Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric -amyloid peptide_1-42 in primary type 1 microglia

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (A beta) peptides. However, whether the microglial GPNMB can recognize the fibrous A beta peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric A beta(1-42) (o-A beta(1-42)) in rat primary type 1 MG. I-125-labeled o-A beta(1-42) exhibited specific and saturable endosomal/lysosomal degradation in primary-cultured type 1 MG from GPNMB-expressing wild-type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb-knockout mice. The Gpnmb-siRNA significantly inhibits the degradation of I-125-o-A beta(1-42) by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o-A beta(1-42) clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. I-125-labeled o-A beta(1-42) underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose-dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of I-125-o-A beta(1-42) to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o-A beta(1-42), and by 52% by the 9F5 antibody. Interestingly, the I-125-o-A beta(1-42) degradations by MG-like cells from human-induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o-A beta(1-42) in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of A beta(1-42) and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB.