Mitochondrial modulation of store-operated Ca2+ entry in model cells of Alzheimer's disease
Mitochondrial modulation of store-operated Ca2+ entry in model cells of Alzheimer's disease
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DOI：
10.1016/j.bbrc.2012.08.062
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发表时间：
2012-09-21
影响因子：
3.1
通讯作者：
Gong, Yandao
中科院分区：
文献类型：
--
作者：
Ma, Tuo;Gong, Kai;Gong, Yandao
线粒体功能障碍和钙平衡失调是被认为是阿尔茨海默病（AD）大脑的重要特征的早期病理事件。最近的研究表明，线粒体是基于其钙缓冲能力的Ca2+信号的积极调节剂。在此，我们研究了线粒体参与神经2a （N2a）转基因AD模型细胞中储存操作钙进入（SOCE）的调节。结果表明，与空载体对照（N2a WT）细胞相比，转染野生型人APP695 （N2a APPwt）的N2a细胞的SOCE明显降低。线粒体功能阻滞剂（如FCCP、RuR或抗霉素A/寡霉素）的药理学操作可以抑制线粒体钙处理，从而损害N2a WT细胞的SOCE途径。此外，与野生型对照相比，N2a APPwt细胞的线粒体在Ca2+的作用下表现出更严重的肿胀，这是线粒体膜通透性转变（MPT）的指示。此外，环孢素A是一种强效的亲环素D抑制剂，可以阻断MPT，可以显著恢复N2a APPwt细胞中减弱的SOCE。因此，抑制亲环蛋白D可能是阿尔茨海默病的一种治疗策略。(C) 2012爱思唯尔公司版权所有。
Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer's disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca2+ signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca2+, which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer's disease. (C) 2012 Elsevier Inc. All rights reserved.