Soluble amyloid precursor protein: a novel proliferation factor of adult progenitor cells of ectodermal and mesodermal origin

Introduction: Soluble amyloid precursor protein a (sAPPa) is a proteolyte of APP cleavage by a-secretase. The significance of the cleavage and the physiological role of sAPPa are unknown. A crystal structure of a region of the amino terminal of sAPPa reveals a domain that is similar to cysteine-rich growth factors. While a previous study implicates sAPPa in the regulation of neural progenitor cell proliferation in the subventricular zone of adult mice, the ubiquitous expression of APP suggests that its role as a growth factor might be broader. Methods: sAPPa and a-secretase activities were determined in neural progenitor cells (NPCs), mesenchymal stem cells (MSC) and human decidua parietalis placenta stem cells (hdPSC). Inhibition of a-secretase was achieved by treatment with the matrixmetalloproteinase inhibitor GM6001, and proliferation was determined using clonogenic and immunocytochemical analysis of cell-lineage markers. Recovery of proliferation was achieved by supplementing GM6001-treated cells with recombinant soluble APPa. Expression of APP and its cellular localization in the subventricular zone was determined by Western blot and immunohistochemical analyses of APP wild type and knockout tissue. Alterations in pERK and pAKT expression as a function of soluble APPa production and activity in NPCs were determined by Western blot analysis. Results: Here we show that sAPPa is a proliferation factor of adult NPCs, MSCs and hdpPSC. Inhibition of asecretase activity reduces proliferation of these stem cell populations in a dose-dependent manner. Stem cell proliferation can be recovered by the addition of sAPPa in a dose-dependent manner, but not of media depleted of sAPPa. Importantly, sAPPa operates independently of the prominent proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), but in association with ERK signaling and MAP-kinase signaling pathways. Levels of sAPPa and putative a-secretase, ADAM10, are particularly high in the subventricular zone of adult mice, suggesting a role for sAPPa in regulation of NPCs in this microenvironment. Conclusions: These results determine a physiological function for sAPPa and identify a new proliferation factor of progenitor cells of ectodermal and mesodermal origin. Further, our studies elucidate a potential pathway for sAPPa signaling through MAP kinase activation.