Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-D-aspartate receptors in cortical cultures
Amyloid beta peptide 1-42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-D-aspartate receptors in cortical cultures
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DOI：
10.1016/j.ceca.2011.11.008
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发表时间：
2012-02-01
期刊：
影响因子：
4
通讯作者：
Rego, A. C.
中科院分区：
文献类型：
--
作者：
Ferreira, I. L.;Bajouco, L. M.;Rego, A. C.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其导致使人衰弱的认知缺陷。最近的证据表明，淀粉样β肽（A β）寡聚体导致谷氨酸受体失调，导致与早期认知缺陷平行的谷氨酸能突触传递中断。虽然AD中神经元死亡与细胞内Ca 2+（Ca 1（2+））稳态紊乱有关是公认的，但关于含有GluN 2A或GluN 2B亚基的NMDAR对A β诱导的Ca 1（2+）升高和神经元功能障碍的贡献知之甚少。因此，这项工作的主要目标是评估NMDAR亚基在大鼠大脑皮层神经元中由含有寡聚体（以较高百分比）和单体的A β 1-42制剂诱导的Ca-1（2+）稳态失调中的作用。通过分别使用MK-801或选择性GluN 2A和GLUN 2B亚基拮抗剂NVP-AAM 077和艾芬地尔的药理学抑制来评价NMDAR的参与。我们表明，A β，像NMDA，增加钙离子（2+）水平主要通过激活NMDAR含有GluN 2B亚基。相反，GluN 2A-NMDARs拮抗作用增强高浓度A β（1 μ M）诱导的Ca-1（2+）升高，表明GluN 2A和GluN 2B亚基在调节Ca-1（2+）稳态中具有相反的作用。此外，A β调节NMDA诱导的反应，反之亦然。事实上，预先暴露于A β（1 μ M）可降低NMDA诱发的Ca ~（2+）升高，预先暴露于NMDA可降低A β反应。有趣的是，同时添加A β和NMDA增强Ca-1（2+）水平，这种作用由GluN 2A和GluN 2B亚基以相反的方式调节。本研究通过探讨GluN 2A和GluN 2B亚基在AD中A β毒性机制中的作用，有助于理解AD早期发病机制的分子基础。(C)2011爱思唯尔有限公司保留所有权利。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to debilitating cognitive deficits. Recent evidence demonstrates that glutamate receptors are dysregulated by amyloid beta peptide (A beta) oligomers, resulting in disruption of glutamatergic synaptic transmission which parallels early cognitive deficits. Although it is well accepted that neuronal death in AD is related to disturbed intracellular Ca2+ (Ca-i(2+)) homeostasis, little is known about the contribution of NMDARs containing GluN2A or GluN2B subunits on A beta-induced Ca-i(2+), rise and neuronal dysfunction. Thus, the main goal of this work was to evaluate the role of NMDAR subunits in dysregulation of Ca-i(2+) homeostasis induced by A beta 1-42 preparation containing both oligomers (in higher percentage) and monomers in rat cerebral cortical neurons. The involvement of NMDARs was evaluated by pharmacological inhibition with MK-801 or the selective GluN2A and GLUN2B subunit antagonists NVP-AAM077 and ifenprodil, respectively. We show that A beta, like NMDA, increase Ca-i(2+) levels mainly through activation of NMDARs containing GluN2B subunits. Conversely, GluN2A-NMDARs antagonism potentiates Ca-i(2+) rise induced by a high concentration of A beta (1 mu M), suggesting that GluN2A and GluN2B subunits have opposite roles in regulating Ca-i(2+) homeostasis. Moreover, A beta modulate NMDA-induced responses and vice versa. Indeed, pre-exposure to A beta (1 mu M) decrease NMDA-evoked Ca-i(2+) rise and pre-exposure to NMDA decrease A beta response. Interestingly, simultaneous addition of A beta and NMDA potentiate Ca-i(2+) levels, this effect being regulated by GluN2A and GluN2B subunits in opposite manners. This study contributes to the understanding of the molecular basis of early AD pathogenesis, by exploring the role of GluN2A and GluN2B subunits in the mechanism of A beta toxicity in AD. (C) 2011 Elsevier Ltd. All rights reserved.