DISC1 inhibits GSK3β activity to prevent tau hyperphosphorylation under diabetic encephalopathy.

Abstract

Diabetic encephalopathy (DE) is a common complication of type 2 diabetes (T2D), especially in those patients with long T2D history. Persistent high glucose (HG) stimulation leads to neuron damage and manifests like Alzheimer's disease's pathological features such as neurofilament tangle. However, the precise mechanism of high-glucose-induced tau hyperphosphorylation is not fully revealed. We here gave evidence that Disrupted in schizophrenia 1 protein (DISC1) could interact with glycogen synthase kinase 3β (GSK3β) and inhibit its activity to prevent tau hyperphosphorylation. By using DB/DB mice as animal model and HG-treated N2a cell as cell model, we found that DISC1 was downregulated both in vivo and in vitro, complicated with Tau hyperphosphorylation and GSK3β activation. Further, we identified DISC1 interacted with GSK3β by its 198th-237th amino acid residues. Overexpression of full length DISC1 but not mutated DISC1 lacking this domain could prevent HG induced tau hyperphosphorylation. Taken together, our work revealed DISC1 could be an important negative modulators of tau phosphorylation, and suggested that preservation of DISC1 could prevent HG induced neuron damage.