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Alzheimer amyloid Peptide aβ42 regulates gene expression of transcription and growth factors

Item Type:Article
Title:Alzheimer amyloid Peptide aβ42 regulates gene expression of transcription and growth factors
Creators Name:Barucker, C. and Sommer, A. and Beckmann, G. and Eravci, M. and Harmeier, A. and Schipke, C.G. and Brockschnieder, D. and Dyrks, T. and Althoff, V. and Fraser, P.E. and Hazrati, L.N. and St George-Hyslop, P. and Breitner, J.C.S. and Peters, O. and Multhaup, G.
Abstract:The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-{beta} (A{beta}) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and A{beta} represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble A{beta}42 correlate with symptoms of AD, less is known about the biological activities of A{beta} peptides which are generated from the amyloid-{beta} protein precursor. An unbiased DNA microarray study showed that A{beta}42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic A{beta}42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide A{beta}42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble A{beta}42 and may represent useful early biomarkers.
Keywords:Alzheimer's Disease, Amyloid-{beta}, CSF Proteomics, Gene Regulation, ID1-3, IGFBP, Immunohistochemistry, LMO4, Transcription Factors, Animals, Mice
Source:Journal of Alzheimer's Disease
Publisher:IOS Press
Page Range:613-624
Date:1 January 2015
Additional Information:Copyright © 2015, IOS Press and the authors. All rights reserved
Official Publication:https://doi.org/10.3233/JAD-141902
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