Amyloid precursor protein regulates neurogenesis by antagonizing miR-574-5p in the developing cerebral cortex

Wei Zhang, Selvaratnam Thevapriya, Paul J. Kim, Wei-Ping Yu, H. Shawn Je, Eng King Tan and Li Zeng ()
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Wei Zhang: Neural Stem Cell Research Lab, National Neuroscience Institute
Selvaratnam Thevapriya: Neural Stem Cell Research Lab, National Neuroscience Institute
Paul J. Kim: Molecular Neurophysiology Laboratory, Neuroscience & Behavioral Disorders program, DUKE-NUS GMS
Wei-Ping Yu: National Neuroscience Institute
H. Shawn Je: Molecular Neurophysiology Laboratory, Neuroscience & Behavioral Disorders program, DUKE-NUS GMS
Eng King Tan: National Neuroscience Institute
Li Zeng: Neural Stem Cell Research Lab, National Neuroscience Institute

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Amyloid precursor protein (APP) is a transmembrane glycoprotein proteolytically processed to release amyloid beta, a pathological hallmark of Alzheimer’s disease. APP is expressed throughout the developing and mature brain; however, the primary function of this protein is unknown. We previously demonstrated that APP deficiency enhances neurogenesis, but the mechanisms underlying this process are not known. Here we show that APP regulates the expression of microRNAs in the cortex and in neural progenitors, specifically repressing miR-574-5p. We also show that overexpression of miR-574-5p promotes neurogenesis, but reduces the neural progenitor pool. In contrast, the reduced expression of miR-574-5p inhibits neurogenesis and stimulates proliferation in vitro and in utero. We further demonstrate that the inhibition of miR-574-5p in APP-knockout mice rescues the phenotypes associated with APP deficiency in neurogenesis. Taken together, these results reveal a mechanism in which APP regulates the neurogenesis through miRNA-mediated post-transcriptional regulation.

Date: 2014
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DOI: 10.1038/ncomms4330

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