CITALOPRAM DECREASES AMYLOID-B SYNTHESIS IN HUMAN CSF

描述（由申请人提供）：阿尔茨海默病（AD）是一种毁灭性的疾病，估计仅在美国就影响500万患者，并且随着人口老龄化，除非可以开发预防措施，否则预计在未来几十年内将急剧增加。虽然目前还没有批准的治疗方法可以改变疾病的根本原因，但开发抗淀粉样蛋白β疗法的活动非常激烈。然而，这些治疗的最近试验在改变AD的过程中没有成功或非常有限。很可能这些未能使临床诊断为AD的个体受益的原因是在疾病过程中给予治疗太晚。我们有初步证据表明，选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药与人类大脑中较低的A斑块有关。我们还发现，在AD的转基因小鼠模型中，两种SSRI抗抑郁药急性降低了25%的脑A <$水平，直接输注5-羟色胺使体内A <$水平降低了30%，而不影响A2消除率，这表明5-羟色胺信号传导是导致A <$生成减少的原因。我们现在有数据表明，16周的西酞普兰前瞻性治疗显着降低了AD小鼠的斑块负荷。目前的提案将测试临床相关剂量的SSRI是否会减少健康人类受试者的A？我们华盛顿大学的同事最近开发了一种稳定同位素标记动力学（SILK）技术，使这成为可能。SILK测定评估人类受试者中的A？药效学。它使用13 C6-亮氨酸的管理和监测率的13 C6标记的A <$出现在CSF中，以确定A <$合成和清除率。我们建议在12名年龄在18-40岁的受试者中进行随机安慰剂对照比较，这些受试者将在我们的临床研究单位停留36小时期间接受A？生产评估。在开始13 C6-亮氨酸给药和CSF采样之前，每例受试者将随机接受为期4周的安慰剂或20 mg/天的西酞普兰治疗。假设：与接受安慰剂的受试者相比，接受西酞普兰的受试者将显示出显著（p< 0.05）较低的A？产生，如通过SILK测量的。重要性：如果我们的假设得到支持，并且西酞普兰与A <$生成的大幅减少有关，我们将使用这些数据来评估一项前瞻性试验的价值，以测试SSRIs是否降低A <$斑块形成率。虽然这种试验的设计涉及许多因素，但对预防AD的潜在意义很大。 公共卫生相关性：阿尔茨海默病（AD）是一种毁灭性的疾病，预计在未来几十年内将急剧增加。目前还没有批准的治疗方法可以改变疾病的根本原因。我们在人类和动物模型中获得的初步数据表明，SSRI抗抑郁药可以降低淀粉样蛋白β（A？）的含量，这种肽在AD的发展中起着关键的早期作用。该项目将确定与安慰剂相比，SSRI抗抑郁药是否会降低人CSF中A的产生。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. While there is no currently approved treatment that modifies the underlying cause of the disease, there is intense activity towards developing anti-amyloid beta therapies. Recent trials of such treatments however have had no, or very limited, success in altering the course of AD. It is likely that these failures to benefit individuals with clinically diagnosed AD occurred because the treatments were administered too late in the disease process. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A¿ plaques in the human brain. We also found that in a transgenic mouse model of AD two SSRI antidepressants acutely reduced brain A¿ levels by 25% and direct infusion of serotonin reduced A¿ levels by 30% in vivo without affecting A2 elimination rates, suggesting that serotonin signaling is responsible for the reduction in A¿ generation. We now have data demonstrating that prospective treatment with 16 weeks of citalopram significantly reduced plaque burden in AD mice. The current proposal will test whether clinically relevant doses of an SSRI reduce A¿ production in healthy human subjects. This is made possible by the recent development of a stable isotope labeling kinetic (SILK) technique by our colleagues here at Washington University. The SILK assay assesses A¿ pharmacodynamics in human subjects. It uses administration of 13C6-leucine and monitors the rate of 13C6-labeled A¿ appearance in the CSF to determine the rate of A¿ synthesis and clearance. We propose to conduct a randomized placebo-controlled comparison in 12 subjects ages 18-40 who will undergo assessment of A¿ production during a 36-hour stay in our clinical research unit. Each subject will be randomized to treatment with a 4 week course of placebo or 20 mg/day of citalopram, prior to the initiation of the 13C6-leucine administration and CSF sampling. Hypothesis: Compared to the subjects receiving placebo, subjects receiving citalopram will show significantly (p< 0.05) lower A¿ production as measured by SILK. Significance: If our hypothesis is supported and citalopram is associated with a substantial reduction in A¿ production, we will use this data to assess the value of a prospective trial to test whether SSRIs reduce the rate of A¿ plaque formation. While many factors go into the design of such a trial, the potential significance for preventing AD would be large. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating illness, projected to increase dramatically in the next decades. Currently there is no approved treatment that modifies the underlying cause of the illness. We have preliminary data in humans and animal models that SSRI antidepressants can lower the amount of Amyloid beta (A¿), the peptide that plays a critical and early role in the development of AD. This project will determine whether compared to placebo, SSRI antidepressants lower the production of A¿ in human CSF.