Alzheimer amyloid peptide Aβ42 regulates gene expression of transcription and growth factors

Christian Barucker, Anette Sommer, Georg Beckmann, Murat Eravci, Anja Harmeier, Carola G. Schipke, Damian Brockschnieder, Thomas Dyrks, Veit Althoff, Paul E. Fraser, Lili Naz Hazrati, Peter St George-Hyslop, John C.S. Breitner, Oliver Peters, Gerhard Multhaup

Research output: Contribution to journalArticle

Abstract

The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) 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 Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, 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 Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 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 Aβ42 and may represent useful early biomarkers.

Original languageEnglish (US)
Pages (from-to)613-624
Number of pages12
JournalJournal of Alzheimer's Disease
Volume44
Issue number2
DOIs
StatePublished - 2015

Keywords

  • Alzheimer's disease
  • CSF proteomics
  • ID1-3
  • IGFBP
  • LMO4
  • amyloid-β
  • gene regulation
  • immunohistochemistry
  • transcription factors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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  • Cite this

    Barucker, C., Sommer, A., Beckmann, G., Eravci, M., Harmeier, A., Schipke, C. G., Brockschnieder, D., Dyrks, T., Althoff, V., Fraser, P. E., Hazrati, L. N., George-Hyslop, P. S., Breitner, J. C. S., Peters, O., & Multhaup, G. (2015). Alzheimer amyloid peptide Aβ42 regulates gene expression of transcription and growth factors. Journal of Alzheimer's Disease, 44(2), 613-624. https://doi.org/10.3233/JAD-141902