Division of Neurology, Duke University Medical Center, Durham, NC 27710, U.S.A.
ASN Neuro. 2011 Nov 30;3(5):249-58. doi: 10.1042/AN20110018.
While the presence of an inflammatory response in AD (Alzheimer's disease) is well known, the data on inflammation are conflicting, suggesting that inflammation either attenuates pathology, exacerbates it or has no effect. Our goal was to more fully characterize the inflammatory response in APP (amyloid precursor protein) transgenic mice with and without disease progression. In addition, we have examined how anti-Aβ (amyloid β-peptide) immunotherapy alters this inflammatory response. We have used quantitative RT-PCR (reverse transcription-PCR) and protein analysis to measure inflammatory responses ranging from pro-inflammatory to anti-inflammatory and repair factors in transgenic mice that develop amyloid deposits only (APPSw) and amyloid deposits with progression to tau pathology and neuron loss [APPSw/NOS2-/- (nitric oxide synthase 2-/-)]. We also examined tissues from previously published immunotherapy studies. These studies were a passive immunization study in APPSw mice and an active vaccination study in APPSw/NOS2-/- mice. Both studies have already been shown to lower amyloid load and improve cognition. We have found that amyloid deposition is associated with high expression of alternative activation and acquired deactivation genes and low expression of pro-inflammatory genes, whereas disease progression is associated with a mixed phenotype including increased levels of some classical activation factors. Immunotherapy targeting amyloid deposition in both mouse models resulted in decreased alternative inflammatory markers and, in the case of passive immunization, a transient increase in pro-inflammatory markers. Our results suggest that an alternative immune response favours retention of amyloid deposits in the brain, and switching away from this state by immunotherapy permits removal of amyloid.
虽然 AD（阿尔茨海默病）中存在炎症反应是众所周知的，但炎症数据存在矛盾，表明炎症要么减轻了病理，要么加重了病理，要么没有影响。我们的目标是更全面地描述具有和不具有疾病进展的 APP（淀粉样前体蛋白）转基因小鼠中的炎症反应。此外，我们还研究了抗 Aβ（淀粉样 β 肽）免疫疗法如何改变这种炎症反应。我们使用定量 RT-PCR（逆转录-PCR）和蛋白质分析来测量从促炎到抗炎和修复因子的炎症反应，这些因子在仅发生淀粉样蛋白沉积的转基因小鼠（APPSw）和发生淀粉样蛋白沉积并进展为 tau 病理学和神经元丧失的转基因小鼠中（APPSw/NOS2-/-（一氧化氮合酶 2-/-））。我们还检查了以前发表的免疫疗法研究中的组织。这些研究是在 APPSw 小鼠中进行的被动免疫研究和在 APPSw/NOS2-/- 小鼠中进行的主动疫苗接种研究。这两项研究都已表明可以降低淀粉样蛋白负荷并改善认知。我们发现淀粉样蛋白沉积与替代激活和获得的去激活基因的高表达以及促炎基因的低表达相关，而疾病进展与包括某些经典激活因子水平增加的混合表型相关。针对两种小鼠模型中淀粉样蛋白沉积的免疫疗法导致替代炎症标志物减少，而在被动免疫的情况下，促炎标志物短暂增加。我们的结果表明，替代免疫反应有利于大脑中淀粉样蛋白沉积的保留，而通过免疫疗法从这种状态切换可以允许去除淀粉样蛋白。
