Abstract
The effects of tau hyperphosphorylation and aggregation on axonal transport were investigated in the optic nerve of mice transgenic for human mutant P301S tau. Transport was examined using cholera toxin B tracing. Retrograde transport was reduced in transgenic mice at 3 and 5 months of age, when compared to C57/Bl6 control mice. Anterograde axonal transport was also reduced in 3-month-old transgenic mice. Mild excitotoxic injury of retinal ganglion cells resulted in greater nerve cell loss in retinas from 3- and 5-month old P301S transgenic mice, when compared to controls. In conjunction with the detection of abnormal tau in the optic nerve in human and experimental glaucoma, the present findings suggest that tau hyperphosphorylation and aggregation may constitute targets for neuroprotective therapies in glaucoma as well as tauopathies.
Highlights
Microtubule-associated protein tau is believed to play a role in the assembly and stabilisation of microtubules [1]
Disruption of brainderived neurotrophic factor (BDNF) transport contributes to retinal ganglion cell death in glaucoma [13,14] where, in an experimental model, we have previously described an altered distribution of dynein [15]
We show that aggregation of human mutant P301S tau in retinal ganglion cells (RGCs) is associated with a reduction of both anterograde and retrograde axonal transport in vivo, and with a markedly increased effect of mild excitotoxic injury
Summary
Microtubule-associated protein tau is believed to play a role in the assembly and stabilisation of microtubules [1]. We previously showed that in retinal ganglion cells from a mouse line transgenic for human mutant P301S tau, dynactin, which is required for the binding of cargo to dynein motor proteins, is abnormally distributed [11]. We show that aggregation of human mutant P301S tau in RGCs is associated with a reduction of both anterograde and retrograde axonal transport in vivo, and with a markedly increased effect of mild excitotoxic injury.
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