Mechanisms for NSAID Alzheimer Prevention

流行病学研究表明，非类固醇抗炎药(NSAID)，特别是布洛芬 以及萘普生和其他非选择性环氧合酶(COX)抑制剂)与低风险相关 阿尔茨海默病(AD)。这种联系是有因果关系的，这得到了我们团队和其他人工作的支持， 显示布洛芬减少了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进入了一项名为Adapt的AD预防试验，该试验现在正在出现，可降低58%的AD风险 (P=0.01，ICAD，2008年7月，J.Breitner)。其作用机制尚不清楚，因为与布洛芬不同，萘普生 不会通过分泌酶降低A？42的产量。我们的数据显示，萘普生也能抑制A？ 寡聚体诱导的神经退行性变被认为会导致认知缺陷。低聚物很小 与AD发病有关的A？肽的组装，现在被证明选择性地与兴奋性结合 突触后部位的突触并导致树突棘和突触丢失，类似于早期观察到的 阿尔茨海默病的海马区和颞区。我们的实验室和其他实验室已经发现了寡聚体引起的失调 已知的影响认知功能的RAC信号通路；更具体地说，我们专注于 RAC；PAK；LIMK1；COFILIN控制树突棘中肌动蛋白的组装和拆解作为一种机制 突触丢失(赵等人，2006年)。然后我们发现Fyn激酶位于该途径的上游(Ma等人， 2008)与抑制突触毒性的Fyn基因敲除一致(Chin等人，2005；Chin等人，2004)和 这一通路的缺陷可以被环氧合酶抑制剂纠正，从而降低体外突触毒性 在活体内。Fyn结合tau并在AD患者的缠结神经元中积聚，这表明有必要进行测试 Tau病理模型中的非甾体抗炎药。由于出于安全考虑，ADAPT试验被暂停，我们继续 研究布洛芬，它有很强的理据，在有效性方面比萘普生更安全 剂量。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 支持联合使用非甾体抗炎药和抗氧化剂(Fotuhi等人，2008年)。目标。目标1)使用主要 神经元培养以确定：(A)COX-1和COX-2在非甾体抗炎药保护作用中的相对作用。 诱导性突触丢失，被认为是导致AD认知障碍的原因；(B)COX如何影响A？诱导的突触丢失 突触和(C)无法减少氧化损伤的非类固醇抗炎药是否与天然抗氧化剂协同作用， -硫辛酸盐，以保护突触免受A。目的2)将评估布洛芬、萘普生或抗氧化剂的作用 早期和晚期干预对tau病理三重转基因小鼠的影响及其是否具有保护作用 从突触丢失，tau病理，神经变性和认知缺陷。AIM 3)将评估是否短线 长期服用非类固醇抗炎药，然后停药，是否会导致持续的治疗效果，以及 非类固醇抗炎药与抗氧化剂--硫辛酸酯有协同作用，据报道，这种抗氧化剂可以减缓AD的进展。

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 ¿-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, ¿-lipoate, to protect synapses from A¿. Aim 2) will evaluate the role of ibuprofen, naproxen or the antioxidant ¿-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 ¿-lipoate, an antioxidant reported to slow AD progression.