Pimplikar Sanjay W
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA,
J Clin Immunol. 2014 Jul;34 Suppl 1:S64-9. doi: 10.1007/s10875-014-0032-5. Epub 2014 Apr 8.
The top-down, reductionist approach of the past three decades has resulted in remarkable progress in identifying genes and proteins involved in Alzheimer's disease (AD), including β-amyloid (Aβ) peptides and tau protein. Recently, a number of genes of the innate immune pathway have been identified as AD risk factors and several microglial proteins have been shown to be chronically activated in AD brains. Together, these observations suggest a crucial role for neuroinflammation in AD pathogenesis and emerging evidence suggests that neuroinflammation is both a cause and a consequence of AD. Epidemiological studies show that long-term users of anti-inflammatory drugs are protected from AD but anti-inflammatory treatment in mild AD patients has not been successful. These observations suggest that anti-inflammatory treatment is likely to be successful if initiated prior to the onset of neurological symptoms. Finally, after the remarkable success of the reductionist approach, a complimentary bottom-up systems approach is necessary to gain a better understanding of the highly complex, multifactorial nature of AD pathogenesis.
在过去三十年中，自上而下的还原论方法在识别与阿尔茨海默病（AD）相关的基因和蛋白质方面取得了显著进展，这些基因和蛋白质包括β-淀粉样蛋白（Aβ）肽和tau蛋白。最近，先天免疫途径的一些基因已被确定为AD的风险因素，并且已证明几种小胶质细胞蛋白在AD大脑中被长期激活。这些观察结果共同表明神经炎症在AD发病机制中起着关键作用，并且新出现的证据表明神经炎症既是AD的原因也是其结果。流行病学研究表明，长期使用抗炎药物的人可预防AD，但在轻度AD患者中进行抗炎治疗尚未成功。这些观察结果表明，如果在神经症状出现之前开始抗炎治疗，可能会取得成功。最后，在还原论方法取得显著成功之后，需要一种互补的自下而上的系统方法，以更好地理解AD发病机制高度复杂、多因素的性质。
