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An ocular glymphatic clearance system removes ?-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. ?-amyloid (A?) 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 A? 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, A? 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC7356596 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Wang Xiaowei X Lou Nanhong N Eberhardt Allison A Yang Yujia Y Kusk Peter P Xu Qiwu Q Förstera Benjamin B Peng Sisi S Shi Meng M Ladrón-de-Guevara Antonio A Delle Christine C Sigurdsson Björn B Xavier Anna L R ALR Ertürk Ali A Libby Richard T RT Chen Lu L Thrane Alexander S AS Nedergaard Maiken M

Science translational medicine 20200301 536

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 subsequent ...[more]

PMID: 32213628

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Project description:Background and purposeThere is growing evidence of leakage of gadolinium in an impaired blood-retina barrier. We investigated gadolinium enhancement in different eye compartments and correlated the enhancement with specific ophthalmologic diseases.Materials and methodsIn a prospective clinical study (ClinicalTrials.gov Identifier: NCT05035251), 95 patients (63 with and 32 without ophthalmologic disease) were examined before and after gadolinium administration (20 and 120 minutes) with heavily T2-weighted FLAIR. The cohort was divided according to the location of pathology into anterior and posterior eye compartment groups. Relative signal intensity increase in the anterior eye chamber, vitreous body with retina, optic nerve sheath, and the Meckel cave was analyzed and correlated with the final clinical diagnosis.ResultsIn patients with a disorder in the anterior eye compartment, significant signal intensity increases were found in the central anterior eye chamber (P 20 minutes = .000, P 120 minutes = .000), lateral anterior eye chamber (P 20 minutes = .001, P 120 minutes = .005), and vitreous body with retina (P 20 minutes = .02) compared with the control group. Patients with pathologies in the posterior eye compartment showed higher signal intensity levels in the central anterior eye compartment (P 20 minutes = .041) and vitreous body with retina (P 120 minutes = .006).ConclusionsIncreased gadolinium enhancement was found in the central and lateral anterior eye compartments and the vitreous body with retina in patients with anterior eye compartment disorders 20 and 120 minutes after contrast application, suggesting impairment of the blood-aqueous barrier. In patients with a disorder in the posterior eye compartment, pathologic enhancement indicated disruption of the blood-retinal barrier that allows gadolinium to diffuse into the vitreous body with retina from posterior to anterior, opposite to the known physiologic glymphatic pathway.

Project description:BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.ResultsWe show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.

Dataset Information

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

Publications

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

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