卫生相关性：考虑到阿尔茨海默病(AD)病例的大量和不断增加以及该病毁灭性的病程，迫切需要开发针对AD关键病理机制的药物。持续的研究揭示了对AD背后的发病机制和分子机制的更多见解，并为疾病修改疗法创造了更多希望，而不仅仅是对症治疗。β-分泌酶(BACE1)是淀粉样前体蛋白(APP)产生的两个关键酶之一，而淀粉样前体蛋白一直被认为是AD的病理标志。最近的发现表明，在散发性AD脑样本中，BACE1活性显著增加。与这些研究相关联，我们发现轻度认知障碍(MCI)患者脑脊液中BACE1酶活性水平和BACE1蛋白水平均升高。因此，BACE1抑制剂以及潜在的临床试验先导研究对于AD的早期检测至关重要。最近，我们和其他人发现，在AD转基因小鼠中，阻断肿瘤坏死因子信号可以通过抑制BACE1来减少淀粉样斑块和A？的产生。临床研究还表明，使用肿瘤坏死因子融合蛋白拮抗剂Enteracept对1例AD患者有利。然而，Enteracept是一种融合蛋白药物，不能穿透脑血屏障(BBB)，颈部周围注射可能会给患者带来潜在风险。因此，我们决定使用肿瘤坏死因子抑制剂沙利度胺来测试这一概念。我们的新方法是基于开发针对BACE1的TNF1抑制剂药物，从而提供影响特定下游途径的能力。作为这一概念的证明，我们将在AD受试者中合理使用沙利度胺来追求这种药物，并测试我们的假设，即沙利度胺降低AD受试者脑脊液BACE1和Ab，并改善脑脊液神经元标志的神经元丢失。我们认为沙利度胺可能是BACE1的一种抑制剂。

DESCRIPTION (provided by applicant): Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Because beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A¿ generation, which has been considered a pathological hallmarker for AD. Recent discoveries have shown that BACE1 activity was significantly increased in the brain and CSF affected AD mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A¿ production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor. PUBLIC HEALTH RELEVANCE: Considering the large and increasing number of Alzheimer's disease (AD) cases and the devastating course of the disease, there is a great need for developing drugs that target critical pathologic mechanisms in AD. Continuing research has revealed additional insights into the pathogenesis and molecular mechanisms behind AD and has created more hope for disease-modifying therapies, rather than merely symptomatic treatment. Beta-secretase (BACE1) is one of the two key enzymes in processing the amyloid precursor protein (APP) for A¿ production, which has long been considered the pathological hallmark of AD. Recent discoveries have shown that BACE1 activity was significantly increased in sporadic AD brain samples. In correlation with these studies, we have discovered an elevation in both BACE1 enzymatic activity level and BACE1 protein level in the CSF from patients with mild cognitive impairment (MCI). Thus, BACE1 inhibitors, as well as potential pilot studies for clinical trials, are crucial for the early detection of AD. Recently, we and others have discovered that blocking TNF signaling reduces amyloid plaques and A¿ production through inhibition of BACE1 in AD transgenic mice. The clinical study has also demonstrated that using the TNF fusion protein antagonist, Enteracept, has been beneficial to one AD case. However, Enteracept is a fusion protein drug which is not penetrable to the brain blood barrier (BBB), and peri-neck injections may carry potential risks for patients. Thus, we decided to test this notion by using the TNF inhibitor Thalidomide. Our novel approach is based on developing TNF1 inhibitor drugs that target BACE1 and, thus, provide the ability to influence specific downstream pathways. As a proof of this concept, we will administer Thalidomide to logically pursue this drug in AD subjects and test our hypothesis that thalidomide decreases CSF BACE1 and Ab and improves CSF neuronal markers for neuron loss in AD subjects. We propose that Thalidomide may represent a BACE1 inhibitor.