Dataset Information

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

ABSTRACT: The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer's disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expressing hTau. Our results revealed that hTau is particularly abundant in the inner nuclear layer (INL) cells of the retina. By electroretinogram (ERG) recording, light-induced retinal cell activation was not altered in hTau compared with mTKO littermates. Surprisingly, the ERG response mediated by cone photoreceptor stimulation was even stronger in hTau than in mTKO retinae. Immunofluorescent analysis of retinal sections allowed us to observe thicker inner retina in hTau than in mTKO eyes. By Western Blotting (WB), the upregulation of mTOR that was found in hTau mice may underlie retinal structure and function increases. Taken together, our results not only indicate that hTau expression is not toxic for retinal cells but they also suggest that it may play a positive role in visual physiology. The use of hTau may be envisaged to improve visual recovery in ocular diseases affecting the retinal function such as glaucoma or diabetic retinopathy.

SUBMITTER: Rodriguez L

PROVIDER: S-EPMC6117378 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

Rodriguez Léa L Mdzomba Julius Baya JB Joly Sandrine S Boudreau-Laprise Mélissa M Planel Emmanuel E Pernet Vincent V

Frontiers in molecular neuroscience 20180824

The implication of the microtubule-associated protein (MAP) Tau in the ocular manifestations of Alzheimer's disease (AD) is elusive due to the lack of relevant animal model. However, signs of AD have been reported in the brain of transgenic mice expressing human Tau (hTau). To assess whether hTau is sufficient to induce AD pathogenesis in the retina as well, in the present study, we compared the retinal structure and function of KO mice deprived of Tau (mTKO) with those of transgenic mice expres ...[more]

PMID: 30197586

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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: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.

Dataset Information

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

Publications

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons.

Similar Datasets

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