GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions
Abstract Background Although 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...
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doaj-aac18fd2322c401fa9ff04bd8b07ec7d2020-11-25T02:22:13ZengBMCMolecular Neurodegeneration1750-13262018-11-0113111710.1186/s13024-018-0295-zGSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functionsHuazhang Zhu0Weizhen Zhang1Yingying Zhao2Xingsheng Shu3Wencong Wang4Dandan Wang5Yangfan Yang6Zhijun He7Xiaomei Wang8Ying Ying9Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen UniversityDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen UniversityDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterDepartment of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences CenterAbstract Background Although 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. Methods To 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. Results We 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. Conclusions Our 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.http://link.springer.com/article/10.1186/s13024-018-0295-zDiabetic retinopathyRetinal neurodegenerationRetinal ganglion cellsHyperphosphorylated tauGSK3βSynaptic and mitochondrial dysfunction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Huazhang Zhu Weizhen Zhang Yingying Zhao Xingsheng Shu Wencong Wang Dandan Wang Yangfan Yang Zhijun He Xiaomei Wang Ying Ying |
spellingShingle |
Huazhang Zhu Weizhen Zhang Yingying Zhao Xingsheng Shu Wencong Wang Dandan Wang Yangfan Yang Zhijun He Xiaomei Wang Ying Ying GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions Molecular Neurodegeneration Diabetic retinopathy Retinal neurodegeneration Retinal ganglion cells Hyperphosphorylated tau GSK3β Synaptic and mitochondrial dysfunction |
author_facet |
Huazhang Zhu Weizhen Zhang Yingying Zhao Xingsheng Shu Wencong Wang Dandan Wang Yangfan Yang Zhijun He Xiaomei Wang Ying Ying |
author_sort |
Huazhang Zhu |
title |
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
title_short |
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
title_full |
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
title_fullStr |
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
title_full_unstemmed |
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
title_sort |
gsk3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2018-11-01 |
description |
Abstract Background Although 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. Methods To 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. Results We 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. Conclusions Our 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. |
topic |
Diabetic retinopathy Retinal neurodegeneration Retinal ganglion cells Hyperphosphorylated tau GSK3β Synaptic and mitochondrial dysfunction |
url |
http://link.springer.com/article/10.1186/s13024-018-0295-z |
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