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

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.

Automated summary

RhoGDI alpha interacts with Tau in Alzheimer's disease and vascular dementia, affecting Tau phosphorylation and apoptosis. Overexpression of RhoGDI alpha can inhibit the generation of NFTs and delay the progress of these two types of dementia.