Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?
Dysregulation of neuronal calcium homeostasis in Alzheimer's disease - A therapeutic opportunity?
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DOI：
10.1016/j.bbrc.2016.09.053
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发表时间：
2017-02-19
影响因子：
3.1
通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
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作者：
Popugaeva E;Pchitskaya E;Bezprozvanny I
阿尔茨海默病(AD)是一种记忆丧失的疾病。突触丢失是阿尔茨海默病记忆障碍的主要原因。参与阿尔茨海默病记忆丧失的信号通路正在进行深入的研究。本文综述了神经细胞钙信号在阿尔茨海默病突触丢失中的作用。早老素的家族性AD(FAD)突变与突触钙信号的异常直接相关，很可能是通过影响早老素的内质网(ER)钙泄漏功能。由于RyanR2的表达和功能增加，在AD脊椎中观察到通过Ryanodine受体(RyanR2)过度释放ER钙离子。在AD脊椎中，由于STIM2蛋白的下调，导致储存操作的钙离子进入(NSOC)途径被破坏。由于这些钙信号的异常，突触上钙调素依赖的激酶II(CaMKII)和钙依赖的磷酸酶钙调神经磷酸酶(CaN)活性的平衡被转移，使长时程增强(LTP)和长时程抑制(LTD)突触机制之间的平衡发生倾斜。其结果是，通过LTD机制，AD脑内突触被削弱和消除，导致记忆丧失。靶向突触钙信号通路为AD治疗药物的开发提供了机会。
Alzheimer’s disease (AD) is the disease of lost memories. Synaptic loss is a major reason for memory defects in AD. Signaling pathways involved in memory loss in AD are under intense investigation. The role of deranged neuronal calcium (Ca2+) signaling in synaptic loss in AD is described in this review. Familial AD (FAD) mutations in presenilins are linked directly with synaptic Ca2+ signaling abnormalities, most likely by affecting endoplasmic reticulum (ER) Ca2+ leak function of presenilins. Excessive ER Ca2+ release via type 2 ryanodine receptors (RyanR2) is observed in AD spines due to increase in expression and function of RyanR2. Store-operated Ca2+ entry (nSOC) pathway is disrupted in AD spines due to downregulation of STIM2 protein. Because of these Ca2+ signaling abnormalities, a balance in activities of Ca2+-calmodulin-dependent kinase II (CaMKII) and Ca2+-dependent phosphatase calcineurin (CaN) is shifted at the synapse, tilting a balance between long-term potentiation (LTP) and long-term depression (LTD) synaptic mechanisms. As a result, synapses are weakened and eliminated in AD brains by LTD mechanism, causing memory loss. Targeting synaptic calcium signaling pathways offers opportunity for development of AD therapeutic agents.