アポE含有リポタンパク質によるLRP1を介した網膜グリア細胞のα２-マクログロブリン発現抑制とNMDA誘発興奮毒性に対する網膜神経節細胞保護効果

• Published in: 日本薬理学会年会要旨集 p. 3-B-P-180
• Main Authors: 林, 秀樹, 南, 厚徳, 森, みすず, 高木, 教夫, 見世, 加南子
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: lipoprotein; neurodegeneration; protection; retina
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.96.0_3-B-P-180

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that is abundantly expressed in the central nervous system. In our previous study, glia-derived apolipoprotein E-containing lipoproteins (ELPs) protected retinal ganglion cells (RGCs) from glutamate-induced excitotoxicity via an LRP1 in vitro. We have also shown that α2-macroglobulin (a2M) interferes with the protective effect of ELPs. It is reported that a2M is increased in vitreous humor of glaucoma patients. However, the details of its function are unknown. Here we observed that N-methyl-D-aspartate (NMDA)-induced excitotoxicity in retinae of rats showed RGC degeneration and increased amount of a2M in vitreous humor three days after NMDA injection into vitreous humor. Then, intravitreal injection of ELPs suppressed RGC degeneration and the increased amount of a2M. In addition, ELPs decreased a2M mRNA and protein levels in primary cultured retinal glia. LRP1 siRNA blocked the inhibitory effect of ELPs on a2M expression, and the addition of ELPs enhanced the phosphorylation of STAT3 in retinal glia. Thus, ELPs demonstrate optic nerve protection from excitotoxicity and also reveal an indirect protective effect by suppressing the a2M expression, which is a neuroprotective disturbing factor. We hope that a reduction of a2M mediated by the ELP-LRP1-STAT3 pathway might be an additional protective mechanism against excitotoxicity in the retina.