NSAID Inhibition Microglial Activation and AD Pathology

描述(由申请人提供)：流行病学研究表明，早期 长期服用非甾体类抗炎药(特别是布洛芬)可能会显著降低风险 治疗和延缓AD的发病。然而，目前还不清楚这是否会 关联是因果的，如果是，涉及什么机制，哪些非类固醇抗炎药是 最有效的，所需的剂量或启动干预的最佳时间。 非甾体抗炎药的选择可能很关键，因为我们发现 在动物模型中，抗炎剂实际上会增加淀粉样蛋白的沉积。 相比之下，我们已经证明，长期口服非处方药 布洛芬可以减少或延缓炎症的发展，A13 转基因小鼠(HuAPPsw)的蓄积和神经斑块病理 携带在家族性阿尔茨海默病中发现的突变的人类基因。布洛芬诱导 反应性小胶质细胞、IL-1b和营养不良轴突显著减少 这表明炎症和继发性神经退行性变得到了减轻。 可溶性和不溶性AG的减少，正如威尔特所说，不仅是 炎症诱导的毒性，但由于AG聚集物的积累而产生的毒性 也会因这种治疗而减少。再加上流行病学，这些 数据表明，一种廉价且相对安全的延缓AD和 可能已经有可能将病例数量减少一半以上。我们 建议进一步探讨非甾体抗炎药预防AD发病机制的关键问题 包括干预时间和增加的IL-1的作用(目标1)， 延迟病理所需的剂量以及吞噬作用和 抗凝乳杆菌胰蛋白酶(目标2)。在目标3中，我们将使用 无毒的非甾体抗炎药治疗与减少心脏病和增加 突触功能和抗氧化活性的作用(目标3)。我们还提议 非甾体抗炎药对小胶质细胞作用机制的体内外研究 表现为淀粉样蛋白降解受阻，推测与 减少淀粉样蛋白负荷和神经性斑块病理(目标4)。完成 这些研究将使我们更好地理解 小胶质细胞在AD发病机制中的作用并有助于规划临床试验 毒性相对较低的批准药物已经 与人类研究中AD风险的降低有关。

DESCRIPTION (provided by applicant): Epidemiological studies suggest that early and chronic NSAID consumption (notably ibuprofen) may significantly reduce risk for and delay the onset of AD. However, it is not known whether this association is causal and if so, what mechanisms are involved, which NSAIDs are most efficacious, the dose required or the best time to initiate intervention. NSAID choice may be critical because we have found that selected anti-inflammatory agents actually increase amyloid deposition in animal models. In contrast, we have shown that chronic oral dosing with the over-the-counter medication ibuprofen can reduce or delay the development of inflammation, A13 accumulation and neuritic plaque pathology in transgenic mice (HuAPPsw) carrying a mutant human gene found in familial AD. Ibuprofen induced significant reductions in reactive microglia, IL-lB and dystrophic neurites suggesting that inflammation and secondary neurodegeneration are reduced. Reductions in both soluble and insoluble AG as welt argue that not only inflammation-induced toxicity, but toxicity due to accumulating AG aggregates would also be reduced by this treatment. Coupled with the epidemiology, these data suggest that an inexpensive and relatively safe method for delaying AD and reducing the number of cases by more than half may already be available. We propose to further explore key issues of NSAID prevention of AD pathogenesis including the time of intervention and the role of increased IL-1 (Aim 1), the dose required to delay pathology and the roles of phagocytosis and antichymotrypsin (Aim 2). In Aim 3 we will study the target involved using a non-toxic NSAID treatment linked to reduced heart disease and increased synaptic function and the role of antioxidant activity (Aim 3). We also propose to test in vitro and in vivo several mechanisms of NSAID effects on microglia exhibiting blocked amyloid degradation and hypothesized to be relevant to reducing amyloid load and neuritic plaque pathology (Aim 4). Completion of these studies will lead to a better understanding of the role and control of microglia in AD pathogenesis and contribute to planning clinical trials with approved agents with relatively low toxicity profiles that have already been associated with reduced AD risk in human studies.