Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes.
Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes.
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DOI：
10.1042/an20090035
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发表时间：
2010-01-25
期刊：
影响因子：
4.7
通讯作者：
Silva GA
中科院分区：
文献类型：
--
作者：
Chow SK;Yu D;Macdonald CL;Buibas M;Silva GA
星形胶质细胞对AD（阿尔茨海默病）病理生理的贡献及其潜在的分子和信号机制仍然知之甚少。然而，越来越多的证据表明星形胶质细胞中的钙失调可能起着关键作用。体外星形胶质细胞网络中的细胞间钙波可以在Aβ（淀粉样蛋白β-肽）处理后机械诱导，并且最近在APP（淀粉样前体蛋白）/PS1（早老素1）阿尔茨海默氏症转基因小鼠模型中显示自发形成的细胞间钙波。然而，在体外分离的星形胶质细胞培养中，在没有其他细胞类型的潜在混淆信号的情况下，尚未观察到自发的细胞间钙瞬态和波对Aβ直接刺激的反应。在这里，我们发现相对低浓度的a β可以直接诱导纯化培养的星形胶质细胞内的细胞内钙瞬态和自发的细胞间钙波，这提高了a β暴露对阿尔茨海默病大脑中星形胶质细胞的潜在直接影响的可能性。在Aβ治疗后，脑电波并没有立即发生，而是在自发形成之前延迟了许多分钟，这表明细胞内信号机制需要足够的时间来激活，才能在网络水平上产生明显的细胞间效应。此外，细胞间钙波的动态是不均匀的，具有明显的径向或纵向传播方向。最后，我们还发现中间丝蛋白GFAP（胶质纤维酸性蛋白）和S100B的表达水平变化受a β诱导的钙变化的影响不同，GFAP比S100B更依赖于钙水平。
The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B.