Disturbed calcium homeostasis mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides increase cytoplasmic calcium by at least three mechanisms: stimulation of membrane ion channels or receptors; permeabilization of the membrane; and deregulation of internal calcium channels. Presenilins mutations contribute to the latter. Increased calcium then activates the calpain/cdk5/STAT3 pathway and NFAT1. The transcription factors STAT3 and NFAT1 upregulate BACE1, which then produces more Aβ peptides and a positive feedback mechanism is set up. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; IP3, inositol 1,4,5-triphosphate; NFAT1, nuclear factor of activated T-cells 1; SERCA, sarco endoplasmic reticulum calcium ATPase; STAT, signal transducer and activator of transcription.