The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease.
The complex PrP(c)-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease.
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DOI：
10.1523/jneurosci.1858-12.2012
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发表时间：
2012-11-21
期刊：
影响因子：
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通讯作者：
Lesné SE
中科院分区：
文献类型：
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作者：
Larson M;Sherman MA;Amar F;Nuvolone M;Schneider JA;Bennett DA;Aguzzi A;Lesné SE
在争议中，朊病毒蛋白PrPc的细胞形式被认为介导寡聚Aβ诱导的缺陷。相反，有一致的证据表明Src激酶Fyn被Aβ寡聚体激活，并导致转基因动物的突触和认知障碍。然而，可溶性Aβ激活Fyn的分子机制仍然未知。结合使用人类和转基因小鼠脑组织以及原代皮层神经元，我们证明可溶性Aβ在体内和体外与神经元树突棘处结合PrPc，在那里它与Fyn形成复合物，导致激酶活化。使用抗体6D 11阻止寡聚Aβ与PrPc结合，我们在体外消除了内源性寡聚Aβ诱导的Fyn激活和Fyn依赖性tau过度磷酸化。最后，我们发现Prnp的基因剂量调节Aβ诱导的Fyn/tau改变。总之，我们的研究结果确定了一个完整的信号级联连接一个特定的内源性Aβ寡聚体，Fyn改变和tau蛋白过度磷酸化的细胞和动物模型建模方面的阿尔茨海默病的分子发病机制。
Amidst controversy, the cellular form of the prion protein PrPc has been proposed to mediate oligomeric Aβ-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Aβ oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble Aβ activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble Aβ binds to PrPc at neuronal dendritic spines in vivo and in vitro where it forms a complex with Fyn, resulting in the activation of the kinase. Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrPc, we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβ in vitro. Finally we showed that gene dosage of Prnp regulates Aβ-induced Fyn/tau alterations. Altogether, our findings identify a complete signaling cascade linking one specific endogenous Aβ oligomer, Fyn alteration and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer’s disease.