title: Secreted type of amyloid precursor protein induces glial differentiation by stimulating the BMP/Smad signaling pathway.
abstract: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Although cytotoxicity of amyloid β peptides has been intensively studied within pathophysiology of AD, the physiological function of amyloid precursor protein (APP) still remains unclarified. We have shown previously that secreted APPα (sAPPα) is associated with glial differentiation of neural stem cells. To elucidate specific mechanisms underlying sAPPα-induced gliogenesis, we examined the potential involvement of bone morphogenic proteins (BMPs). BMPs are one of the factors involved in glial differentiation of neural progenitor cells. When expressions of BMP-2, -4, and -7 were examined, upregulation of BMP-4 expression was solely observed as a result of treatment with sAPPα in a time and dose-dependent manner. Furthermore, the treatment of sAPPα promoted phosphorylation of Smad1/5/8, a downstream signaling mediator of BMP receptors. Interestingly, N-terminal domain of APP (1-205) was sufficient to elevate BMP4 expression, resulting in an increase of glial fibrillary acidic protein (GFAP) expression and phosphorylation of Smad1/5/8. However, the application of APP neutralizing antibody and anti-BMP4 antibody significantly suppressed expression of BMP-4 as well as phosphorylation of Smad1/5/8. Thus, our results indicate that sAPPα-induced gliogenesis is in part mediated by the BMP-4 signaling pathway. We also observed upregulation of BMP-4 and phosphorylation of Smad1/5/8 in APP transgenic mice. It is imperative to unravel the mechanisms underlying the role of BMP-4 during APPα-induced glial differentiation in hope of providing novel prevention or treatment for AD.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, United States; Biomolecular Science Center, University of Central Florida, 4000 Central Florida Blvd., BMS Building, Room 223, Orlando, FL 32816-2364, United States.
authors.forename: Young-Don
authors.initials: YD
authors.lastname: Kwak
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, United States.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Hendrix
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, United States; Biomolecular Science Center, University of Central Florida, 4000 Central Florida Blvd., BMS Building, Room 223, Orlando, FL 32816-2364, United States. Electronic address: ksugaya@mail.ucf.edu.
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Sugaya
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology*; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D055415:Bone Morphogenetic Protein 4; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D051785:Smad Proteins
keywords: Alzheimer’s disease; Amyloid precursor protein; BMP/Smad signaling pathway; Down syndrome; Glial differentiation; Stem cell therapy