May Linda M, Anggono Victor, Gooch Helen M, Jang Se E, Matusica Dusan, Kerbler Georg M, Meunier Frederic A, Sah Pankaj, Coulson Elizabeth J
Queensland Brain Institute, University of QueenslandBrisbane, QLD, Australia.
Clem Jones Centre for Ageing Dementia Research, University of QueenslandBrisbane, QLD, Australia.
Front Neurosci. 2017 Aug 8;11:455. doi: 10.3389/fnins.2017.00455. eCollection 2017.
Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Aβ). Although, the neurotoxic Aβ peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Aβ-triggered apoptotic pathway in which Aβ treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Aβ-mediated apoptosis. Although, GIRK channel activity is required for Aβ-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Aβ and its ability to trigger cell death pathways, such as that mediated by p75. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration.
阿尔茨海默病的特征是认知能力下降、神经元退化以及β淀粉样蛋白（Aβ）的积累。尽管人们普遍认为神经毒性Aβ肽会引发阿尔茨海默病中的神经元功能障碍和退化，但其发生机制仍不清楚。在此，我们描述了一种新的、由Aβ触发的凋亡途径，其中Aβ处理导致G蛋白激活的内向整流钾通道（GIRK/Kir3）上调，引起神经元钾外流和Aβ介导的凋亡。虽然GIRK通道活性是Aβ诱导神经元退化所必需的，但我们发现这并不充分，p75神经营养因子受体（p75）的协同信号传导对于钾外流和细胞死亡也是必需的。我们的结果确定了GIRK通道在介导凋亡中的新作用，并提供了Aβ的兴奋性毒性与其触发细胞死亡途径（如由p75介导的途径）的能力之间先前缺失的机制联系。我们认为这种死亡信号通路导致了阿尔茨海默病中神经元的功能障碍，并导致它们最终退化。
