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Author (up) Freude, K.K.; Penjwini, M.; Davis, J.L.; LaFerla, F.M.; Blurton-Jones, M. url  doi
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  Title Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells Type Journal Article
  Year 2011 Publication The Journal of Biological Chemistry Abbreviated Journal J Biol Chem  
  Volume 286 Issue 27 Pages 24264-24274  
  Keywords Alzheimer Disease/metabolism/pathology; Antigens, Differentiation/biosynthesis/genetics; Cell Differentiation; Cell Line; Embryonic Stem Cells/*metabolism/pathology; *Gene Expression Regulation; Humans; Neurons/*metabolism/pathology; Serum Amyloid A Protein/*biosynthesis/genetics; Tubulin/biosynthesis/genetics  
  Abstract Human embryonic stem cells (hESCs) offer tremendous potential for not only treating neurological disorders but also for their ability to serve as vital reagents to model and investigate human disease. To further our understanding of a key protein involved in Alzheimer disease pathogenesis, we stably overexpressed amyloid precursor protein (APP) in hESCs. Remarkably, we found that APP overexpression in hESCs caused a rapid and robust differentiation of pluripotent stem cells toward a neural fate. Despite maintenance in standard hESC media, up to 80% of cells expressed the neural stem cell marker nestin, and 65% exhibited the more mature neural marker beta-3 tubulin within just 5 days of passaging. To elucidate the mechanism underlying the effects of APP on neural differentiation, we examined the proteolysis of APP and performed both gain of function and loss of function experiments. Taken together, our results demonstrate that the N-terminal secreted soluble forms of APP (in particular sAPPbeta) robustly drive neural differentiation of hESCs. Our findings not only reveal a novel and intriguing role for APP in neural lineage commitment but also identify a straightforward and rapid approach to generate large numbers of neurons from human embryonic stem cells. These novel APP-hESC lines represent a valuable tool to investigate the potential role of APP in development and neurodegeneration and allow for insights into physiological functions of this protein.  
  Address Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0021-9258 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:21606494; PMCID:PMC3129207 Approved no  
  Call Number refbase @ user @ Serial 16981  
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