Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer's disease cerebral cortex
Selective changes of calcineurin (protein phosphatase 2B) activity in Alzheimer's disease cerebral cortex
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DOI：
10.1006/exnr.2000.7534
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Lee, JM
中科院分区：
文献类型：
--
作者：
Lian, QY;Ladner, CJ;Lee, JM
神经原纤维缠结含有异常过度磷酸化的 tau 蛋白，是阿尔茨海默病 (AD) 的神经病理学标志之一。 tau 蛋白磷酸化状态的改变可能是由于激酶活性增加或/和磷酸酶活性降低所致。在本研究中，我们表征了死后上额叶皮层和感觉运动皮层中的人类钙调神经磷酸酶活性，并测量了中度至重度 AD 个体 (n = 7) 和年龄匹配对照 (n = 5) 样本中的钙调神经磷酸酶活性。 AD 额叶皮层基础磷酸酶活性降低 25% (P < 0.05)。与年龄匹配的对照相比，P2 和总细胞匀浆中镍刺激的钙调磷酸酶活性分别降低了 52% (P < 0.05) 和 30% (P < 0.05)。在感觉运动皮层中未检测到磷酸酶活性差异。额叶中镍刺激的钙调神经磷酸酶活性的降低与神经原纤维缠结病理相关（总细胞匀浆，r = -0.77，P < 0.05；P2 分数，r = -0.76，P < 0.02），但与弥漫性或神经炎斑块无关。尽管上额皮质中的钙调神经磷酸酶活性发生了变化，但通过免疫印迹测定的钙调神经磷酸酶蛋白水平在对照和 AD 病例中相似。此外，未观察到钙调神经磷酸酶调节蛋白（亲环蛋白 A 和 FKBP12）水平的变化。这些研究表明，钙调磷酸酶活性的降低可能在成对螺旋丝的形成和/或稳定中发挥作用，并且活性的降低并不伴随钙调磷酸酶蛋白表达的降低。 (C) 2001 年学术出版社。
Neurofibrillary tangles, which contain abnormally hyperphosphorylated forms of tau protein, are one of the neuropathological hallmarks of Alzheimer's disease (AD). This altered phosphorylation state of tau protein may be due to increased kinase activity or/and decreased phosphatase activity. In the present study, we characterized human calcineurin phosphatase activity in postmortem superior frontal cortex and sensorimotor cortex and measured calcineurin phosphatase activity in samples from individuals with moderate to severe AD (n = 7) and age-matched controls (n = 5). Basal phosphatase activity was reduced by 25% (P < 0.05) in AD frontal cortex. Nickel-stimulated calcineurin activity was decreased by 52% (P < 0.05) and 30% (P < 0.05) in P2 and total cell homogenate, respectively, compared to age matched controls. No differences in phosphatase activities were detected in the sensorimotor cortex. The decrease in nickel-stimulated calcineurin phosphatase activity in frontal lobe correlated with the neurofibrillary tangle pathology (total cell homogenate, r = -0.77, P < 0.05; P2 fraction, r = -0.76, P < 0.02), but not with diffuse or neuritic plaques. Despite the changes in calcineurin phosphatase activity in the superior frontal cortex, calcineurin protein levels determined by immunoblot were similar in control and AD cases. In addition, no changes in calcineurin regulatory proteins (cyclophilin A and FKBP12) levels were observed. These studies suggest that decrease of calcineurin activity may play a role in paired-helical filament formation and/or stabilization, and the decrease of activity was not accompanied by a decrease of calcineurin protein expression. (C) 2001 Academic Press.