Laboratory for Cognitive and Molecular Morphometry, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Neurobiol Aging. 2011 Mar;32(3):387-97. doi: 10.1016/j.neurobiolaging.2009.02.025. Epub 2009 Apr 5.
The amyloid-β peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of Aβ (fAβ) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fAβ toxicity at low concentrations. In addition to neuronal loss, fAβ induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fAβ toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fAβ. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fAβ, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fAβ-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fAβ when compared with young microglia.
β淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的发病机制中起核心作用。Aβ的纤维形式（fAβ）通过尚未充分了解的机制对神经元产生毒性作用。我们已经表明，老年灵长类皮质在低浓度下对 fAβ毒性具有选择性易感性。除神经元丢失外，fAβ还诱导老年恒河猴皮质中大量小胶质细胞激活。我们现在证明抑制小胶质细胞激活可消除 fAβ毒性。巨噬细胞/小胶质细胞抑制因子（MIF）的注射或泵输送显著降低了 fAβ引起的小胶质细胞激活和损伤体积。当 fAβ刺激时，从小胶质细胞中分离出的小胶质细胞产生大量的活性氧，MIF 以剂量依赖性方式抑制其产生。这是首次明确的体内证明，fAβ诱导的小胶质细胞激活和炎症至少部分介导了其对神经元的毒性作用。结合我们早期的观察结果，这些发现表明与年轻小胶质细胞相比，老年灵长类小胶质细胞可能对 fAβ表现出过度的炎症反应。
