Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Neurosci. 2010 Nov 17;30(46):15369-73. doi: 10.1523/JNEUROSCI.2637-10.2010.
Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ)-containing plaques within the brain that is accompanied by a robust microglial-mediated inflammatory response. This inflammatory response is reliant upon engagement of innate immune signaling pathways involving the toll-like receptors (TLRs). Studies assessing the roles of TLRs in AD pathogenesis have yielded conflicting results. We have assessed the roles of the TLRs through genetic inactivation of the TLR2/4 coreceptor, CD14, in a transgenic murine model of AD. Transgenic mice lacking CD14 exhibited reduced insoluble, but not soluble, levels of Aβ at 7 months of age. This corresponded with decreased plaque burden resulting from a reduction in number and size of both diffuse and thioflavin S-positive plaques and an overall reduction in the number of microglia. These findings are inconsistent with the established actions of these receptors. Moreover, loss of CD14 expression was associated with increased expression of genes encoding the proinflammatory cytokines Tnfα and Ifnγ, decreased levels of the microglial/macrophage alternative activation markers Fizz1 and Ym1, and increased expression of the anti-inflammatory gene Il-10. Thus, the loss of CD14 resulted in a significant change in the inflammatory environment of the brain, likely reflecting a more heterogeneous population of microglia within the brains of the animals. The reduction in plaque burden was not a result of changes in the expression of various Aβ degrading enzymes or proteins associated with Aβ clearance. These data suggest that CD14 is a critical regulator of the microglial inflammatory response that acts to modulate Aβ deposition.
阿尔茨海默病（AD）的特征是大脑内β-淀粉样蛋白（Aβ）沉积斑块，伴有强烈的小胶质细胞介导的炎症反应。这种炎症反应依赖于涉及 toll 样受体（TLR）的固有免疫信号通路的参与。评估 TLR 在 AD 发病机制中的作用的研究得出了相互矛盾的结果。我们通过敲除 TLR2/4 共受体 CD14，在 AD 的转基因小鼠模型中评估了 TLR 的作用。缺乏 CD14 的转基因小鼠在 7 个月大时表现出可溶性 Aβ水平降低，但不溶性 Aβ水平降低。这与斑块负担减少有关，原因是弥漫性和硫黄素 S 阳性斑块的数量和大小减少，以及小胶质细胞数量总体减少。这些发现与这些受体的既定作用不一致。此外，CD14 表达的丧失与促炎细胞因子 Tnfα 和 Ifnγ 的编码基因表达增加、小胶质细胞/巨噬细胞替代激活标志物 Fizz1 和 Ym1 的水平降低以及抗炎基因 Il-10 的表达增加有关。因此，CD14 的缺失导致大脑炎症环境发生重大变化，这可能反映了动物大脑中小胶质细胞的异质性增加。斑块负担的减少不是各种 Aβ降解酶或与 Aβ清除相关的蛋白质表达变化的结果。这些数据表明，CD14 是小胶质细胞炎症反应的关键调节剂，可调节 Aβ 沉积。
