Amyloid-β-(1-42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice
Amyloid-β-(1-42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice
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DOI：
10.1074/jbc.m606736200
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发表时间：
2006-12-15
影响因子：
4.8
通讯作者：
Mayne, Michael
中科院分区：
文献类型：
--
作者：
Supnet, Charlene;Grant, Jeff;Mayne, Michael
细胞内钙稳态的破坏先于阿尔茨海默病（AD）中发生的神经变性。在许多神经元钙调节蛋白中，我们专注于内质网（ER）驻留的兰尼碱受体（RyR），因为它们在表达突变型早老素-1的小鼠海马中增加，并与神经毒性相关。其他人已经观察到在人类死后海马区域中ryanodine结合升高，这表明RyR（s）参与AD发病机制。在这里，我们报告，细胞外淀粉样蛋白β（A β）-（1-42）特异性增加RyR-3，但不是RyR-1或RyR-2，基因表达在皮质神经元从C57 B16小鼠。此外，内源性产生的A β-（1-42）增加了转基因（Tg）CRND 8小鼠（AD小鼠模型）皮质神经元中的RyR-3 mRNA和蛋白。与非Tg同窝对照组相比，在4至4.5月龄Tg动物的脑组织中也观察到RyR-3 mRNA和蛋白的增加。在标称细胞外钙的实验中，与同窝对照组相比，来自Tg小鼠的神经元在ryanodine或谷氨酸盐处理后细胞内钙显著增加，这通过针对RyR-3的小干扰RNA处理而被消除，表明较高水平的钙源自RyR-3调节的储存。总之，这些观察结果表明，A β-（1-42）介导的细胞内钙稳态的变化部分通过直接增加RyR-3的表达和功能来调节。
yDisruption of intracellular calcium homeostasis precedes the neurodegeneration that occurs in Alzheimer disease ( AD). Of the many neuronal calcium-regulating proteins, we focused on endoplasmic reticulum (ER)-resident ryanodine receptors (RyRs) because they are increased in the hippocampus of mice expressing mutant presenilin-1 and are associated with neurotoxicity. Others have observed that ryanodine binding is elevated in human postmortem hippocampal regions suggesting that RyR(s) are involved in AD pathogenesis. Here we report that extracellular amyloid-beta(A beta)-(1-42) specifically increased RyR-3, but not RyR-1 or RyR-2, gene expression in cortical neurons from C57Bl6 mice. Furthermore, endogenously produced A beta-(1-42) increased RyR-3 mRNA and protein in cortical neurons from transgenic (Tg) CRND8 mice, a mouse model of AD. Increased RyR-3 mRNA and protein was also observed in brain tissue from 4- to 4.5-month-old Tg animals compared with non-Tg littermate controls. In experiments performed in nominal extracellular calcium, neurons from Tg mice had significant increases in intracellular calcium following ryanodine or glutamate treatment compared with littermate controls, which was abolished by treatment with small interfering RNA directed to RyR-3, indicating that the higher levels of calcium originated from RyR-3-regulated stores. Taken together, these observations suggest that A beta-(1-42)-mediated changes in intracellular calcium homeostasis is regulated in part through a direct increase of RyR-3 expression and function.