title: Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice.
abstract: BACKGROUND
  In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the alpha-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 alpha-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 beta-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.
  
  
  CONCLUSIONS
  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 alpha-secretase activity.
authors.affiliation: Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Mainz, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Prinzen
authors.forename: Dietrich
authors.initials: D
authors.lastname: Trümbach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
authors.forename: Falk
authors.initials: F
authors.lastname: Fahrenholz
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human