Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice

Topic: Brain proteins, microglia and lab models

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. 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 alpha-secretase activity.

@article{prinzen2009-19196476,
  author  = {Prinzen, C. and Trümbach, D. and Wurst, W. and Endres, K. and Postina, R. and Fahrenholz, F.},
  title   = {{Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice}},
  journal = {BMC genomics},
  year    = {2009},
  doi     = {10.1186/1471-2164-10-66},
  pmid    = {19196476},
  url     = {https://doi.org/10.1186/1471-2164-10-66}
}

Key findings

• 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.
• 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.

Why it matters

This study in mice found that overexpressing the alpha-secretase ADAM10 affected many genes and was previously shown to reduce amyloid plaques and cognitive deficits. It is an animal study of gene expression, and it does not show that this approach treats or prevents Alzheimer disease in people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/1471-2164-10-66
• PubMed: 19196476
• Original source →
• Free full text: BMC Genomics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing Journal of the Royal Statistical Society Series B (Statistical Methodology) · 1995-01-01 · usefulness score 52/100 · Laboratory science
• A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model The Journal of clinical investigation · 2004-05-01 · usefulness score 50/100 · Risk genes beyond APOE

Later studies that cite this one

2 studies in the alzhub library list this one in their references.

• The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain Progress in neurobiology · 2015-10-29 · usefulness score 46/100 · Risk genes beyond APOE
• Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future Progress in brain research · 2012-01-01 · usefulness score 39/100 · Down syndrome and Alzheimer's

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• Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected] Nature genetics · 1993-09-01 · usefulness score 40/100
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• Expression of human Cu-Zn superoxide dismutase gene in transgenic mice: model for gene dosage effect in Down syndrome Free radical research communications · 1991-01-01 · usefulness score 37/100
• Chronic elevation of S100 beta protein does not alter APP mRNA expression or promote beta-amyloid deposition in the brains of aging transgenic mice Brain research · 1995-12-01 · usefulness score 33/100
• Fecal corticosterone levels in RCAN1 mutant mice Comparative medicine · 2012-04-01 · usefulness score 30/100
• Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain Colombia medica (Cali, Colombia) · 2014-10-01 · usefulness score 32/100

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