Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2.

Stem cell research

PubMedID: 25460605

Takamatsu K, Ikeda T, Haruta M, Matsumura K, Ogi Y, Nakagata N, Uchino M, Ando Y, Nishimura Y, Senju S. Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2. Stem Cell Res. 2014;13(3PA):442-453.
The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS) cell-derived macrophage-like cells for Alzheimer's disease (AD). In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aß added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aß. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aß. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2), which is a protease with Aß-degrading activity. In vitro, expression of NEP2 but not anti-Aß scFv enhanced the effect to reduce the level of soluble Aß oligomer in the culture medium and to alleviate the neurotoxicity of Aß. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2) in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aß in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.