TY - JOUR
T1 - Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice
AU - Prinzen, Claudia
AU - Trümbach, Dietrich
AU - Wurst, Wolfgang
AU - Endres, Kristina
AU - Postina, Rolf
AU - Fahrenholz, Falk
N1 - Funding Information:
We thank Dr. Michael Bonin and Sven Poths (Microarray Facility, Department of Human Genetics, Tübingen, Germany), and Dr. Florian Wagner (RZPD German Resource Center for Genome Research, Berlin, Germany) for support of the microarray analysis. We also thank Annette Roth (Institute of Biochemistry, University Mainz, Germany) for performing the real-time RT-PCR. We are grateful to Dr. Fred van Leuven (Katholieke Univer-siteit Leuven/Belgium) for the APP[V717I]mice. We acknowledge the financial support by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), Förderkennzeichen FKZ01GS0470, FKZ01GS08130, and FKZ01GS08133, the financial support by the Helmholtz Association in the framework of the Virtual Institute of Neurodegeneration and Ageing and the Helmholtz Alliance for Mental Health in an Ageing Society, and the support by DFG (German Research Foundation) in the framework of the SFB 596: Molecular Mechanisms of Neurodegeneration, subproject A12.
PY - 2009/2/5
Y1 - 2009/2/5
N2 - Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant. Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and β-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down syndrome patients. Conclusion: In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of inflammation markers was observed. These results are further supportive for the strategy to treat AD by increasing the α-secretase activity.
AB - Background: In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results: To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant. Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and β-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down syndrome patients. Conclusion: In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of inflammation markers was observed. These results are further supportive for the strategy to treat AD by increasing the α-secretase activity.
UR - http://www.scopus.com/inward/record.url?scp=61449084743&partnerID=8YFLogxK
U2 - 10.1186/1471-2164-10-66
DO - 10.1186/1471-2164-10-66
M3 - Article
C2 - 19196476
AN - SCOPUS:61449084743
SN - 1471-2164
VL - 10
JO - BMC Genomics
JF - BMC Genomics
M1 - 66
ER -