title: Aβ42 oligomers selectively disrupt neuronal calcium release.
abstract: Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 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 Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia.
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Lazzari
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Maulilio J
authors.initials: MJ
authors.lastname: Kipanyula
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Agostini
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy; Department of Biomedical Sciences, Consiglio Nazionale delle Ricerche Institute of Neurosciences, University of Padua, Padua, Italy; Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
authors.affiliation: Department of Biomedical Sciences, University of Padua, Padua, Italy. Electronic address: cristina.fasolato@unipd.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fasolato
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000502:physiology* / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016257:Fura-2; D006801:Humans; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology* / Q000633:toxicity*; D058105:Polymerization; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; C578936:Grm5 protein, mouse; D010446:Peptide Fragments; D064529:Receptor, Metabotropic Glutamate 5; C075222:amyloid beta-protein (1-42); D011189:Potassium Chloride; D002118:Calcium; D016257:Fura-2
keywords: Alzheimer's disease; Aβ42 monomers; Aβ42 oligomers; Calcium stores; ERD4 cameleon; Endoplasmic reticulum; Fura-2; Mouse cortical neurons