An ocular glymphatic clearance system removes β-amyloid from the rodent eye

Abstract

Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified an ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve in rodents. β-amyloid (Aβ) was cleared from the retina and vitreous via a pathway dependent on glial water channel aquaporin-4 (AQP4) and 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 efflux, whereas 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 results suggest that, in rodents, the removal of fluid and metabolites from the intraocular space occurs through a glymphatic pathway that might be impaired in glaucoma.

In Vivo Evidence for Impaired Glymphatic Function in the Visual Pathway of Patients With Normal Pressure Hydrocephalus

“…Stud-ies of a glymphatic system in the optic nerve of rodents and humans have shown that tracers injected into the CSF enter the optic nerve via paravascular spaces. 6,7,10 We suggest that the main path from the CSF compartment into the visual pathway for gadobutrol is via paravascular routes, which is a prerequisite for a visual glymphatic system. 1 Furthermore, the tracer serves as a model for organic molecules with similar properties, and our findings can thus indicate impaired extravascular transport of other substances (e.g., amyloid-β).…”

“…4,5 Several studies have since supported this hypothesis. [6][7][8][9][10] In 2019, we published novel in vivo findings indicating the existence of a glymphatic system in the human visual pathway. 11 Using a magnetic resonance imaging (MRI) contrast agent (gadobutrol) as a tracer molecule, we demonstrated enrichment within the visual pathway.…”

“…Indeed, impairment of the glymphatic system in the retina and optic nerve of rodents has been demonstrated in glaucoma. 7,8 An increased prevalence of glaucoma has been found in idiopathic normal pressure hydrocephalus (iNPH), a form of neurodegenerative disease and dementia subtype 14,[16][17][18][19] histologically overlapping with Alzheimer's disease. 20 Moreover, contrast-enhanced MRI of iNPH has indicated impaired glymphatic function in the brain.…”

Realistic boundary conditions for perivascular pumping in the mouse brain reconcile theory, simulation, and experiment

“…(38) measured a resistance of 5.149±1.103 mmHg/(µL/min) 241 in CD-1 wild-type mice using a similar constant-rate infusion 242 method. This higher resistance also explains their elevated 243 resting ICP (6.988±1.030 mmHg) as compared to other studies 244 with lower ICP levels (≈ 4 mmHg) (39)(40)(41). This overesti-245 mation of the resistance and resting ICP may be due to the 246 high pressure gradient established by the authors while the 247 pipette was in the brain parenchyma to assess ventricle punc-248 ture (≈ 29 mmHg).…”

Fluid transport from the dental pulp revisited

“…In the brain, another organ in the body lacking lymphatic vessels, interstitial fluid moves through the parenchyma via paravenous drainage pathways to the central nerve system (16) named the glymphatic system. A similar system has recently been described in the eye, which also lacks lymphatic vessels in the retina and optic nerve head (17). In the brain, cerebrospinal fluid is driven by arterial pulsations in the parenchyma (18).…”