Alzheimer Amyloid Peptide Aβ₄₂ Regulates Gene Expression of Transcription and Growth Factors

Article type: Research Article

Authors: Barucker, Christian^{a; b} | Sommer, Anette^c | Beckmann, Georg^c | Eravci, Murat^a | Harmeier, Anja^{a; 1} | Schipke, Carola G.^d | Brockschnieder, Damian^c | Dyrks, Thomas^c | Althoff, Veit^a | Fraser, Paul E.^e | Hazrati, Lili-Naz^f | George-Hyslop, Peter St^e | Breitner, John C.S.^{g; h} | Peters, Oliver^d | Multhaup, Gerhard^{a; b; *}

Affiliations: [a] Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany | [b] Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada | [c] Bayer Pharma AG, Global Drug Discovery, Berlin, Germany | [d] Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charite–Universitätsmedizin Berlin, Berlin, Germany | [e] Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada | [f] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada | [g] Douglas Mental Health University Institute, Verdun, QC, Canada | [h] Department of Psychiatry, McGill University Faculty of Medicine, Montreal, QC, Canada

Correspondence: [*] Correspondence to: Gerhard Multhaup, Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, 3655 Promenade Sir-William-Osler, Montreal, QC, H3G 1Y6, Canada. Tel.: +1 514 398 3621; Fax: +1 514 398 2045; E-mail: [email protected].

Note: [1] Present address: F. Hoffmann-La Roche AG, Pharma Research & Early Development, DTA Neuroscience Basel, Switzerland.

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.

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

DOI: 10.3233/JAD-141902

Journal: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 613-624, 2015