Role of presenilins in neuronal calcium homeostasis.
Role of presenilins in neuronal calcium homeostasis.
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DOI：
10.1523/jneurosci.1554-10.2010
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发表时间：
2010-06-23
期刊：
影响因子：
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通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
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作者：
Zhang H;Sun S;Herreman A;De Strooper B;Bezprozvanny I
阿尔茨海默病（Alzheimer's disease，AD）是一种进行性、不可逆的神经退行性疾病。早老素家族性AD（FAD）突变与钙（Ca 2+）信号传导异常有关。为了解释这些结果，我们以前提出，早老素的功能作为内质网（ER）的被动Ca 2+泄漏通道。为了直接研究早老素在神经元ER Ca 2+稳态中的作用，我们在此对条件性早老素双敲除小鼠（PScDKO小鼠; PS1 dTAG/dTAG，PS2−/−）和三重转基因AD小鼠（3xTg小鼠; KI-PS1 M146 V，Thy 1-APPKM 670/671 NL，Thy 1-tauP 301 L）的原代神经元培养物进行了一系列Ca 2+成像实验。这些结果进一步支持了早老素在神经元中作为ER Ca ~（2+）泄漏通道的假说。有趣的是，我们发现早老素在海马而不是纹状体神经元的ER Ca 2+泄漏功能中起主要作用。我们进一步发现，在海马神经元早老素介导的ER Ca 2+泄漏功能的损失是通过增加兰尼碱受体（RyanR）的表达和功能来补偿的。长期喂食RyanR抑制剂丹曲林给APPPS 1小鼠（Thy 1-APPKM 670/671 NL，Thy 1-PS1 L166 P）导致海马和皮质区域淀粉样蛋白负荷增加，突触标记物丢失和神经元萎缩。这些结果表明，早老素的ER Ca ~（2+）泄漏功能的破坏可能在AD发病机制中起重要作用。
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. Familial AD (FAD) mutations in presenilins have been linked to calcium (Ca2+) signaling abnormalities. To explain these results we previously proposed that presenilins function as endoplasmic reticulum (ER) passive Ca2+ leak channels. To directly investigate the role of presenilins in neuronal ER Ca2+ homeostasis we here performed a series of Ca2+ imaging experiments with primary neuronal cultures from conditional presenilin double-knockout mice (PScDKO mice; PS1dTAG/dTAG, PS2−/−) and from a triple transgenic AD mice (3xTg mice; KI-PS1M146V, Thy1-APPKM670/671NL, Thy1-tauP301L). Obtained results provided further support to the hypothesis that presenilins function as ER Ca2+ leak channels in neurons. Interestingly, we discovered that presenilins play a major role in ER Ca2+ leak function in hippocampal but not in striatal neurons. We further discovered that in hippocampal neurons loss of presenilin-mediated ER Ca2+ leak function was compensated by an increase in expression and function of ryanodine receptors (RyanR). Long-term feeding of RyanR inhibitor dantrolene to APPPS1 mice (Thy1-APPKM670/671NL, Thy1-PS1L166P) resulted in an increased amyloid load, loss of synaptic markers and neuronal atrophy in hippocampal and cortical regions. These results indicate that disruption of ER Ca2+ leak function of presenilins may play an important role in AD pathogenesis.