Neuroscience Research, GPRD, Abbott, Ludwigshafen, Germany.
Br J Pharmacol. 2012 Mar;165(5):1572-83. doi: 10.1111/j.1476-5381.2011.01646.x.
β-amyloid (Aβ) oligomers have been implicated in the early pathophysiology of Alzheimer's disease (AD). While the precise nature of the molecular target has not been fully revealed, a number of studies have indicated that Aβ oligomers modulate neuron-specific ion channels. We recently provided evidence that Aβ oligomers suppress isolated P/Q-type calcium currents in cultured nerve cells. Using a heterologous expression system, we aimed to prove a direct effect on the membrane channel mediating such current.
The effects of a synthetically generated Aβ oligomer, Aβ globulomer, were investigated on P/Q-type currents recorded from Xenopus laevis oocytes expressing the full P/Q-type calcium channel or the pore-forming subunit only. We also examined the effects of Aβ globulomer on recombinant NMDA receptor currents. Finally, we compared the modulation by Aβ globulomer with that induced by a synthetic monomeric Aβ.
Aβ globulomer directly and dose-dependently modulated P/Q-type calcium channels. A leftward shift of the current-voltage curve indicated that the threshold for channel opening was reduced. The effect of Aβ globulomer was also present when only the α1A subunit of the normally tripartite channel was expressed. In contrast, the monomeric Aβ had no effect on P/Q current. Also globulomer Aβ had no effect on glutamate-induced NMDA currents.
The α1A subunit of the P/Q-type calcium channel is directly modulated by oligomeric Aβ. Threshold reduction as well as an increase in current at synaptic terminals may facilitate vesicle release and could trigger excitotoxic events in the brains of patients with AD.
β-淀粉样蛋白（Aβ）寡聚体与阿尔茨海默病（AD）的早期病理生理学有关。虽然分子靶标的确切性质尚未完全揭示，但许多研究表明 Aβ寡聚体调节神经元特异性离子通道。我们最近提供的证据表明，Aβ寡聚体抑制培养神经细胞中的分离 P/Q 型钙电流。使用异源表达系统，我们旨在证明对介导这种电流的膜通道的直接影响。
研究了合成生成的 Aβ 寡聚体 Aβ 球蛋白对表达全长 P/Q 型钙通道或仅表达通道形成亚基的非洲爪蟾卵母细胞中 P/Q 型电流的影响。我们还检查了 Aβ 球蛋白对重组 NMDA 受体电流的影响。最后，我们比较了 Aβ 球蛋白的调制与合成单体 Aβ 诱导的调制。
Aβ 球蛋白直接且剂量依赖性地调节 P/Q 型钙通道。电流-电压曲线的左移表明通道开放的阈值降低。当仅表达通常的三部分通道的α1A 亚基时，Aβ 球蛋白的作用也存在。相比之下，单体 Aβ 对 P/Q 电流没有影响。球蛋白 Aβ 也对谷氨酸诱导的 NMDA 电流没有影响。
P/Q 型钙通道的α1A 亚基被寡聚体 Aβ 直接调节。阈值降低以及突触末梢电流增加可能有助于囊泡释放，并可能引发 AD 患者大脑中的兴奋性毒性事件。
