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GSK3?-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 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 GSK3? 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 GSK3? 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 GSK3?-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.

SUBMITTER: Zhu H

PROVIDER: S-EPMC6251088 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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

Zhu Huazhang H Zhang Weizhen W Zhao Yingying Y Shu Xingsheng X Wang Wencong W Wang Dandan D Yang Yangfan Y He Zhijun Z Wang Xiaomei X Ying Ying Y

Molecular neurodegeneration 20181122 1

<h4>Background</h4>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 disease ...[more]

PMID: 30466464

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Project description:Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2-25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3-25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3-25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

Project description:Diabetic retinopathy (DR) has been considered a microvascular disease, but it has become evident that neurodegeneration also plays a key role in this complex pathology. Indeed, this complexity is reflected in its progression which occurs at different rates in different type 2 diabetic (T2D) individuals. Based on this concept, our group has identified three DR progression phenotypes that might reflect the interindividual differences: phenotype A, characterized by low microaneurysm turnover (MAT <6), phenotype B, low MAT (<6) and increased central retinal thickness (CRT); and phenotype C, with high MAT (≥6). In this study, we evaluated the progression of DR neurodegeneration, considering ganglion cell+inner plexiform layers (GCL+IPL) thinning, in 170 T2D individuals followed for a period of 5 years, to explore associations with disease progression or risk phenotypes. Ophthalmological examinations were performed at baseline, first 6 months, and annually. GCL+IPL average thickness was evaluated by optical coherence tomography (OCT). Microaneurysm turnover (MAT) was evaluated using the RetMarkerDR. ETDRS level and severity progression were assessed in seven-field color fundus photography. In the overall population there was a significant loss in GCL+IPL (-0.147 μm/year), independently of glycated hemoglobin, age, sex, and duration of diabetes. Interestingly, this progressive thinning in GCL + IPL reached higher values in phenotypes B and C (-0.249 and -0.238 μm/year, respectively), whereas phenotype A remained relatively stable. The presence of neurodegeneration in all phenotypes suggests that it is the retinal vascular response to the early neurodegenerative changes that determines the course of the retinopathy in each individual. Therefore, classification of different DR phenotypes appears to offer relevant clarification of DR disease progression and an opportunity for improved management of each T2D individual with DR, thus playing a valuable role for the implementation of personalized medicine in DR.

Project description:Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics.

Dataset Information

GSK3?-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions.

Publications

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

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