Involvement of the γ‐Secretase‐Mediated EphA4 Signaling Pathway in Synaptic Pathogenesis of Alzheimer's Disease
Involvement of the γ‐Secretase‐Mediated EphA4 Signaling Pathway in Synaptic Pathogenesis of Alzheimer's Disease
复制标题
DOI：
10.1111/j.1750-3639.2012.00587.x
复制
发表时间：
2012-11
期刊：
影响因子：
6.4
通讯作者：
C. Matsui;E. Inoue;A. Kakita;Kohei Arita;Maki Deguchi-Tawarada;A. Togawa;Akio Yamada;Y. Takai;H. Takahashi
中科院分区：
文献类型：
--
作者：
C. Matsui;E. Inoue;A. Kakita;Kohei Arita;Maki Deguchi-Tawarada;A. Togawa;Akio Yamada;Y. Takai;H. Takahashi
突触丢失与阿尔茨海默病(AD)的认知障碍有关。然而，这种突触损伤背后的分子机制还不是很清楚。EphA4是γ分泌酶的底物，γ分泌酶裂解的EphA4胞内域通过激活Rac信号通路促进树突棘的形成。在这里，我们发现在AD患者的额叶中，rac1的数量显著减少，并且与EICD的水平相关。生化分析表明，膜相关EICD的数量减少，并与膜相关的rac1的水平密切相关，被认为是活性的rac1。突触支架蛋白突触后密度(PSD)-95在AD时特异性降低，且PSD-95的含量与rac1的水平相关。此外，rac1和PSD-95的含量与tau的磷酸化程度呈负相关，tau的磷酸化程度对神经纤维缠结的形成至关重要。这些结果提示，EICD介导的RAC信号通路的减弱参与了AD的突触发病机制。
Loss of synapses is associated with cognitive impairment in Alzheimer's disease (AD). However, the molecular mechanism underlying this synaptic impairment is not well understood. EphA4 is a substrate of γ‐secretase, and the γ‐secretase‐cleaved EphA4 intracellular domain (EICD) is known to enhance the formation of dendritic spines via activation of the Rac signaling pathway. Here, we show that the amount of Rac1 is significantly reduced, and correlated with the level of EICD in the frontal lobes of AD patients. Biochemical analyses revealed that the amount of membrane‐associated EICD was decreased and strongly correlated with the level of membrane‐associated Rac1, which is considered to be active Rac1. The synaptic scaffolding protein, postsynaptic density (PSD)‐95, was specifically decreased in AD, and the amount of PSD‐95 correlated with the level of Rac1. Moreover, the amounts of Rac1 and PSD‐95 were negatively correlated with the extent of tau phosphorylation, which is crucial for neurofibrillary tangle formation. These results suggest that attenuation of the EICD‐mediated Rac signaling pathway is involved in the synaptic pathogenesis of AD.