Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric β-amyloid...

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (Aβ) peptides. However, whether the microglial GPNMB can recognize the fibrous Aβ 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 Aβ_1-42 (o-Aβ_1-42) in rat primary type 1 MG. ¹²⁵I-labeled o-Aβ_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 ¹²⁵I-o-Aβ_1-42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o-Aβ_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. ¹²⁵I-labeled o-Aβ_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 ¹²⁵I-o-Aβ_1-42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o-Aβ_1-42, and by 52% by the 9F5 antibody. Interestingly, the ¹²⁵I-o-Aβ_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-Aβ_1-42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aβ_1-42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB.