Murphy G M, Zhao F, Yang L, Cordell B
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305-5485, USA.
Am J Pathol. 2000 Sep;157(3):895-904. doi: 10.1016/s0002-9440(10)64603-2.
Inflammation is an important neuropathological change in Alzheimer's disease (AD). However, the pathophysiological factors that initiate and maintain the inflammatory response in AD are unknown. We examined AbetaPP(V717F) transgenic mice, which show numerous brain amyloid-beta (Abeta) deposits, for expression of the macrophage colony-stimulating factor (M-CSF) and its receptor (M-CSFR). M-CSF is increased in the brain in AD and dramatically augments the effects of Abeta on cultured microglia. AbetaPP(V717F) animals 12 months of age showed large numbers of microglia strongly labeled with an M-CSFR antibody near Abeta deposits. M-CSFR mRNA and protein levels were also increased in brain homogenates from AbetaPP(V717F) animals. Dystrophic neurites and astroglia showed no M-CSFR labeling in the transgenic animals. A M-CSF antibody decorated neuritic structures near hippocampal Abeta deposits in transgenic animals. M-CSF mRNA was also increased in AbetaPP(V717F) animals in comparison with wild-type controls. Simultaneous overexpression of M-CSFR and its ligand in AbetaPP(V717F) animals could result in augmentation of Abeta-induced activation of microglia. Because chronic activation of microglia is thought to result in neuronal injury, the M-CSF system may be a potential target for therapeutic intervention in AD.
炎症是阿尔茨海默病（AD）重要的神经病理学改变。然而，引发并维持AD炎症反应的病理生理因素尚不清楚。我们检测了表现出大量脑淀粉样β蛋白（Aβ）沉积的AβPP（V717F）转基因小鼠，以观察巨噬细胞集落刺激因子（M-CSF）及其受体（M-CSFR）的表达情况。AD患者大脑中的M-CSF增加，并显著增强了Aβ对培养的小胶质细胞的作用。12月龄的AβPP（V717F）动物在Aβ沉积物附近有大量被M-CSFR抗体强烈标记的小胶质细胞。AβPP（V717F）动物脑匀浆中的M-CSFR mRNA和蛋白水平也有所增加。在转基因动物中，营养不良的神经突和星形胶质细胞未显示M-CSFR标记。一种M-CSF抗体标记了转基因动物海马Aβ沉积物附近的神经突结构。与野生型对照相比，AβPP（V717F）动物中的M-CSF mRNA也有所增加。AβPP（V717F）动物中M-CSFR及其配体的同时过度表达可能导致Aβ诱导的小胶质细胞激活增强。由于小胶质细胞的慢性激活被认为会导致神经元损伤，M-CSF系统可能是AD治疗干预的潜在靶点。
