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Apolipoprotein E-Containing Lipoproteins and LRP1 Protect From NMDA-Induced Excitotoxicity Associated With Reducing α2-Macroglobulin in Müller Glia

PURPOSE: Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to det...

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Detalles Bibliográficos
Autores principales: Hayashi, Hideki, Mori, Misuzu, Harashima, Mina, Hashizume, Tatsuya, Furiya, Miho, Mukaigaito, Chihaya, Takemura, Emi, Yamada, Mariko, Mise, Kanako, Yuan, Bo, Takagi, Norio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556555/
https://www.ncbi.nlm.nih.gov/pubmed/34698771
http://dx.doi.org/10.1167/iovs.62.13.23
Descripción
Sumario:PURPOSE: Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to determine whether E-LPs protect RGCs from N-methyl- [Formula: see text]-aspartate (NMDA)-induced excitotoxicity, and to investigate the details of an indirect neuroprotective mechanism of E-LPs by reducing α2-macroglobulin, which interferes with the neuroprotective effect of E-LPs, in Müller glia. METHODS: Excitotoxicity was caused by intravitreal injection of NMDA, and then retinae were subjected to immunoblotting or quantitative reverse transcription-PCR. Primary cultures of mouse mixed retinal cells and mouse Müller glia were used for evaluating the effects of E-LPs on the expression of α2-macroglobulin. RESULTS: Intravitreal injection of E-LPs protected the optic nerve from degeneration and attenuated the increase in α2-macroglobulin in aqueous humor and retina of rats. E-LPs directly decreased the expression and secretion of α2-macroglobulin in primary cultures of Müller glia; this decrease in production of α2-macroglobulin was blocked by knockdown of the low-density lipoprotein receptor-related protein 1 (LRP1) with small interfering RNA. E-LPs promoted the phosphorylation of STAT3, whereas Stattic, an inhibitor of STAT3, restored the expression of α2-macroglobulin decreased by E-LPs. CONCLUSIONS: In addition to our previous findings of the protection of RGCs by E-LPs, the new observations in Müller glia indicate that a reduction of the intraocular α2-macroglobulin, regulated by the E-LP-LRP1-STAT3 pathway, might be an additional protective mechanism against excitotoxicity in the retina.