Corneal Immune Cell Alterations and Tau Pathology in a Mouse Model of Alzheimer’s Disease

Purpose: Early diagnosis of Alzheimer's disease (AD) remains a formidable challenge. Although retinal markers are extensively studied, the cornea-the eye's primary transparent window-presents a potential but poorly understood platform for biomarker discovery. This study systematically characterized AD-associated corneal pathological evolution using the 5 × FAD mouse model. Methods: Corneas from wild-type (WT) and 5 × FAD mice (ages 3, 5, 7, and 10 months; both sexes included) were analyzed using multimodal approaches: whole-mount immunostaining with 3D reconstruction, immunoblotting, RNA sequencing, and mass spectrometry proteomics. Results: Although local human APP production was absent, a defined temporal cascade emerged selectively in the peripheral cornea. Dendritic cell (DC) morphological simplification (reduced perimeter and branching) occurred as early as 3 months, preceding significant DC expansion at 5 months and CD3⁺ T cell infiltration at 7 months. Tau hyperphosphorylation (Thr181) surfaced at 7 months, coinciding with heightened GSK3β activity (reduced pGSK3β Ser9). By 10 months, significant peripheral subbasal nerve plexus and superficial nerve terminals loss were observed, with residual fibers exhibiting markedly elevated phosphorylated tau burden. Multi-omics at 7 months validated this pro-inflammatory state, identifying upregulated adhesion molecules (ICAM1 and ITGB2) and the T cell chemoattractant IL-16. Conclusions: Corneal neuro-immune remodeling-manifesting as early DC dysfunction followed by T cell recruitment and tau pathology-precedes overt nerve degeneration. These findings suggest the cornea as a potential, noninvasively accessible site for monitoring AD progression.