Accumulation of the amyloid-beta peptide (Abeta) in the cerebral cortex is a critical event in the pathogenesis of Alzheimer’s disease. The betaamyloid protein precursor (APP) is cleaved by one of two betasecretases (BACE and BACE2), producing a soluble derivative of the protein and a membrane anchored 99 -amino acid carboxy-terminal fragment (C99). The C99 fragment serves as substrate for gammasecretase to generate the 4 kDa amyloid-beta peptide (Abeta), which is deposited in the Alzheimer’s disease patients’ brains. PION, or GSAP, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and the APP C-terminal fragment, suggesting that PION may be a potential therapeutic target for the treatment of Alzheimer’s disease.