title: Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.
abstract: Mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD) and have been associated with calcium (Ca2+) signaling abnormalities. Here, we demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation as well as enhanced low-level Ca2+signaling in unstimulated cells. Parallel studies in InsP3R-expressing and -deficient cells revealed that enhanced Ca2+ release from the endoplasmic reticulum as a result of the specific interaction of PS1-M146L with the InsP3R stimulates amyloid beta processing,an important feature of AD pathology. These observations provide molecular insights into the "Ca2+ dysregulation" hypothesis of AD pathogenesis and suggest novel targets for therapeutic intervention.
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: King-Ho
authors.initials: KH
authors.lastname: Cheung
authors.forename: Diana
authors.initials: D
authors.lastname: Shineman
authors.forename: Marioly
authors.initials: M
authors.lastname: Müller
authors.forename: César
authors.initials: C
authors.lastname: Cárdenas
authors.forename: Lijuan
authors.initials: L
authors.lastname: Mei
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Foskett
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D053763:Presenilins / Q000502:physiology*; D018411:Spodoptera
chemical_list: D016229:Amyloid beta-Peptides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053763:Presenilins; D002118:Calcium