Mechanisms for NSAID Alzheimer Prevention

描述（由申请人提供）： 流行病学研究表明，非甾体抗炎药（NSAID），特别是布洛芬和萘普生和其他非选择性环氧合酶（考克斯）抑制剂与阿尔茨海默病（AD）的风险较低相关。这种关联是因果关系的，这得到了我们小组和其他人的工作的支持，表明布洛芬减少了AD动物模型中的认知缺陷和斑块发病机制的证据。即使是短期的萘普生或布洛芬纠正LTP和认知缺陷，之前可检测到的减少。Naughten进入了一项名为ADAPT的AD预防试验，该试验目前正在将AD风险降低58%（p=0.01，ICAD July 08，J. Breitner）。其机制尚不清楚，因为与布洛芬不同，萘普生不会通过3-分泌酶降低A 42的产生。我们的数据表明，萘普生也可以抑制A-寡聚体诱导的神经变性，假设导致认知缺陷。A？低聚物是与AD发病机制有关的A ²肽的小集合体，现在证明它们选择性地结合突触后位点的兴奋性突触，并导致树突棘和突触丢失，类似于在AD的海马和颞叶区域早期观察到的情况。我们的实验室和其他实验室已经涉及已知影响认知功能的rac信号传导途径的寡聚体诱导的失调;更具体地说，我们专注于rac>PAK> LIMK 1>cofilin控制树突棘中的肌动蛋白组装和拆卸作为突触损失的机制（Zhao等人，2006年）。然后我们发现fyn激酶在该途径的上游（Ma等人，2008）与fyn敲除抑制A突触毒性一致（Chin等人，2005; Chin等人，2004），并且该途径中的缺陷可以通过考克斯抑制剂校正，导致体外和体内突触毒性降低。Fyn结合tau并在AD中的缠结承载神经元中积累，这表明需要在具有tau病理的模型中测试NSAID。由于ADAPT试验因安全性问题而停止，我们继续研究布洛芬，布洛芬在有效剂量下具有强有力的理由和比萘普生更好的安全性。与我们显示NSAID和抗氧化剂的不同益处的数据一致，流行病学支持NSAID和抗氧化剂的组合（Fotuhi等人，2008年）。目标.目的1）使用原代神经元培养物来确定：（a）考克斯-1和考克斯-2在NSAID保护免受A？寡聚体诱导的突触损失中的相对作用，据信A？寡聚体诱导的突触损失导致AD中的认知缺陷;（B）考克斯如何影响A？诱导的突触损失;以及（c）NSAID不能减少氧化损伤，是否与天然抗氧化剂1-硫辛酸协同作用以保护突触免受A？。目的2）将评估布洛芬、萘普生或抗氧化剂1-硫辛酸在早期和晚期干预的具有tau病理学的三重转基因小鼠中的作用，以及它们是否保护突触丧失、tau病理学、神经变性和认知缺陷。目的3）将评估NSAID短期治疗后停药是否会导致治疗效果的持续性，以及NSAID是否与1-硫辛酸（一种据报道可减缓AD进展的抗氧化剂）协同作用。 公共卫生相关性： 退伍军人健康和医疗保健问题。AD（AD）是一种主要的老年退行性疾病，据报道在美国是第四大死亡原因。因此，它在老龄化的退伍军人群体中普遍存在。该提案旨在研究AD动物模型中的萘普生，以了解它如何预防AD，并找到一种与萘普生协同作用的方法，从而可能减少预防所需的剂量。

DESCRIPTION (provided by applicant): Epidemiological studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs), notably, ibuprofen and naproxen and other non-selective cyclooxygenase (COX) inhibitors) are associated with lower risk for Alzheimer Disease (AD). That this association is causal is supported by work from our group and others, showing that ibuprofen reduced cognitive deficits and evidence of plaque pathogenesis in AD animal models. Even short term naproxen or ibuprofen corrected LTP and cognitive deficits, prior to detectable reduction in A¿. Naproxen went into an AD prevention trial called ADAPT, which is now emerging as reducing AD risk 58% (p=0.01, ICAD July 08, J. Breitner). The mechanisms remain unclear because unlike ibuprofen, naproxen does not lower A¿42 production via 3-secretase. Our data show that naproxen can also suppress the A¿-oligomer-induced neurodegeneration postulated to cause cognitive deficits. A¿ oligomers are small assemblies of A¿ peptide implicated in AD pathogenesis, which are now shown to bind selectively to excitatory synapses at postsynaptic sites and cause dendritic spine and synapse loss, similar to observed early in hippocampal and temporal regions in AD. Our lab and others have implicated oligomer-induced dysregulation of rac signaling pathways known to influence cognitive function; more specifically we focused on rac>PAK>LIMK1>cofilin control of actin assembly and disassembly in dendritic spines as a mechanism of synapse loss (Zhao et al., 2006). We then found that fyn kinase was upstream of this pathway (Ma et al., 2008) consistent with fyn knockout suppressing A¿ synaptotoxicity (Chin et al., 2005; Chin et al., 2004) and that defects in this pathway could be corrected by COX inhibitors resulting in reduced synaptotoxicity in vitro and in vivo. Fyn binds tau and accumulates in tangle bearing neurons in AD, suggesting the need to test NSAIDs in models with tau pathology. Since ADAPT trial was halted over safety concerns, we continue to investigate ibuprofen, which has strong rationale and a better safety profile than naproxen at efficacious dosages. Consistent with our data showing different benefits from NSAIDs and antioxidants, epidemiology supports combined NSAIDs and antioxidants (Fotuhi et al., 2008). Objectives. Aim 1) To use primary neuron cultures to determine: (a) relative roles of COX-1 and COX-2 in NSAID protection from A¿ oligomer- induced synapse loss, believed to cause cognitive deficits in AD; (b) how COX influences A¿-induced loss of synapses and (c) whether NSAIDs, which fail to reduce oxidative damage, synergize with a natural antioxidant, 1-lipoate, to protect synapses from A¿. Aim 2) will evaluate the role of ibuprofen, naproxen or the antioxidant 1-lipoate in triple transgenic mice with tau pathology with early and late intervention and whether they protect from synapse loss, tau pathology, neurodegeneration and cognitive deficits. Aim 3) will evaluate whether short term treatment with NSAIDs, followed by withdrawal, will lead to persistence of treatment effects, and whether NSAIDs synergize with 1-lipoate, an antioxidant reported to slow AD progression. PUBLIC HEALTH RELEVANCE: Veterans Health and Health Care Issues. AD (AD) is a major degenerative disease of aging reported as the fourth leading cause of death in the United States. As such it is prevalent in aging veteran populations. This proposal aims to study naproxen in animal models for AD, to understand how it works to prevent AD and to find a way to synergize with naproxen, potentially reducing the doses needed for prevention.