Abstract
In Alzheimer disease (AD), the perturbation of the endoplasmic reticulum (ER) calcium (Ca²⁺) homeostasis has been linked to presenilins, the catalytic core in γ-secretase complexes cleaving the amyloid precursor protein (APP), thereby generating amyloid-β (Aβ) peptides. Here we investigate whether APP contributes to ER Ca²⁺ homeostasis and whether ER Ca²⁺ could in turn influence Aβ production. We show that overexpression of wild-type human APP (APP(695)), or APP harboring the Swedish double mutation (APP(swe)) triggers increased ryanodine receptor (RyR) expression and enhances RyR-mediated ER Ca²⁺ release in SH-SY5Y neuroblastoma cells and in APP(swe)-expressing (Tg2576) mice. Interestingly, dantrolene-induced lowering of RyR-mediated Ca²⁺ release leads to the reduction of both intracellular and extracellular Aβ load in neuroblastoma cells as well as in primary cultured neurons derived from Tg2576 mice. This Aβ reduction can be accounted for by decreased Thr-668-dependent APP phosphorylation and β- and γ-secretases activities. Importantly, dantrolene diminishes Aβ load, reduces Aβ-related histological lesions, and slows down learning and memory deficits in Tg2576 mice. Overall, our data document a key role of RyR in Aβ production and learning and memory performances, and delineate RyR-mediated control of Ca²⁺ homeostasis as a physiological paradigm that could be targeted for innovative therapeutic approaches.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / complications*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Aminophenols / therapeutic use
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Analysis of Variance
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Animals
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Brain / cytology
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Caffeine / pharmacology
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Calcium / metabolism
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Calcium Channel Blockers / therapeutic use
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Cells, Cultured
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Cytosol / drug effects
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Cytosol / metabolism
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Dantrolene / pharmacology
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Disease Models, Animal
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Embryo, Mammalian
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum / pathology
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Enzyme Inhibitors / therapeutic use
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Exploratory Behavior / drug effects
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Humans
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Inositol 1,4,5-Trisphosphate Receptors / genetics
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Inositol 1,4,5-Trisphosphate Receptors / metabolism
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Maleimides / therapeutic use
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Maze Learning / drug effects
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Proteins / metabolism
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Memory Disorders / drug therapy
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Memory Disorders / etiology*
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Memory Disorders / metabolism*
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Mice
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Mice, Transgenic
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Muscle Relaxants, Central / pharmacology
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Mutation / genetics
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Nerve Tissue Proteins / metabolism
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Neuroblastoma / pathology
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Neurons / drug effects
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Neurons / physiology
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Patch-Clamp Techniques
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Peptide Fragments / metabolism
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology
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Purines / therapeutic use
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RNA, Messenger / metabolism
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Reaction Time / drug effects
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Recognition, Psychology / drug effects
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Roscovitine
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Ryanodine Receptor Calcium Release Channel / genetics
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Ryanodine Receptor Calcium Release Channel / metabolism*
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Transfection
Substances
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3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
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Aminophenols
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Calcium Channel Blockers
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Enzyme Inhibitors
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Inositol 1,4,5-Trisphosphate Receptors
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Maleimides
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Membrane Proteins
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Muscle Relaxants, Central
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Nerve Tissue Proteins
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Peptide Fragments
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Purines
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RNA, Messenger
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Ryanodine Receptor Calcium Release Channel
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amyloid beta-protein precursor C-terminal fragment beta, human
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Roscovitine
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Caffeine
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Amyloid Precursor Protein Secretases
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Dantrolene
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Calcium