Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB
Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB
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DOI：
10.1002/glia.22502
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发表时间：
2013-07-01
期刊：
影响因子：
6.2
通讯作者：
Genazzani, Armando A.
中科院分区：
文献类型：
--
作者：
Lim, Dmitry;Iyer, Anand;Genazzani, Armando A.
阿尔茨海默氏病（AD）的淀粉样蛋白假说表明，可溶性淀粉样蛋白（A）是最终导致神经退行性变的级联反应的启动剂。最近，我们报道了A通过靶向Ca 2+信号传导的关键元件，如mGluR 5和IP 3R 1，特异性地在海马星形胶质细胞中扰乱Ca 2+稳态。在本研究中，我们剖析了A下调神经胶质细胞Ca 2+的信号传导事件级联：（i）100 nM A导致处理4-6 h后细胞溶质钙增加;（ii）处理24 h后mGluR 5增加;（iii）这种增加被钙调神经磷酸酶（CaN）和NF-κ B抑制剂阻断。此外，我们表明，A治疗神经胶质细胞导致Bcl 10的去磷酸化和CaN-Bcl 10相互作用的增加。最后，mGluR 5染色在AD患者海马星形胶质细胞A斑附近增强，并与p65 NF-kB亚基的核积累和CaNA染色增加共定位。总之，我们的数据表明，纳摩尔[A]通过CaN及其下游靶点NF-κ B，可能通过海马星形胶质细胞中Bcl 10的串扰，使Ca 2+稳态失调。
The amyloid hypothesis of Alzheimer's disease (AD) suggests that soluble amyloid (A) is an initiator of a cascade of events eventually leading to neurodegeneration. Recently, we reported that A deranged Ca2+ homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca2+ signaling, such as mGluR5 and IP3R1. In the present study, we dissect a cascade of signaling events by which A deregulates glial Ca2+: (i) 100 nM A 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 A 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 A plaques and co-localizes with nuclear accumulation of the p65 NF-kB subunit and increased staining of CaNA. Taken together our data suggest that nanomolar [A] deregulates Ca2+ homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes.