Morgan Dave
Alzheimer Research Laboratory, Department of Pharmacology and Molecular Therapeutics, University of South Florida, MDC Box 9, Tampa, FL 33612, United States.
Neurochem Int. 2006 Jul;49(2):190-4. doi: 10.1016/j.neuint.2006.03.017. Epub 2006 Jun 5.
Alzheimer's disease is a large and growing health problem. Several lines of transgenic mice overexpressing the amyloid precursor protein (APP) develop both diffuse and compacted amyloid deposits which increase in size and number with age. In the vicinity of compacted deposits, these mice develop neuritic dystrophy and activation of glia. Ultimately, these mice also develop memory deficits. Immunotherapy against the Abeta peptide has been effective in both clearing amyloid deposits from the brain, and improving the mnemonic performance of the transgenic mice. Associated with these actions, are changes in the expression of microglial markers. In some cases, the glial activation markers decline, consistent with reduced provocation from amyloid deposits. However, in a time course study, we found that some markers of microglial activation increase transiently once the immunotherapy is initiated. Still another marker continues to rise for up to 3 months of treatment, and remains elevated even after the parenchymal amyloid deposits are largely removed. These changes are consistent with a shift in the microglial phenotype, transitioning from a condition associated with inflammation and ineffective in clearing Abeta deposits to one with reduced inflammation, and capable of clearing deposited amyloid.
阿尔茨海默病是一个日益严重的重大健康问题。多条过表达淀粉样前体蛋白（APP）的转基因小鼠品系会出现弥漫性和致密性淀粉样沉积物，其大小和数量会随着年龄增长而增加。在致密沉积物附近，这些小鼠会出现神经纤维营养不良和胶质细胞激活。最终，这些小鼠还会出现记忆缺陷。针对β淀粉样肽的免疫疗法在清除大脑中的淀粉样沉积物以及改善转基因小鼠的记忆表现方面均有效。与这些作用相关的是小胶质细胞标志物表达的变化。在某些情况下，胶质细胞激活标志物下降，这与淀粉样沉积物引发的刺激减少一致。然而，在一项时间进程研究中，我们发现一旦开始免疫治疗，一些小胶质细胞激活标志物会短暂增加。还有另一种标志物在治疗长达3个月的时间里持续上升，甚至在实质淀粉样沉积物大部分被清除后仍保持升高。这些变化与小胶质细胞表型的转变一致，即从与炎症相关且清除β淀粉样沉积物无效的状态转变为炎症减少且能够清除沉积淀粉样物质的状态。
