Secreted amyloid precursor proteins promote proliferation and glial differentiation of adult hippocampal neural progenitor cells

Amyloid precursor protein (APP) is an integral membrane glycoprotein present at high levels in nerve cells. Two soluble secreted forms, sAPPa and sAPP beta, are processed from APP by two mutually exclusive proteolytic pathways. sAPPa shows a range of neuroprotective and growth factor properties, including reduction of neuronal injury and improvement in memory performance, in contrast to the generally less potent sAPP beta. In addition, sAPPa has been shown to increase the proliferation of both embryonic neural stem cells and neural progenitor cells (NPCs) derived from the subventricular zone (SVZ) of the adult brain. However, an effect of sAPPa (or sAPP beta) on adult hippocampal progenitor cell proliferation and differentiation has not previously been observed. In this study, we examined the effect of both the a- and beta-cleaved ectodomains of sAPP on adult NPCs isolated from the subgranular zone (SGZ) of the rat hippocampus in the presence or absence of depolarizing conditions. Assays were performed to examine the effect of sAPPa and sAPP beta on SGZ-derived adult NPC proliferation in parallel with SVZ-derived cells and on differentiation with SGZ-derived cells. We observed both sAPPa and sAPP beta increased the proliferation of SGZ-derived NPCs in vitro. Further, treatment of SGZ-derived NPCs with either sAPPa or sAPP beta increased the number of cells expressing the astrocytic marker GFAP and promoted cell survival. The effect on differential fate was observed in both the presence and absence of depolarizing conditions. Thus, both sAPPa and sAPP beta exert a complex range of effects on SGZ-derived adult NPCs, including increasing NPC proliferation, maintaining cell viability, yet promoting glial over neuronal differentiation. These findings provide the first direct support for the secreted forms of APP regulating SGZ-derived NPCs, and raise the possibility some or all of the effects may have therapeutic benefit in models of neurological disease. (C) 2011 Wiley Periodicals, Inc.