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Natalie D. Bull, Alessandra Guidi, Maria G. Spillantini, Keith R. Martin; Tau Hyperphosphorylation In Retinal Ganglion Cells Is Associated With Reduced Axonal Transport And Enhanced Sensitivity To Excitotoxic Injury. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2604.
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Tau proteins play a key role in the stabilization of microtubules essential for normal axonal transport. Binding of tau to microtubules is regulated by phosphorylation. Tau hyperphosphorylation is associated with neurodegeneration and has been detected in glaucomatous retinae. We investigated whether tau hyperphosphorylation affects axonal transport in RGCs, and whether this influences neuronal survival after retinal injury.
Mice transgenic for human P301S tau expressed under the Thy1 promotor control and age-matched wild-type C57 mice were used. Hyperphosphorylated tau has been detected in RGCs from 2 months of age in P301S mice, which experience CNS (but not retinal) neurodegeneration from about 3 months of age. Activity of retrograde and anterograde transport in the optic nerve was examined using cholera toxin B tracing. RGC survival was quantified after intravitreal injection of 2 nmol NMDA plus 5 nmol glycine.
Retrograde RGC transport was significantly depressed in P301S mice at both 3 months (p=0.01; P301S n=6; C57 n=6) and 5 months (p=0.007; P301S n=10; C57 n=4) of age, compared to controls. In all cases, transport was delayed but not completely blocked. Furthermore, anterograde RGC transport was also significantly reduced in 3-month old P301S mice (p=0.002; n=5), compared to controls (n=5), but not in either 1 month- or 5 month-old mice. In vivo exposure of RGCs to a mild excitotoxic insult resulted in greater neuronal death in P301S mice at both 3 months (p=0.039; P301S n=6; C57 n=4) and 5 months (p=0.007; P301S n=7; C57 n=6), compared to controls.
These results demonstrate that tau hyperphosphorylation is associated with a relative slowing of RGC axonal transport, particularly retrograde transport, which is sufficient to increase RGC sensitivity to injury-induced death. RGC tau hyperphosphorylation has been detected in human and experimental glaucoma, where it may contribute to impaired retrograde transport of neurotrophins and neurodegeneration. Pharmacological modulation of tau phosphorylation could therefore provide a future target for neuroprotective therapies in glaucoma.
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