Amar Fatou, Sherman Mathew A, Rush Travis, Larson Megan, Boyle Gabriel, Chang Liu, Götz Jürgen, Buisson Alain, Lesné Sylvain E
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55414, USA.
N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN 55414, USA.
Sci Signal. 2017 May 9;10(478):eaal2021. doi: 10.1126/scisignal.aal2021.
Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Aβ) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ56 interacted with -methyl-d-aspartate receptors (NMDARs), increased NMDAR-dependent Ca influx, and consequently increased intracellular calcium concentrations and the activation of Ca-dependent calmodulin kinase IIα (CaMKIIα). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIα was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies.
淀粉样蛋白形成蛋白的寡聚体形式被认为是包括阿尔茨海默病（AD）在内的许多神经退行性疾病中的主要起始生物活性物质。淀粉样β蛋白（Aβ）寡聚体与AD相关的微管相关蛋白tau的磷酸化和聚集有关。为了研究不同组装体激活的特定分子途径，我们从AD模型Tg2576小鼠中分离出各种形式的Aβ。我们发现，Aβ56是一种在患者出现明显AD症状之前就能检测到的56 kDa寡聚体，它能诱导神经元信号传导发生特定变化。在原代皮质神经元中，Aβ56与N-甲基-D-天冬氨酸受体（NMDARs）相互作用，增加NMDAR依赖性钙内流，从而增加细胞内钙浓度并激活钙依赖性钙调蛋白激酶IIα（CaMKIIα）。在培养的神经元和Tg2576小鼠的大脑中，激活的CaMKIIα与tau的位点特异性磷酸化增加和分选错误有关，这两者都与AD病理学相关。相比之下，将培养的原代皮质神经元暴露于其他寡聚体Aβ形式（二聚体和三聚体）不会引发这些效应。我们的结果表明，不同的Aβ组装体以选择性方式激活神经元信号通路，剖析每种寡聚体引起的分子事件可能为更有效的治疗策略提供依据。
