Transgenic mice, inflammation & the Alzheimer phenotype

炎症越来越被认为是阿尔茨海默病（AD）的致病机制。在淀粉样蛋白沉积转基因小鼠模型中，与降低AD风险相关的非甾体抗炎药（NSAIDs）可降低β负荷。接种Abeta疫苗也能减少Abeta的负荷，保护转基因小鼠免于记忆缺陷，但会激活小胶质细胞，这是炎症的一种迹象。我们在此报道，在APP+PSI双转基因小鼠淀粉样蛋白沉积模型中，用修饰的非甾体抗炎药治疗转基因小鼠也可以减少β负荷并激活小胶质细胞。该应用程序将测试疫苗接种和改良的非甾体抗炎药方法在淀粉样蛋白去除、学习记忆和/或基因表达变化方面是可加性饱和的还是相互抵消的。我们还将确定修饰的非甾体抗炎药的哪些成分对化合物的小胶质细胞激活和淀粉样蛋白减少作用至关重要。我们将比较一系列抗炎剂的能力，通过不同的机制，在注射脂多糖或注射抗β抗体的转基因小鼠中改变小胶质细胞活化和β负荷。由于这两种药物通过不同的机制激活小胶质细胞，我们希望澄清哪些抗炎药物可能与潜在的AD疫苗治疗联合使用。最后，我们将确定在双重转基因小鼠中修饰的基因子集，这些基因是淀粉样蛋白沉积和可能的记忆功能障碍的伴随物，而不是通过衰老或转基因过表达修饰的基因。

Inflammation is increasingly viewed as the pathogenic mechanism in Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs (NSAIDs) associated with reduced risk of AD reduce Abeta load in a transgenic mouse model of amyloid deposition. Vaccination with Abeta also reduces Abeta load and protects transgenic mice from memory deficits, but activates microglia, a sign of inflammation. We report here that treatment of transgenic mice with a modified NSAID can also reduce Abeta load and activate microglia in an APP+PSI doubly transgenic mouse model of amyloid deposition. This application will test whether the vaccination and modified NSAID approaches are additive saturable or counteract each other with respect to amyloid removal, learning and memory and/or gene expression changes known to occur in these transgenic animals. We will also determine which components of the modified NSAID are critical for the microglial activation and amyloid reducing effects of the compound. We will compare the ability of a range of anti-inflammatory agents, working via different mechanisms, to modify microglial activation and Abeta load in transgenic mice injected with lipopolysaccharide or injected with anti- Abeta antibodies. Because these two agents activate microglia by different mechanisms, we hope to clarify which anti-inflammatory drugs might be useful to consider in conjunction with potential vaccine therapies for AD. Finally, we will determine a subset of genes modified in the doubly transgenic mice that are concomitants of amyloid deposition and, possibly, memory dysfunction, as opposed to genes which are modified by aging or transgene overexpression.