Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate.
Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate.
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DOI：
10.1523/jneurosci.4367-12.2013
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发表时间：
2013-02-27
期刊：
影响因子：
--
通讯作者：
Parker I
中科院分区：
文献类型：
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作者：
Demuro A;Parker I
与阿尔茨海默病（AD）相关的Aβ肽的寡聚体形式通过从细胞外和细胞内来源将Ca 2+释放到胞质溶胶中来破坏细胞Ca 2+调节。我们通过对非洲爪蟾卵母细胞注射Aβ寡聚体后的Ca 2+反应进行成像，阐明了细胞内Aβ42的作用。观察到两种类型的信号：（i）依赖于细胞外Ca 2+内流的局部“通道样”瞬变，其类似于来自通过细胞外应用寡聚物形成的淀粉样蛋白孔的信号;（ii）局部瞬变和全局Ca 2+波，类似于由三磷酸肌醇（IP 3）介导的Ca 2+喷流和波。后者的反应被抑制的IP 3受体（咖啡因和肝素）的拮抗剂，通过预处理与Gi/o-蛋白抑制剂百日咳毒素，和通过预处理与锂耗尽膜肌醇脂质。我们发现，G蛋白介导的刺激IP 3产生和随后的胞内Aβ寡聚体从内质网释放Ca 2+具有细胞毒性，可能代表AD中的一种新的病理机制，该机制可能因早老素中AD相关突变而进一步加剧，以促进IP 3受体/通道的开放。
Oligomeric forms of Aβ peptides associated with Alzheimer`s disease (AD) disrupt cellular Ca2+ regulation by liberating Ca2+ into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular Aβ42 by imaging Ca2+ responses to injections of Aβ oligomers into Xenopus oocytes. Two types of signal were observed: (i) local, 'channel-like' transients dependent on extracellular Ca2+ influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; (ii) local transients and global Ca2+ waves, resembling Ca2+ puffs and waves mediated by inositol trisphosphate (IP3). The latter responses were suppressed by antagonists of the IP3 receptor (caffeine and heparin), by pretreatment with the Gi/o-protein inhibitor pertussis toxin, and by pre-treatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP3 production and consequent liberation of Ca2+ from the endoplasmic reticulum by intracellular Aβ oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP3 receptor/channels.