BETA-AMYLOID CA2+-CHANNEL HYPOTHESIS FOR NEURONAL DEATH IN ALZHEIMER-DISEASE
BETA-AMYLOID CA2+-CHANNEL HYPOTHESIS FOR NEURONAL DEATH IN ALZHEIMER-DISEASE
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DOI：
10.1007/bf00926750
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发表时间：
1994-11-23
影响因子：
4.3
通讯作者：
ROJAS, E
中科院分区：
文献类型：
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作者：
ARISPE, N;POLLARD, HB;ROJAS, E
阿尔茨海默病（AD）淀粉样蛋白（A β P[1-40]）通过与含有肽的脂质体融合进入平面脂质双分子层时形成阳离子选择通道。由于已提出肽在体内以膜结合和可溶性形式存在，我们还测试了可溶性A β P直接掺入膜的可能性[1-40]。我们发现肽也可以在膜片移液管尖端形成的酸性磷脂双分子层以及平面脂质双分子层系统中形成类似的通道。与脂质体介导的掺入一样，无溶剂膜斑块中的A β P[1-40]通道表现出多重阳离子选择性（Cs+>Li+>Ca（2+）大于或等于K+），并对三聚氰胺敏感。等效的a β P[1-40]淀粉样蛋白通道可以通过两种不同的方法检测，这一事实因此为我们最初的观察提供了额外的验证。在脂质体复合物的平面脂质双层中加入β - p通道的进一步研究也表明，通道活性可以表达400至4000 pS之间更高范围的自发转变。在这些条件下，淀粉样蛋白通道继续具有阳离子选择性，但失去了对三聚氰胺的敏感性。相比之下，淀粉样蛋白通道在任何电导范围内都对尼群地平不敏感。我们计算，如果这些通道在细胞中表达，随后的离子通量沿着其电化学电位梯度将破坏细胞内稳态。因此，我们将这些数据解释为β -淀粉样蛋白Ca2（+）通道假说对阿尔茨海默病神经元死亡的进一步支持。
The Alzheimer's Disease (AD) amyloid protein (A beta P[1-40]) forms cation selective channels when incorporated into planar lipid bilayers by fusion with liposomes containing the peptide. Since the peptide has been proposed to occur in vivo in both membrane-bound and soluble forms, we also tested the possibility of direct incorporation of the soluble A beta P[1-40] into the membrane. We found the peptide can also form similar channels in acidic phospholipid bilayers formed at the tip of a patch pipet, as well as in the planar lipid bilayer system. As in the case of liposome mediated incorporation, the A beta P[1-40]-channel in the solvent-free membrane patch exhibits multiple cation selectivity (Cs+>Li+>Ca(2+)greater than or equal to K+), and sensitivity to tromethamine. The fact that equivalentA beta P[1-40] amyloid channels can be detected by two different methods thus provides additional validation of our original observation. Further studies with a beta P-channels incorporated into planar lipid bilayers from the liposome complex have also revealed that the channel activity can express spontaneous transitions to a much higher range of conductances between 400 and 4000 pS. Under these conditions, the amyloid channel continues to be cation selective but loses its tromethamine sensitivity. By contrast, amyloid channels were insensitive to nitrendipine at either conductance range. We calculate that if such channels were expressed in cells, the ensuing ion fluxes down their electrochemical potential gradients would disrupt cellular homeostasis. We therefore interpret these data as providing further support for our beta-amyloid Ca2(+)-channel hypothesis for neuronal death in Alzheimer's Disease.