Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, QC H3G 1Y6, Canada.
J Neuroinflammation. 2012 Apr 2;9:62. doi: 10.1186/1742-2094-9-62.
A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated.
To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway.
Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.
越来越多的证据表明，炎症是阿尔茨海默病最早的神经病理学事件之一。因此，我们最近发现在没有淀粉样斑块的情况下，年轻的三个月大的转基因 McGill-Thy1-APP 小鼠的海马体中存在早期的促炎反应，但与淀粉样β肽寡聚物的细胞内积累有关。这种促炎过程在病理学进展中的作用仍有待阐明。
为了阐明这一点，我们用米诺环素（一种具有抗炎和神经保护作用的四环衍生物）对年轻的、无斑块的 McGill-Thy1-APP 转基因小鼠进行了一个月的治疗。治疗在三个月大时结束，此时小鼠仍然没有斑块。米诺环素治疗纠正了年轻转基因安慰剂小鼠中观察到的诱导型一氧化氮合酶和环氧化酶-2的上调。此外，炎症标志物的下调与淀粉样前体蛋白水平和淀粉样前体蛋白相关产物的减少相关。β-位淀粉样前体蛋白裂解酶 1 的活性和水平在转基因安慰剂小鼠中上调，而米诺环素治疗将这些水平恢复正常。抗炎和β-分泌酶 1 的作用部分可以通过抑制核因子 kappa B 途径来解释。
我们的研究表明，神经炎症的药理学调节可能代表了一种有前途的方法，可以预防或延迟阿尔茨海默病病理学在其初始的、临床前阶段的发展。这些结果为炎症和淀粉样蛋白病理学之间的相互作用开辟了新的前景。
