Journal
NEUROBIOLOGY OF AGING
Volume 36, Issue 2, Pages 877-885Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.10.020
Keywords
A beta 42 oligomers; A beta 42 monomers; Mouse cortical neurons; Alzheimer's disease; Calcium stores; Endoplasmic reticulum; Fura-2; ERD4 cameleon
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Funding
- Italian Ministry of University and Scientific Research (PRIN) [2009CCZSES_002, FIRB 2011 RBAP11X42L]
- Veneto Region (RISIB Project)
- Italian Institute of Technology
- University of Padua (INVS Strategic Project) [CPDR129193, CPDR092557]
- University of Padua
- CARIPARO Foundation
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Accumulation of amyloid-beta (A beta) peptides correlates with aging and progression of Alzheimer's disease (AD). A beta peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca2+ homeostasis. By cytosolic and endoplasmic reticulum Ca2+ measurements, we here define the short-term effects of synthetic A beta 42 on neuronal Ca2+ dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, A beta 42 did not cause Ca2+ release or Ca2+ influx. Similarly, 1-hour treatment with A beta 42 modified neither the resting cytosolic Ca2+ level nor the long-lasting Ca2+ influx caused by KCl-induced depolarization. In contrast, A beta 42 oligomers, but not monomers, significantly altered Ca2+ release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)-and caffeine-induced Ca2+ mobilization without alteration of the total store Ca2+ content. Ca2+ dysregulation by A beta 42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca2+ store dysfunction is directly involved in A beta 42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. (C) 2015 Elsevier Inc. All rights reserved.
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