Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Aβ42 reduces their differentiation potential
1 Center for Molecular Biology of the University of Heidelberg (ZMBH), D-69120 Heidelberg, Germany
2 Institute for Neurodegeneration and Neurobiology, Neurology, Saarland University, D-66421 Homburg/Saar, Germany
3 Department of Neurodegeneration and Restorative Research, Center for Neurological Medicine, University of Göttingen, D-37073 Göttingen, Germany
4 DFG Research Center for Molecular Physiology of the Brain (CMPB), D-37073 Göttingen, Germany
5 Max Planck Institute for Experimental Medicine, Proteomics, D-37075 Göttingen, Germany
6 German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
7 Department of Neurology, D-89075 Ulm, Germany
BMC Medicine 2008, 6:38 doi:10.1186/1741-7015-6-38Published: 16 December 2008
Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several β-amyloid peptides (Aβ) are generated. In contrast to the form with 40 amino acids (Aβ40), the variant with 42 amino acids (Aβ42) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Aβ effects have been studied extensively, little is known about specific genome-wide effects triggered by Aβ42 or Aβ40 derived from their direct precursor C99.
A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Aβ peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference.
Here we studied the transcriptomic and proteomic responses to increased or decreased Aβ42 and Aβ40 levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Aβ42- and Aβ40-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Aβ42/Aβ40 ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Aβ42/Aβ40 ratio, whereas a decreased ratio did not result in up-regulation of CRABP1.
We conclude that increasing the Aβ42/Aβ40 ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.