The Babraham Institute, Cambridge CB22 3AT, UK.
Pflugers Arch. 2010 Feb;459(3):441-9. doi: 10.1007/s00424-009-0736-1. Epub 2009 Oct 1.
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 Ca(2+) signaling pathways responsible for cognition. Hydrolysis of the beta-amyloid precursor protein (APP) yields two products that can influence Ca(2+) signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca(2+) that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca(2+) within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca(2+) 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 Ca(2+) signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca(2+) signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca(2+)-dependent protein phosphatase calcineurin. The alteration in Ca(2+) signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.
阿尔茨海默病（AD）是一种渐进性神经退行性疾病，由淀粉样代谢物增加引起。AD 的钙假说探讨了淀粉样蛋白形成途径的激活如何影响负责认知的神经元 Ca(2+)信号通路的重塑。β-淀粉样前体蛋白（APP）的水解产生两种可能影响 Ca(2+)信号的产物。首先，释放到细胞外的淀粉样物质形成寡聚物，增强被泵入内质网（ER）的 Ca(2+)的进入。内质网腔内 Ca(2+)水平的增加增强了肌浆网 Ca(2+)释放通道（RYRs）对 Ca(2+)释放量增加的敏感性。其次，APP 细胞内结构域可能改变关键信号成分的表达，如 RYR。据推测，这种 Ca(2+)信号的重构将导致 AD 发病早期出现的学习和记忆缺陷。特别是，Ca(2+)信号重构可能通过增强依赖 Ca(2+)依赖性蛋白磷酸酶钙调神经磷酸酶激活的长时程抑制机制来消除新获得的记忆。Ca(2+)信号的改变也将导致痴呆后期特征性的神经退行性变。
