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Tasneem Khatib, Andrew Osborne, Peter S Widdowson, Keith R Martin; Tau dysfunction in glaucoma: modulation of optic nerve axonal transport via gene therapy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3716.
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© ARVO (1962-2015); The Authors (2016-present)
Disruption of axonal transport (AT) in retinal ganglion cells (RGCs) is a hallmark of glaucomatous optic neuropathy. Tau hyperphosphorylation (TauH), with subsequent loss of microtubule stability and formation of neurotoxic aggregates may contribute to this AT impairment. We assessed pathological TauH in experimental glaucoma and whether optic nerve AT (ONAT) can be modulated in a mouse model of tauopathy by overexpressing mature BDNF (mBDNF) and its receptor TrkB through an AAV2 viral vector (TrkB-2A-mBDNF; QTA020V).
Sprague Dawley rats underwent laser induced intraocular pressure (IOP) elevation. IOP and the RGC-specific positive scotopic threshold response (pSTR) were assessed at multiple timepoints and tissue processed for TauH quantification. To assess modulation of optic nerve AT in a mouse model of tauopathy, 4-month old mice homozygous for human mutant P301S tau were injected intravitreally with AAV2 TrkB mBDNF. Cholera toxin B (CTB) was administered 1 month later with tissue collection 24 hours post CTB injection. ONAT was quantified by measuring CTB intensity at 100 µm intervals.
Pathological TauH at the AT8 epitope was elevated by 4.5-fold at 2 days (p=0.007) and 2-fold at 1 month (p=0.07) in our experimental glaucoma model, and elevated 2.5-fold at 1 month at the PHF-1 epitope (p=0.01). Early post-injury, there was a 3-fold increase in the inactive form of tau protein kinase GSK3B (p=0.025) but this did not persist. There were no changes in the pSTR response. Injection of AAV2-GFP itself did not affect retinal TauH relative to PBS or naïve controls. Administration of AAV2 TrkB mBDNF resulted in a 2.6-fold increase in proximal optic nerve AT (p<0.0001). This correlated with a reduction in both the AT8 and PHF-1 immunoreactivity in the optic nerve, while total tau remained unchanged.
Pathological TauH occurs following IOP elevation, the strongest risk factor for glaucoma progression. Regulation of phosphorylation via increased inactivation of the tau protein kinase GSK3B appears in the early response to injury but this negative regulation is subsequently lost. These changes may contribute to disruption of AT in glaucoma. Administration of BDNF and TrkB via an RGC-specific viral vector improves ONAT in a tauopathy model. Studies are ongoing to assess the efficacy of our construct on AT and TauH when administered in an experimental glaucoma model.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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