Transgenic mice, inflammation & the Alzheimer phenotype

炎症越来越多地被视为阿尔茨海默病（AD）的致病机制。与AD风险降低相关的非甾体抗炎药（NSAID）可降低淀粉样蛋白沉积转基因小鼠模型中的Abeta负荷。用Abeta接种疫苗还可以减少Abeta负荷并保护转基因小鼠免受记忆缺陷的影响，但会激活小胶质细胞，这是炎症的标志。我们在此报告，在淀粉样蛋白沉积的APP+PSI双转基因小鼠模型中，用改良的NSAID治疗转基因小鼠也可以降低Abeta负荷并激活小胶质细胞。本申请将测试疫苗接种和修饰的NSAID方法在淀粉样蛋白去除、学习和记忆和/或已知发生在这些转基因动物中的基因表达变化方面是否是可加性饱和的或相互抵消的。我们还将确定修饰的NSAID的哪些组分对化合物的小胶质细胞活化和淀粉样蛋白减少作用至关重要。我们将比较通过不同机制起作用的一系列抗炎剂在注射脂多糖或注射抗Abeta抗体的转基因小鼠中改变小胶质细胞活化和Abeta负载的能力。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有助于与AD的潜在疫苗疗法结合考虑。最后，我们将确定在双转基因小鼠中修饰的基因的子集，其是淀粉样蛋白沉积的伴随物，并且可能是记忆功能障碍，而不是通过老化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.