GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions

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.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0295-z) contains supplementary material, which is available to authorized users.

RETRACTED: Sanhua Decoction, a Classic Herbal Prescription, Exerts Neuroprotection Through Regulating Phosphorylated Tau Level and Promoting Adult Endogenous Neurogenesis After Cerebral Ischemia/Reperfusion Injury

“…Tau is a microtubule-associated protein, which contributes to microtubule aggregation and stability, the development of nerve cells, and the transport of axons (Ebneth et al, 1998;Biernat and Mandelkow, 1999). Abnormal hyperphosphorylation of tau protein has been reported after cerebral ischemia/reperfusion, resulting in microtubule depolymerization and ultimately neuron apoptosis (Ali and Kim, 2015;Zhu et al, 2018). Studies have revealed that tau-deficient mice are protected from neurological deficits and have less infarct volume following experimental ischemic stroke (Bi et al, 2017).…”

Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy

“…In fact, C57BL/6 mice fed HFD (for 16-20 weeks), in which obesity is present, were shown to present retinal ganglion cell (RGC) dysfunction (measured by the response of the retina to patterned light stimuli-PERG). However, HFD (42%-45% kcal from fat) for 24 weeks failed to induce the increased retinal vascular permeability, one of the main features of early stages of DR, which only occurs after 48 weeks of HFD feeding [59,60] (Table 2), suggesting that in a diabetes model induced by HFD feeding, the electrophysiological abnormalities of RGCs precede the development of visible retinal microvascular damage. Consistently, in another study, the same mouse strain (C57BL/6J) fed HFD (59.5% kcal from fat) for 1 month developed mildly compromised retinal light responses, with decreased oscillatory potential (OP) and delayed OP implicit times), even before systemic hyperglycemia was installed, suggesting that neural retina dysfunction may precede systemic hyperglycemia.…”

Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

“…A recent study shows that a significant decrease in β-catenin protein levels is inversely associated with increased activation of GSK3β in the prefrontal cortical lobe structures of human AD brains [113], further strengthening the notion that GSK3β activity is associated with Wnt/β-catenin signaling in AD brain. Notably, GSK3β is a key kinase for tau phosphorylation, and overactivation of GSK3β is intimately linked to tau hyperphosphorylation, Aβ deposition, plaque-associated microglial-mediated inflammatory responses and memory impairment [111, 112, 114].…”