Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2

The microtubule tau is implicated in multiple degenerative diseases such as glaucoma, although how tau instigates retinopathy is ambivalent. Previous retinal assessment of mouse models of tauopathy indicate that mutations on four-repeat (4R) tau associated with disease induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how altering tau isoform expression impacts the retina, we utilized transgenic mice overexpressing mutant 3R tau (m3R tau-Tg) known to exhibit neurodegeneration in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy uniquely altered in m3R tau-Tg retina. In adult 3Rtau-Tg retinas, upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. Coincidently, decreased cell density in the ganglion cell layer (GCL) and thickness of the inner plexiform layer (IPL) were observed in adult m3R tau-Tg dorsal peripheral retinas. Together, these data indicate that mutant 3R tau may mediate toxicity in RGCs through promoting caspase-2 expression that results in retinal ganglion cell degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test potential therapeutics for glaucoma.