Protective effects of apolipoprotein E-containing lipoproteins against glaucomatous optic neuropathy

[Speaker] Hideki Hayashi:1
[Co-author] Mariko Yamada:1, Misuzu Mori:1, Mio Kobayashi:1, Hikaru Koide:1, Takuya Kojima:1, Chihaya Mukaigaito:1, Bo Yuan:1, Norio Takagi:1
1:Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, Japan

Lipoproteins secreted from glia have important roles of lipid metabolism and transport in the central nervous system. Apolipoprotein (apo) E is a major apo in the central nervous system. It has been reported that apo E-containing lipoproteins not only transport lipids from glia to neurons but also stimulate synaptogenesis in central nervous system neurons. We have also reported that glia-derived apo E-containing lipoproteins promote axon extension of retinal ganglion cells and protect them from neurodegeneration induced by trophic factor-withdrawal and glutamate excitotoxicity via low density lipoprotein receptor-related protein 1 (LRP1). It has been shown that alpha 2-macroglobulin (a2M), which acts as an LRP1 ligand, is elevated in aqueous humor of patients with glaucoma. Here, we showed that administration of apo E-containing lipoproteins attenuated retinal degeneration led by intravitreal injection of N-methyl-D-aspartate in rats, a model of glaucoma. The apo E-containing lipoproteins also decreased the elevated a2M level in aqueous humor of the glaucoma model. The neuroprotective effect of apo E-containing lipoproteins against excitotoxicity in primary cultured retinal ganglion cells was interfered by a2M, but an exogenous administration of the lipoproteins overcame the interference. Furthermore, addition of apo E-containing lipoproteins into the medium of primary cultured retinal glia decreased mRNA and protein levels of a2M in a receptor-mediated manner. These findings indicate a potential therapeutic approach of apo E-containing lipoproteins or LRP1 agonists by decreasing the a2M level in the retina as treatments for neurodegenerative disorders such as glaucoma.
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