Interaction of p24alpha2 with gamma-secretase complex attenuates gamma-cleavage of APP

Abstract

impairments, suggesting that deficits in neurogenesis may play a role in the disease or contribute to neuropathology. To address this, in this study we examined possible molecular link(s) between neurogenic signaling and FAD proteins.Methods:To determine the significance of APP cleavage by a-secretase and the role of sAPPa in adult neurogenesis we inhibited a-secretase activity in neural progenitor cells using metalloproteinase inhibitor. To determine the role of PS1 in adult neurogenesis we developed a siRNA-expressing lentiviral vector system for the silencing of PS1 in the neurogenic microenvironments in the adult mouse brain. Results: We show that inhibition of a-secretase decreases neural progenitor cell proliferation without affecting their differentiation, and that this decrease can be rescued by sAPPa. In addition, sAPPa can rescue proliferation deficits of neural progenitor cells derived from APP knockout mice. We further show that knocking down PS1 expression in the neurogenic niches of the adult brain enhances cell cycle exit of neural progenitor cell and induces their differentiation. Neural progenitor cells expressing reduced levels of PS1 could differentiate into neurons and glia. Conclusions: This study suggests that sAPPa and PS1 regulate neural progenitor cell maintenance in the adult brain. The results of these studies imply that FAD-linked mutations may alter neurogenic processes in Alzheimer’s disease.