German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
1] Department of Experimental Neurology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Charitéplatz 1, 10117 Berlin, Germany.
Nat Commun. 2014 Nov 19;5:5422. doi: 10.1038/ncomms6422.
Astrocytic network alterations have been reported in Alzheimer's disease (AD), but the underlying pathways have remained undefined. Here we measure astrocytic calcium, cerebral blood flow and amyloid-β plaques in vivo in a mouse model of AD using multiphoton microscopy. We find that astrocytic hyperactivity, consisting of single-cell transients and calcium waves, is most pronounced in reactive astrogliosis around plaques and is sometimes associated with local blood flow changes. We show that astroglial hyperactivity is reduced after P2 purinoreceptor blockade or nucleotide release through connexin hemichannels, but is augmented by increasing cortical ADP concentration. P2X receptor blockade has no effect, but inhibition of P2Y1 receptors, which are strongly expressed by reactive astrocytes surrounding plaques, completely normalizes astrocytic hyperactivity. Our data suggest that astroglial network dysfunction is mediated by purinergic signalling in reactive astrocytes, and that intervention aimed at P2Y1 receptors or hemichannel-mediated nucleotide release may help ameliorate network dysfunction in AD.
星形胶质细胞网络改变在阿尔茨海默病（AD）中已有报道，但潜在的途径仍未确定。在这里，我们使用多光子显微镜在 AD 的小鼠模型中测量了星形胶质细胞内的钙、脑血流和淀粉样β斑块。我们发现，星形胶质细胞的过度活跃，包括单个细胞瞬变和钙波，在斑块周围的反应性星形胶质细胞中最为明显，有时与局部血流变化有关。我们表明，星形胶质细胞的过度活跃在 P2 嘌呤能受体阻断或通过连接蛋白半通道释放核苷酸后减少，但通过增加皮质 ADP 浓度而增加。P2X 受体阻断没有效果，但强烈表达于斑块周围反应性星形胶质细胞的 P2Y1 受体的抑制作用可完全使星形胶质细胞过度活跃正常化。我们的数据表明，星形胶质细胞网络功能障碍是由反应性星形胶质细胞中的嘌呤能信号传导介导的，并且针对 P2Y1 受体或半通道介导的核苷酸释放的干预可能有助于改善 AD 中的网络功能障碍。
