Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis*

Background: Amyloid-β precursor protein is implicated in neural stem cell development. Results: Neurogenin 2 expression and neuronal differentiation correlated with amyloid-β precursor protein expression in neural stem/progenitor cells. Conclusion: Amyloid-β precursor protein regulates neuronal differentiation by altering neurogenin 2 expression. Significance: The study provides a new mechanism to explain the effects of amyloid-β precursor protein on neural stem cell differentiation. Amyloid-β precursor protein (APP) is well studied for its role in Alzheimer disease, although its normal function remains uncertain. It has been reported that APP stimulates the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs). In this study we examined the role of APP in NSPC differentiation. To identify proteins that may mediate the effect of APP on NSPC differentiation, we used a gene array approach to find genes whose expression correlated with APP-induced neurogenesis. We found that the expression of neurogenin 2 (Ngn2), a basic helix-loop-helix transcription factor, was significantly down-regulated in NSPCs from APP knock-out mice (APPKO) and increased in APP transgenic (Tg2576) mice. Ngn2 overexpression in APPKO NSPCs promoted neuronal differentiation, whereas siRNA knockdown of Ngn2 expression in wild-type NSPCs decreased neuronal differentiation. The results demonstrate that APP-stimulated neuronal differentiation of NSPCs is mediated by Ngn2.

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