Journal
NEURON
Volume 58, Issue 6, Pages 871-883Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2008.04.015
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Funding
- NIA NIH HHS [AG10124, P30 AG010124] Funding Source: Medline
- NIGMS NIH HHS [R01 GM056328-08, R01 GM056328-10, GM56328, R37 GM056328, R01 GM056328-09, R01 GM056328, R01 GM056328-07] Funding Source: Medline
- NIMH NIH HHS [R01 MH059937-10, R01 MH059937, MH059937, R01 MH059937-08, R01 MH059937-07, R01 MH059937-09] Funding Source: Medline
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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 InsP(3). 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.
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