Tauopathy induces degeneration and impairs regeneration of sensory nerves in the cornea

Abstract

Purpose : The cornea is transparent and innervated by a dense collection of sensory nerves originating from the ocular branch of the trigeminal nerve. This study was designed to comprehensively analyze alterations of corneal sub-basal nerve plexus in a mouse model of tauopathy (P301L transgenic mice) to test the possibility of using corneal nerves as a biomarker for tauopathy and to investigate its potential underlying mechanisms.

Methods : Corneal sensitivity, thickness and epithelial wound healing were measured non-invasively by aeshesiometer, optical coherence tomography and fluorescein staining, respectively. Tau, corneal nerves and immune cells were examined by immunohistochemistry or Western blot. Transcriptome changes in the trigeminal ganglion (TG) were determined by RNAseq.

Results : At the early stage of tauopathy, although corneal sensitivity, thickness and nerve fiber density were not greatly altered, corneal nerve abnormalities were observed in the peripheral region of young P301L mice. With aging, the density of abnormal nerves increased, while corneal sensitivity, epithelial thickness, nerve fiber density and length decreased in middle-aged P301L mice compared with WT mice. After corneal epithelial injury in young mice, no difference in reepithelialization was observed between two groups of mice, however, the regeneration of corneal nerves in P301L mice lagged behind WT mice, which was reflected by delayed recovery of corneal sensitivity, decreased corneal nerve density and length and density of CD45⁺ dendriform cells in P301L mice. RNAseq analysis revealed that gene sets related with ribosome, proteasome and protein export were significantly downregulated in TGs from 3-month old P301L mice compared with those from age-matched WT mice.

Conclusions : Our data provide compelling evidence that corneal nerves were changed in a mouse model of tauopathy in an age-dependent manner. Moreover, tau overexpression impairs corneal nerve regeneration, which may involve tauopathy-induced decreases in de novo protein synthesis and transportation. These results suggest that cornea may serve as a promising ocular site for the early diagnosis of tauopathy.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.