Article: article from journal or magazin.
Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta-induced retinal degeneration.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
In normal retinas, amyloid-β (Aβ) accumulates in the subretinal space, at the interface of the retinal pigment epithelium, and the photoreceptor outer segments. However, the molecular and cellular effects of subretinal Aβ remain inadequately elucidated. We previously showed that subretinal injection of Aβ(1-42) induces retinal inflammation, followed by photoreceptor cell death. The retinal Müller glial (RMG) cells, which are the principal retinal glial cells, are metabolically coupled to photoreceptors. Their role in the maintenance of retinal water/potassium and glutamate homeostasis makes them important players in photoreceptor survival. This study investigated the effects of subretinal Aβ(1-42) on RMG cells and of Aβ(1-42)-induced inflammation on retinal homeostasis. RMG cell gliosis (upregulation of GFAP, vimentin, and nestin) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Aβ(1-42). On day 3, we detected modifications in the protein expression patterns of cyclooxygenase 2 (COX-2), glutamine synthetase (GS), Kir4.1 [the inwardly rectifying potassium (Kir) channel], and aquaporin (AQP)-4 water channels in RMG cells and of the photoreceptor-associated AQP-1. The integrity of the blood-retina barrier was compromised and retinal edema developed. Aβ(1-42) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis. Indomethacin treatment decreased inflammation and reversed the Aβ(1-42)-induced gliosis and modifications in the expression patterns of COX-2, Kir4.1, and AQP-1, but not of AQP-4 or GS. Nor did it improve edema. Our study pinpoints the adaptive response to Aβ of specific RMG cell functions.
Amyloid beta-Peptides/administration & dosage, Amyloid beta-Peptides/toxicity, Animals, Apoptosis/drug effects, Blood-Retinal Barrier/drug effects, Blood-Retinal Barrier/pathology, Endoplasmic Reticulum Stress/drug effects, Gene Expression/drug effects, Gliosis/pathology, Homeostasis/drug effects, Inflammation/pathology, Mice, Mice, Inbred C57BL, Peptide Fragments/administration & dosage, Peptide Fragments/toxicity, Photoreceptor Cells, Vertebrate/drug effects, Photoreceptor Cells, Vertebrate/pathology, Retina/drug effects, Retina/pathology, Retinal Degeneration/genetics, Retinal Degeneration/pathology
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