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Unfolded protein response signaling by transcription factor XBP‐1 regulates ADAM10 and is affected in Alzheimer's disease
Author(s) -
Reinhardt Sven,
Schuck Florian,
Grösgen Sven,
Riemenschneider Matthias,
Hartmann Tobias,
Postina Rolf,
Grimm Marcus,
Endres Kristina
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-234864
Subject(s) - adam10 , proteases , transcription factor , signal transduction , amyloid precursor protein , amyloid precursor protein secretase , biology , transgene , genetically modified mouse , metalloproteinase , amyloid beta , microbiology and biotechnology , unfolded protein response , alzheimer's disease , endocrinology , chemistry , medicine , gene , matrix metalloproteinase , enzyme , biochemistry , endoplasmic reticulum , disease , disintegrin , peptide
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.—Reinhardt, S., Schuck, F., Grösgen, S., Riemenschneider, M., Hartmann, T., Postina, R., Grimm, M., Endres, K. Unfolded protein response signaling by transcription factor XBP‐1 regulates ADAM10 and is affected in Alzheimer's disease. FASEB J. 28, 978–997 (2014). www.fasebj.org