Alzheimer Amyloid Peptide A beta(42) Regulates Gene Expression of Transcription and Growth Factors

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

来源：Journal of Alzheimer's Disease, 2015, 44(2): 613-624.

DOI：10.3233/JAD-141902

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

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 A beta(40) 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.

• 出版日期2015
• 单位McGill