A Murine Model of Alzheimer’s Disease Shows Gender-Specific Ocular Surface Findings

Abstract

Purpose : The aim of this study is to evaluate ocular surface features in a mouse model of familial Alzheimer’s disease (FAD).

Methods : Corneal surface epithelium of 9-month-old female and male 5XFAD (FAD mouse model; mixed background) and wild-type (WT) littermates were evaluated clinically by fluorescein corneal staining (0-4 scores). Tear production was measured using phenol red thread and central corneal sensation was assessed using Cochet-Bonnet esthesiometer. Tear levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-17A were measured using Bioplex multiplex bead assay. Corneal nerve density was measured on confocal micrographs of whole-mounted corneas stained with βIII-tubulin, using NeuronJ plugin for ImageJ. T-test was used to assess statistical significance. P<0.05 was considered significant.

Results : While female 5XFAD mice demonstrated significantly higher corneal fluorescein staining score (3.0±0.8) compared to female controls (0.5±0.6; p=0.002), no significant difference was observed between male 5XFAD (1.0±0.8) and male control mice (0.2+0.5; p=0.16). Similarly, although we observed significantly lower tear production in female 5XFAD mice (1.5±0.7 mm) vs. controls (6.6±1.1 mm; p=0.004), we did not observe significant difference in males (4.5±0.7 vs. 4.3±1.4 mm; p=0.18). In addition, we observed significantly reduced corneal sensation in female 5XFAD mice (3.2±0.3 cm) compared with controls (5.7±0.5 cm; p=0.003) mice, as well as in male 5XFAD mice (4.7±0.3 cm) compared with male controls (5.6±0.4 cm; p=0.03), although the decrease in male mice was not as pronounced. Similarly, we observed decreased corneal nerve density in both female and male 5XFAD mice in the corneal periphery compared with controls (104.6±14.0 vs. 130.5± 8.1 mm/mm²; p=0.03 and 102.8 ±5.7 vs. 127.7±7.4 mm/mm²; p=0.002). Female 5XFAD mice showed higher levels of TNF-α (125.7±26.8 pg/mL), IFN-γ (5.5±1.0 pg/mL), and IL-17A (14.6±2.1 pg/mL) in their tears compared to controls (55.1±3.5 pg/mL; p=0.01, 3.8±0.6 pg/mL; p=0.02, and 4.5±5.1 pg/mL; p=0.01, respectively). However, we did not detect significant differences in the tear levels of TNF-α, IFN-γ, and IL-17A between 5XFAD male mice and controls (p>0.05).

Conclusions : FAD is associated with ocular surface disease including reduced nerve density and enhanced tear inflammatory cytokine levels that is more prominent in females.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.