GSK3\u03b2-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions

Huazhang Zhu,Ying Ying,Yingying Zhao,Dandan Wang,Zhijun He,Xiaomei Wang,Yangfan Yang,Xingsheng Shu,Wencong Wang,Weizhen Zhang

doi:10.1186/s13024-018-0295-z

Abstract

BackgroundAlthough diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration.MethodsTo this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro.ResultsWe demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner.ConclusionsOur study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities.

Highlights

Diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes
The resulting loss of IRS-1 and Akt activity by high-fat diet (HFD) intake is predicted to activate glycogen synthase kinase 3β (GSK3β), a major tau kinase, leading to increased tau phosphorylation. This process may further dysregulate insulin signaling since GSK3β per se directly phosphorylates IRS-1 at Ser 322 to facilitate IRS-1 inactivation [46], aggravating tau pathology. In support of this hypothesis, we found that GSK3β inactivation by intraocular injection of its inhibitor TWS119 resulted in the rescue of mitochondrial dysfunction (Additional file 1: Fig. S10c), synapse loss and visual impairment in HFD-induced diabetes mouse models, in association with reduced tau phosphorylation in the retina
We develop a new therapeutic strategy in which intravitreal injection of a short interfering RNA (siRNA) specific for tau or an inhibitor of GSK3β reverses synapse loss and visual dysfunction of RGCs by attenuating tau hyperphosphorylation at the onset of diabetic retinopathy (DR)

Summary

Introduction

Diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Diabetic retinopathy (DR) has long been regarded as a microvascular disorder, it has become evident that inner retinal neurodegeneration, including electroretinogram (ERG) abnormalities, ganglion cells loss, reactive gliosis, and inner retinal thinning [1] occurs in people with DR. Mounting evidence shows that neuroretinal alterations are present even in the absence of any visible microvascular signs of DR [2, 3] These observations support the concept that DR may be a neurodegenerative eye disease occurring in the early phase of DR [4]. Key molecules involved in synapse degeneration in DR are still poorly defined

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