NSAID Inhibition Microglial Activation and AD Pathology

描述（由申请人提供）：流行病学研究表明， 长期服用NSAID（特别是布洛芬）可能会显著降低风险 ，并延缓其发病。然而，目前尚不清楚这是否 关联是因果关系，如果是，涉及的机制是什么，哪些NSAID是 最有效、所需剂量或开始干预的最佳时间。 NSAID的选择可能是至关重要的，因为我们发现， 抗炎剂实际上增加了动物模型中的淀粉样蛋白沉积。 相比之下，我们已经表明，长期口服非处方药， 药物布洛芬可以减少或延缓炎症的发展，A13 转基因小鼠（HuAPPsw）中的蓄积和神经炎斑块病理学 携带家族性AD中发现的突变人类基因诱导的 反应性小胶质细胞、IL-1B和营养不良性神经突的显著减少 表明炎症和继发性神经变性减少。 可溶性和不溶性AG的减少表明，不仅 炎症诱导的毒性，但由于AG聚集体积累而产生的毒性 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的方法， 将案件数量减少一半以上可能已经可行。我们 建议进一步探讨NSAID预防AD发病机制的关键问题 包括干预的时间和增加IL-1的作用（目的1）， 延迟病理所需的剂量以及吞噬作用和 抗糜蛋白酶（Aim 2）。在目标3中，我们将使用 无毒NSAID治疗与减少心脏病和增加 突触功能和抗氧化活性的作用（目的3）。我们亦建议 在体外和体内测试NSAID对小胶质细胞作用的几种机制 显示淀粉样蛋白降解受阻，并假设与 减少淀粉样蛋白负荷和神经炎斑病理学（目的4）。完成 这些研究将有助于更好地了解 小胶质细胞在AD发病机制，并有助于规划临床试验， 已批准的具有相对低毒性特征的药物， 与人类研究中AD风险降低相关。

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.