CITALOPRAM DECREASES AMYLOID-B SYNTHESIS IN HUMAN CSF

描述(申请人提供)：阿尔茨海默病(AD)是一种毁灭性的疾病，估计仅在美国就有500万患者受到影响，并预计在未来几十年内随着人口老龄化而急剧增加，除非能够制定预防措施。虽然目前还没有批准的治疗方法来改变疾病的根本原因，但在开发抗淀粉样β蛋白疗法方面有强烈的活动。然而，最近这些治疗方法的试验在改变AD病程方面没有或非常有限的成功。这些未能使临床诊断为阿尔茨海默病的患者受益的原因很可能是因为治疗在疾病过程中实施得太晚。我们有初步证据表明，选择性5-羟色胺再摄取抑制剂(SSRI)抗抑郁药与人脑中较低的A‘斑块有关。我们还发现，在AD转基因小鼠模型中，两种SSRI抗抑郁药显著降低了脑内A？水平25%，体内直接注射5-羟色胺使A？水平降低了30%，而不影响A2的清除速度，这表明5-羟色胺信号是导致A‘生成减少的原因。我们现在有数据表明，西酞普兰16周的前瞻性治疗显著减少了AD小鼠的斑块负担。目前的提案将测试临床相关剂量的SSRI是否会减少健康受试者的A？产生。这是由我们在华盛顿大学的同事最近开发的一种稳定的同位素标记动力学(丝素)技术实现的。丝素试验评估受试者的A？药效学。它使用13C6-亮氨酸给药，并监测脑脊液中13C6标记的A？的出现率，以确定A？的合成和清除速度。我们建议对12名年龄在18-40岁的受试者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？生产的评估。在开始13C6-亮氨酸给药和脑脊液采样之前，每个受试者将被随机分为4周的安慰剂疗程或20毫克/天的西酞普兰治疗。假设：与服用安慰剂的受试者相比，接受西酞普兰治疗的受试者在Silk测试中表现出显著(p&lt；0.05)较低的A？产生。意义：如果我们的假设得到支持，并且西酞普兰与A？的产生显著减少有关，我们将使用该数据来评估一项前瞻性试验的价值，以测试SSRI是否降低A？斑块的形成。虽然这种试验的设计考虑了许多因素，但对预防AD的潜在意义将是巨大的。 与公共卫生相关：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来改变疾病的根本原因。我们在人类和动物模型中的初步数据表明，SSRI抗抑郁药可以降低淀粉样β蛋白(A？)的含量，淀粉样β蛋白是一种在AD发展过程中发挥关键和早期作用的多肽。该项目将确定与安慰剂相比，SSRI抗抑郁药是否降低了人类脑脊液中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.