Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro,", Novara, Italy.
Glia. 2013 Jul;61(7):1134-45. doi: 10.1002/glia.22502. Epub 2013 Apr 25.
The amyloid hypothesis of Alzheimer's disease (AD) suggests that soluble amyloid β (Aβ) is an initiator of a cascade of events eventually leading to neurodegeneration. Recently, we reported that Aβ deranged Ca(2+) homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca(2+) signaling, such as mGluR5 and IP3 R1. In the present study, we dissect a cascade of signaling events by which Aβ deregulates glial Ca(2+) : (i) 100 nM Aβ leads to an increase in cytosolic calcium after 4-6 h of treatment; (ii) mGluR5 is increased after 24 h of treatment; (iii) this increase is blocked by inhibitors of calcineurin (CaN) and NF-kB. Furthermore, we show that Aβ treatment of glial cells leads to de-phosphorylation of Bcl10 and an increased CaN-Bcl10 interaction. Last, mGluR5 staining is augmented in hippocampal astrocytes of AD patients in proximity of Aβ plaques and co-localizes with nuclear accumulation of the p65 NF-kB subunit and increased staining of CaNAα. Taken together our data suggest that nanomolar [Aβ] deregulates Ca(2+) homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes.
阿尔茨海默病（AD）的淀粉样蛋白假说表明，可溶性淀粉样蛋白β（Aβ）是引发级联事件的启动子，最终导致神经退行性变。最近，我们报道 Aβ 通过靶向 Ca（2+）信号的关键元件，如 mGluR5 和 IP3 R1，特异性扰乱海马星形胶质细胞中的 Ca（2+）稳态。在本研究中，我们剖析了 Aβ 使神经胶质细胞 Ca（2+）失调的一系列信号事件：（i）100 nM Aβ 处理 4-6 小时后导致细胞浆钙增加；（ii）24 小时后 mGluR5 增加；（iii）该增加被钙调神经磷酸酶（CaN）和 NF-kB 抑制剂阻断。此外，我们表明 Aβ 处理神经胶质细胞导致 Bcl10 去磷酸化和 CaN-Bcl10 相互作用增加。最后，AD 患者海马星形胶质细胞中 mGluR5 染色在 Aβ 斑块附近增强，并与核内 p65 NF-kB 亚基的积累和 CaNAα 的染色增加共定位。综上所述，我们的数据表明，纳米摩尔浓度的[Aβ]通过 CaN 及其下游靶标 NF-kB 调节 Ca（2+）稳态，可能通过 Bcl10 在海马星形胶质细胞中的串扰来实现。
