Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca 2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L) and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP 3R) Ca 2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP 3. These interactions result in exaggerated cellular Ca 2+ signaling in response to agonist stimulation as well as enhanced low-level Ca 2+ signaling in unstimulated cells. Parallel studies in InsP 3R-expressing and -deficient cells revealed that enhanced Ca 2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP 3R stimulates amyloid beta processing, an important feature of AD pathology. These observations provide molecular insights into the "Ca 2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention. © 2008 Elsevier Inc. All rights reserved.