1. Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease.
- Author
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Reinhardt S, Schuck F, Grösgen S, Riemenschneider M, Hartmann T, Postina R, Grimm M, and Endres K
- Subjects
- ADAM Proteins genetics, ADAM10 Protein, Alzheimer Disease genetics, Amyloid Precursor Protein Secretases genetics, Animals, Aspartic Acid Endopeptidases genetics, Aspartic Acid Endopeptidases metabolism, Cell Line, Tumor, DNA-Binding Proteins genetics, Enzyme-Linked Immunosorbent Assay, Humans, Membrane Proteins genetics, Mice, Promoter Regions, Genetic genetics, Regulatory Factor X Transcription Factors, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Signal Transduction physiology, Transcription Factors genetics, Unfolded Protein Response genetics, X-Box Binding Protein 1, ADAM Proteins metabolism, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, DNA-Binding Proteins metabolism, Membrane Proteins metabolism, Transcription Factors metabolism, Unfolded Protein Response physiology
- Abstract
In Alzheimer's disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological α-secretase, is decreased in favor of the amyloid-β-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1-promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ∼50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD.
- Published
- 2014
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