Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease.
Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease.
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DOI：
10.3233/jad-2010-100306
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
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作者：
Supnet C;Bezprozvanny I
阿尔茨海默病（AD）是影响全世界数百万老年人的最常见的神经退行性疾病。阿尔茨海默病的特点是广泛的突触和神经元丧失，导致记忆受损和认知能力下降。阿尔茨海默病的病理原因尚不完全清楚，迄今为止还没有开发出有效的治疗方法。阿尔茨海默病大脑中毒性淀粉样蛋白- β42 （a - β42）肽寡聚物和聚集体的积累被认为是该疾病病理的主要原因，这一观点被称为阿尔茨海默病病因学的“淀粉样蛋白假说”。除了Aβ42水平升高外，在家族性AD的动物模型和散发性AD患者的死后脑样本研究中，还观察到神经元钙（Ca2+）信号的紊乱和Ca2+信号蛋白表达水平的改变。基于这些证据，提出了“AD的Ca2+假说”。特别是，家族性AD与内质网（ER） Ca2+释放增强和细胞质Ca2+水平升高有关。细胞内Ca2+水平的增加可以触发信号级联反应，影响突触的稳定性和功能，并可能对神经元健康有害，如Ca2+依赖性磷酸酶钙调磷酸酶和Ca2+依赖性蛋白酶钙蛋白酶。本文回顾了支持AD发病机制“Ca2+假说”的最新研究结果。我们进一步认为，在很长一段时间内，胞质Ca2+信号异常会损害AD神经元的线粒体功能。我们得出结论，神经元Ca2+信号和线粒体功能的抑制剂和稳定剂可能具有治疗AD的治疗潜力。我们讨论了针对Ca2+通道和线粒体的药物的最新和计划的AD治疗试验。
Alzheimer disease (AD) is the most common neurodegenerative disorder that affects millions of ageing people worldwide. AD is characterized by extensive synaptic and neuronal loss which lead to impaired memory and cognitive decline. The cause of pathology in AD is not completely understood and no effective therapy so far has been developed. The accumulation of toxic amyloid-beta 42 (Aβ42) peptide oligomers and aggregates in AD brain has been proposed to be primarily responsible for the pathology of the disease, an idea dubbed ‘amyloid hypothesis’ of AD etiology. In addition to increase in Aβ42 levels, disturbances in neuronal calcium (Ca2+) signaling and alterations in expression levels of Ca2+ signaling proteins have been observed in animal models of familial AD and in studies of postmortem brain samples from sporadic AD patients. Based on these evidence ‘Ca2+ hypothesis of AD’ has been proposed. In particular, familal AD has been linked with enhanced Ca2+ release from the endoplasmic reticulum (ER) and elevated cytosolic Ca2+ levels. The augmented cytosolic Ca2+ levels can trigger signaling cascades that affect synaptic stability and function and can be detrimental to neuronal health, such as Ca2+-dependent phosphatase calcineurin and Ca2+-dependent proteases calpains. Here we review the latest results supporting ‘Ca2+ hypothesis’ of AD pathogenesis. We further argue that over long period of time supranormal cytosolic Ca2+ signaling can impaire mitochondrial function in AD neurons. We conclude that inhibitors and stablizers of neuronal Ca2+ signaling and mitochondrial function may have a therapeutic potential for treatment of AD. We discuss latest and planned AD therapeutic trials of agents targeting Ca2+ channels and mitochodria.