Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating

10. Cheung K.H., Shineman, D, Müller, M, Cárdenas, C, Mei, Tomita, L, Iwatsubo, T, Lee, V and Foskett, JK

Keywords: calcium, InsP3R, Alzheimer disease


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.

Más información

Título de la Revista: NEURON
Volumen: 58
Editorial: Cell Press
Fecha de publicación: 2008
Página de inicio: 871
Página final: 883
Idioma: Inglés
Financiamiento/Sponsor: Universidad de Pennsylvania


Notas: ISI