A direct interaction between RhoGDIα/Tau alleviates hyperphosphorylation of Tau in Alzheimer's disease and vascular dementia

被引:6
作者
Zhang, Heping [1 ]
Lu, Fan [2 ]
Liu, Panhong [1 ,3 ]
Qiu, Zhaohui [1 ,4 ]
Li, Jianling [1 ,5 ]
Wang, Xiaotong [1 ]
Xu, Hui [1 ]
Zhao, Yandong [1 ,6 ]
Li, Xuemin [1 ,7 ]
Wang, Huadong [1 ]
Lu, Daxiang [1 ]
Qi, Renbin [1 ]
机构
[1] Jinan Univ, Sch Med, Dept Pathophysiol, Key Lab State Adm Tradit Chinese Med, Guangzhou 510632, Guangdong, Peoples R China
[2] Jinan Univ, Affiliated Hosp 1, Dept Emergency, Guangzhou 510630, Guangdong, Peoples R China
[3] Chongqing Med Univ, Affiliated Hosp 2, Dept Pathol, Chongqing 400010, Peoples R China
[4] Sun Yat Sen Univ, Affiliated Hosp 8, Dept Pathol, Shenzhen 518033, Peoples R China
[5] Jinan Univ, Affiliated Hosp 1, Dept Anesthesiol, Guangzhou 510630, Peoples R China
[6] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Pathol, Guangzhou 510655, Peoples R China
[7] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
关键词
RhoGDI alpha; Tau; A beta(25-35); Hypoxia/reoxygenation; Alzheimer's disease; Vascular dementia; Apoptosis; DISSOCIATION-INHIBITOR-ALPHA; PROTEIN-PROTEIN INTERACTION; RESONANCE ENERGY-TRANSFER; AMYLOID-BETA; KINASE; DRUG; OVEREXPRESSION; APOPTOSIS; MIGRATION; SENEGENIN;
D O I
10.1007/s11481-021-10049-w
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
RhoGDI alpha is an inhibitor of RhoGDP dissociation that involves in A beta metabolism and NFTs production in Alzheimer's disease (AD) by regulating of RhoGTP enzyme activity. Our previous research revealed that RhoGDI alpha, as the target of Polygala saponin (Sen), might alleviate apoptosis of the nerve cells caused by hypoxia/reoxygenation (H/R). To further clarify the role of RhoGDI alpha in the generation of NFTs, we explored the relationship between RhoGDI alpha and Tau. We found out that RhoGDI alpha and Tau can bind with each other and interact by using coimmunoprecipitation (Co-IP) and GST pulldown methods in vitro. This RhoGDI alpha-Tau partnership was further verified by using immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) approaches in PC12 cells. Using the RNA interference (RNAi) technique, we found that the RhoGDI alpha may be involved in an upstream signaling pathway for Tau. Subsequently, in A beta(25-35)- and H/R-induced PC12 cells, forced expression of RhoGDI alpha via cDNA plasmid transfection was found to reduce the hyperphosphorylation of Tau, augment the expression of bcl-2 protein, and inhibit the expression of Bax protein (reducing the Bax/bcl-2 ratio) and the activity of caspase-3. In mouse AD and VaD models, forced expression of RhoGDI alpha via injection of a viral vector (pAAV-EGFP-RhoGDI alpha) into the lateral ventricle of the brain alleviated the pathological symptoms of AD and VaD. Finally, GST pulldown confirmed that the binding sites on RhoGDI alpha for Tau were located in the range of the Delta C33 fragment (aa 1-33). These results indicate that RhoGDI alpha is involved in the phosphorylation of Tau and apoptosis in AD and VaD. Overexpression of RhoGDI alpha can inhibit the generation of NFTs and delay the progress of these two types of dementia.
引用
收藏
页码:58 / 71
页数:14
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