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Marius Chiasseu, Laurie Destroismaisons, Christine Vande Velde, Nicole Leclerc, Adriana Di Polo; Tau accumulation in the somato-dendritic compartment of retinal ganglion cells plays a critical role in glaucomatous neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1693.
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© ARVO (1962-2015); The Authors (2016-present)
Alzheimer’s disease and glaucoma share a number of neuropathological features including the loss of retinal ganglion cells (RGCs) and the presence of amyloid beta plaques and tau aggregates. Here, we asked whether there are changes in tau protein expression in the retina and optic nerve during ocular hypertension (OHT) and, if so, whether tau contributes to RGC neurodegeneration in experimental glaucoma.
OHT was induced in Brown Norway rats by injection of hypertonic saline solution into an episcleral vein (Morrison model). Tau protein phosphorylation was evaluated by western blot analysis using a panel of antibodies against total tau and phospho-specific tau epitopes. Tau gene expression was analyzed by quantitative real-time PCR. The cellular localization of tau was investigated by retinal and optic nerve immunohistochemistry using antibodies against tau and cell-specific markers. The functional role of tau in RGC death was investigated with short interference RNA (siRNA) to selectively knockdown tau expression and a control siRNA. RGC soma or axons were quantified by Brn3a immunostaining on flat-mounted retinas or toluidine blue-stained optic nerve cross sections, respectively.
Our results demonstrate that OHT leads to a rapid increase of tau protein in the retina. Both hyperphosphorylated and hypophosphorylated forms of tau were detected in glaucomatous retinas compared to intact controls (N=6-10/group). We show that soon after induction of OHT, tau accumulated primarily in RGC somata and dendrites, while tau in RGC axons within the optic nerve markedly decreased. Surprisingly, the level of tau mRNA in retinas subjected to OHT did not change with respect to intact controls (N=6/group), suggesting that the increase in retinal tau occurs from abnormal translocation from RGC axons rather than upregulation of tau gene expression. Importantly, tau knockdown using a targeted siRNA led to striking protection of RGC soma and axons from OHT-induced damage (1946±39 RGCs/mm2, mean soma ± S.E.M.) compared to retinas treated with control siRNA (1599±40 RGCs/mm2) (ANOVA, p<0.001, N=9/group).
Our data support the conclusion that ocular hypertension glaucoma displays cardinal features of a tauopathy including abnormal compartmental redistribution of tau, altered phosphorylation profile and neurotoxicity.
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