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PMID: 18579078 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

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

Neuron ·Vol. 58 ·No. 6 ·2008-06-26 ·Pages 871-83

Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK

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.

MeSH Terms
Alzheimer Disease/genetics,metabolism,pathology Amyloid beta-Peptides/metabolism Animals Calcium/antagonists & inhibitors,physiology Calcium Signaling/genetics,physiology Cells, Cultured Humans Inositol 1,4,5-Trisphosphate Receptors/genetics,metabolism Ion Channel Gating/physiology Presenilins/physiology Spodoptera
Chemicals
Amyloid beta-Peptides Inositol 1,4,5-Trisphosphate Receptors Presenilins Calcium
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Cheung King-Ho
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Shineman Diana
Müller Marioly
Cárdenas César
Mei Lijuan
Yang Jun
Tomita Taisuke
Iwatsubo Takeshi
Lee Virginia M-Y
Foskett J Kevin
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2008.04.015
Published
2008-06-26
Pages
871-83
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2495086
Subset
IM
Grants
NIGMS NIH HHS · R01 GM056328-07 · United States
NIGMS NIH HHS · GM56328 · United States
NIGMS NIH HHS · R37 GM056328 · United States
NIMH NIH HHS · R01 MH059937-10 · United States
NIMH NIH HHS · R01 MH059937 · United States
NIGMS NIH HHS · R01 GM056328 · United States
NIGMS NIH HHS · R01 GM056328-08 · United States
NIMH NIH HHS · R01 MH059937-07 · United States
NIGMS NIH HHS · R01 GM056328-09 · United States
NIA NIH HHS · P30 AG010124 · United States
NIMH NIH HHS · R01 MH059937-08 · United States
NIA NIH HHS · AG10124 · United States
NIMH NIH HHS · MH059937 · United States
NIMH NIH HHS · R01 MH059937-09 · United States
NIGMS NIH HHS · R01 GM056328-10 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2008.04.015 PMC Full Text View journal details
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