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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 …