Secreted type of amyloid precursor protein induces glial differentiation by stimulating the BMP/Smad signaling pathway

    Authors

    Y. D. Kwak; B. J. Hendrix;K. Sugaya

    Comments

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    Abbreviated Journal Title

    Biochem. Biophys. Res. Commun.

    Keywords

    Stem cell therapy; Alzheimer's disease; Down syndrome; Amyloid precursor; protein; BMP/Smad signaling pathway; Glial differentiation; NEURAL STEM-CELLS; EMBRYONAL CARCINOMA-CELLS; ALZHEIMERS-DISEASE; PROGENITOR CELLS; SUBVENTRICULAR ZONE; ADULT NEUROGENESIS; TRANSGENIC; MICE; HIPPOCAMPUS; ASTROCYTES; FATE; Biochemistry & Molecular Biology; Biophysics

    Abstract

    Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Although cytotoxicity of amyloid p 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 APP alpha (sAPP alpha) is associated with glial differentiation of neural stem cells. To elucidate specific mechanisms underlying sAPP alpha-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 sAPP alpha in a time and dose-dependent manner. Furthermore, the treatment of sAPP alpha, 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 sAPP alpha-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 APP alpha-induced glial differentiation in hope of providing novel prevention or treatment for AD. (C) 2014 Elsevier Inc. All rights reserved.

    Journal Title

    Biochemical and Biophysical Research Communications

    Volume

    447

    Issue/Number

    3

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    394

    Last Page

    399

    WOS Identifier

    WOS:000336413900003

    ISSN

    0006-291X

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