Calcium hypothesis of Alzheimer's disease
Calcium hypothesis of Alzheimer's disease
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DOI：
10.1007/s00424-009-0736-1
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发表时间：
2010-02-01
影响因子：
4.5
通讯作者：
Berridge, Michael J.
中科院分区：
文献类型：
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作者：
Berridge, Michael J.
阿尔茨海默病（Alzheimer's disease，AD）是一种由淀粉样蛋白代谢增加引起的进行性神经退行性疾病。AD的钙假说探讨了淀粉样蛋白生成途径的激活如何作用于重塑负责认知的神经元Ca 2+信号通路。β-淀粉样前体蛋白（APP）的水解产生两种可以影响Ca 2+信号传导的产物。首先，释放到外部的淀粉样蛋白形成寡聚体，其增强被泵入内质网（ER）的Ca 2+的进入。内质网内Ca 2+管腔水平的增加增强了兰尼碱受体（RYR）的敏感性，以增加从内部储存释放的Ca 2+的量。其次，APP胞内结构域可能改变关键信号传导组分如RYR的表达。有人提出，这种Ca 2+信号的重塑将导致在AD发病早期发生的学习和记忆缺陷。特别是，Ca 2+信号重塑可以通过增强依赖于Ca 2+依赖性蛋白磷酸酶钙调磷酸酶激活的长期抑郁机制来消除新获得的记忆。Ca 2+信号传导的改变也将有助于神经变性，这是痴呆症后期的特征。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca2+ signaling pathways responsible for cognition. Hydrolysis of the beta-amyloid precursor protein (APP) yields two products that can influence Ca2+ signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca2+ that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca2+ within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca2+ being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca2+ signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca2+ signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca2+-dependent protein phosphatase calcineurin. The alteration in Ca2+ signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.