Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified a novel ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve. Amyloid-β (Aβ) was cleared from the vitreous via a pathway driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal Aβ was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced, while atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, Aβ leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The discovery of a novel pathway for removal of fluid and metabolites from the intraocular space prompts a reevaluation of the core principles governing eye physiology and provides a framework for new therapeutic approaches to treat common eye diseases, including glaucoma.

One Sentence Summary Glymphatic pathway clears ocular amyloid-β via optic nerve and fails in glaucoma.