Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.
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.
Cheung
King-Ho
KH
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shineman
Diana
D
Müller
Marioly
M
Cárdenas
César
C
Mei
Lijuan
L
Yang
Jun
J
Tomita
Taisuke
T
Iwatsubo
Takeshi
T
Lee
Virginia M-Y
VM
Foskett
J Kevin
JK
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
D016229:Amyloid beta-Peptides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053763:Presenilins; D002118:Calcium