Mechanisms for NSAID Alzheimer Prevention

描述(由申请人提供)： 流行病学研究表明，非类固醇抗炎药(NSAIDs)，特别是布洛芬和萘普生以及其他非选择性环氧合酶(COX)抑制剂)与阿尔茨海默病(AD)的风险较低有关。我们小组和其他人的工作支持了这种联系是因果的，表明布洛芬减少了AD动物模型中的认知缺陷和斑块发病证据。即使是短期的萘普生或布洛芬也能纠正长时程增强和认知缺陷，在可检测到的A？降低之前。Naproxen参加了一项名为Adapt的AD预防试验，该试验现在正在出现，将AD风险降低58%(p=0.01，ICAD 7月8日，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的产量。我们的数据显示，萘普生还可以抑制A？寡聚体诱导的神经变性，这种变性被认为是导致认知障碍的。A？寡聚体是参与AD发病机制的A？肽的小集合，现在被证明选择性地与突触后位置的兴奋性突触结合，导致树突棘和突触丢失，类似于AD早期在海马区和颞区观察到的。我们的实验室和其他实验室已经发现了寡聚体诱导的RAC信号通路的失调，这些信号通路已知会影响认知功能；更具体地说，我们专注于RAC&GT；PAK&GT；LIMK1&GT；Cofilin控制树突棘中肌动蛋白的组装和拆解，作为突触丢失的一种机制(赵等人，2006年)。然后，我们发现Fyn激酶位于这一途径的上游(Ma等人，2008年)，与Fyn基因敲除抑制突触毒性一致(Chin等人，2005；Chin等人，2004)，并且这一途径中的缺陷可以被COX抑制剂纠正，从而在体外和体内降低突触毒性。Fyn结合tau并在AD的缠结神经元中积聚，这表明有必要在tau病理模型中测试非类固醇抗炎药。由于Adapt试验出于安全考虑而暂停，我们继续研究布洛芬，在有效剂量下，布洛芬有很强的理据和比萘普生更好的安全性。与我们的数据显示非类固醇抗炎药和抗氧化剂的不同益处一致，流行病学支持非类固醇抗炎药和抗氧化剂的联合应用(Fotuhi等人，2008年)。目标。目的：1)利用原代神经元培养方法，研究COX-1和COX-2在非甾体抗炎药A？寡聚体诱导的突触丢失保护中的作用；(B)COX如何影响A？诱导的突触丢失；以及(C)不能减少氧化损伤的非甾体抗炎药是否与天然抗氧化剂1-脂酸盐协同作用保护突触免受A？目的2)评价布洛芬、萘普生或抗氧化剂1-脂酸酯对tau病三重转基因小鼠早期和晚期干预的作用，以及它们对突触丢失、tau病、神经退行性变和认知功能障碍的保护作用。目的3)将评估非类固醇抗炎药的短期治疗，然后停药，是否会导致持续的治疗效果，以及非类固醇抗氧化剂1-脂酸盐是否有协同作用，据报道，1-脂酸盐可以减缓AD的进展。 公共卫生相关性： 退伍军人健康和医疗保健问题。AD(AD)是一种主要的衰老退行性疾病，据报道在美国是第四大死亡原因。因此，它在老年退伍军人中很普遍。该提案旨在研究NAPROXEN在AD动物模型中的作用，了解它是如何预防AD的，并找到一种与NAPROXen协同的方法，潜在地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.