AbdAlla Said, Lother Heinz, el Missiry Ahmed, Langer Andreas, Sergeev Pavel, el Faramawy Yasser, Quitterer Ursula
Heinrich-Pette-Institute, Martinistrasse 52, D-20251 Hamburg, Germany.
J Biol Chem. 2009 Mar 6;284(10):6554-65. doi: 10.1074/jbc.M807746200. Epub 2008 Dec 11.
Progressive neurodegeneration and decline of cognitive functions are major hallmarks of Alzheimer disease (AD). Neurodegeneration in AD correlates with dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by Galphaq/11. We report here that impaired Galphaq/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Galphaq/11. Amyloid beta (Abeta) was causal to AT2 oligomerization, because cerebral microinjection of Abeta triggered AT2 oligomerization in the hippocampus of mice in a dose-dependent manner. Abeta induced AT2 oligomerization by a two-step process of oxidative and transglutaminase-dependent cross-linking. The induction of AT2 oligomers in a transgenic mouse model with AD-like symptoms was associated with Galphaq/11 dysfunction and enhanced neurodegeneration. Vice versa, stereotactic inhibition of AT2 oligomers by RNA interference prevented the impairment of Galphaq/11 and delayed Tau phosphorylation. Thus, Abeta induces the formation of cross-linked AT2 oligomers that contribute to the dysfunction of Galphaq/11 in an animal model of Alzheimer disease.
进行性神经退行性变和认知功能衰退是阿尔茨海默病（AD）的主要特征。AD中的神经退行性变与多种信号转导机制功能障碍相关，如由Gαq/11介导的G蛋白刺激的磷酸肌醇水解。我们在此报告，AD患者和小鼠大脑中Gαq/11刺激信号受损与交联寡聚血管紧张素II AT2受体的出现相关，这些受体隔离了Gαq/11。淀粉样β蛋白（Aβ）是AT2寡聚化的原因，因为脑内微注射Aβ以剂量依赖方式触发小鼠海马体中的AT2寡聚化。Aβ通过氧化和转谷氨酰胺酶依赖性交联的两步过程诱导AT2寡聚化。在具有AD样症状的转基因小鼠模型中，AT2寡聚物的诱导与Gαq/11功能障碍和神经退行性变增强相关。反之，通过RNA干扰对AT2寡聚物进行立体定向抑制可防止Gαq/11受损并延迟Tau磷酸化。因此，在阿尔茨海默病动物模型中，Aβ诱导形成交联的AT2寡聚物，导致Gαq/11功能障碍。
