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    • Inflammatory changes are observed in

    2018-11-12

    Inflammatory changes are observed in AD brains, particularly at the vicinity of senile plaques. They are abundant in activated microglia, which are the resident macrophages in the central nervous system, in both human AD samples (Mattiace et al., 1990; Perlmutter et al., 1990) and transgenic mouse models (Frautschy et al., 1998). Aβ-activated microglia release a wide variety of neurotoxic molecules including proinflammatory cytokines (Griffin, 2006), reactive oxygen species (Reddy et al., 2009), and complement proteins (Bonifati and Kishore, 2007), which contribute to the neurodegeneration in AD. On the other hand, microglia have beneficial effects against AD as a result of neurotrophic agent secretion and clearing Aβ by phagocytosis (Mizuno et al., 2004; Yan et al., 2006). In addition, in vitro experiments strongly suggest a role for microglia in phagocytic clearance of Aβ. Phagocytosis of Aβ by exogenously administered microglia was indicated by an in vivo study using intra-hippocampal Aβ-injected rats (Takata et al., 2007). However, their exact role in the pathogenesis of AD remains to be elucidated. Macrophages are innate immune herpes simplex virus type 1 with the capacity to eliminate invading pathogens and dying cells, and maintain homeostasis in many tissues. Manipulation of macrophages to enhance their capacity to efficiently clear Aβ with low neurotoxicity is expected to provide therapeutic treatments for AD (Malm et al., 2010). A recent study demonstrated that peripherally transplanted CD11b+ bone marrow-derived monocytes (BMM) migrate into the vicinity of Aβ plaques, and that these modified cells secreted the proteolytic enzyme neprilysin and reduced the Aβ burden in model mice (Lebson et al., 2010). These results suggest the potential of bone marrow-derived myeloid-lineage cells in alleviating AD pathology and as therapeutic agents. However, to use myeloid-lineage cells in AD therapy, an adequate supply of therapeutic cells is necessary. Preparation of a large quantity of myeloid lineage cells from bone marrow or peripheral blood of AD patients for the treatment is not practical and the limited cellular sources obstruct the development of a cell-based therapy. Recently, we have developed an iPS cell-based method to generate abundant quantities of myeloid lineage cells. Using this technology, it may be possible to resolve the issue of limited cell sources (Senju et al., 2009). Previously, we have reported the generation of iPS cell-derived macrophage-like myeloid lineage cells (iPS-MC) that were genetically modified to express a membrane-bound form of single chain antibody (scFv) specific to Aβ. In the in vitro analysis, the Aβ-specific scFv-transfectant iPS-MC exhibited efficient Aβ-specific phagocytic activity (Senju et al., 2011). Neprilysin is a membrane-bound protease with efficient Aβ degradation activity (Iwata et al., 2001). The amino acid sequence of membrane metallo-endopeptidase-like protein (MMEL, neprilysin-2) has been reported to be highly homologous with neprilysin. Neprilysin-2 (NEP2) has two alternatively spliced forms: a membrane-bound and soluble-secreted variant. The soluble-secreted form is also known as soluble, secreted endopeptidase (SEP) (Ikeda et al., 1999). In mice, Nep2 is expressed in testis and involved in sperm function, as well as modulating fertilization and early embryonic development (Ghaddar et al., 2000). NEP2 has also been characterized in the human brain, and a recent study reported that NEP2 activity is reduced in mild cognitive impaired patients and AD patients (Huang et al., 2012). Also Hafez and colleagues have demonstrated using gene knockout and transgenic animals that NEP2 contributes to Aβ degradation in vivo (Hafez et al., 2011). In this study, we genetically modified macrophage-like myeloid lineage cells with proliferating capacity generated from human iPS cells (iPS-ML) (Haruta et al., 2013; Koba et al., 2013) to express the Aβ-degrading protease NEP2. In vitro, the transfected macrophages secreted NEP2 and reduced the levels of Aβ1–42 oligomers in the culture medium. In addition, they protected co-cultured SH-SY5Y neuroblastoma cells from the toxicity of Aβ1–42 oligomers. To evaluate the potential for AD therapy, we examined whether iPS-ML could lower the levels of Aβ1–42 peptide in brain interstitial fluid (ISF) in AD model mice. To this end, we set up a microdialysis-based ISF sampling system to examine the level of soluble Aβ1–42 peptide in the mouse brain ISF. Administration of NEP2-secreting iPS-ML into the hippocampus of the AD model transgenic mice diminished Aβ1–42 in the ISF, thereby suggesting the possibility of NEP2-secreting iPS-ML as a therapeutic means for AD.