Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death.
The nature of the toxic form of amyloid-beta peptide (Abeta) involved in early Alzheimer's disease (AD) pathology and whether it is the fibrillar or the oligomeric peptide that is the most deleterious to neurons remain controversial. This work aimed to compare the neurotoxicity of different amyloid-beta peptide 1-42 (Abeta1-42) assemblies, using fresh and aged samples enriched in oligomeric and fibrillar species, respectively, and also isolated oligomers and fibrils. The results obtained with fresh and aged Abeta1-42 preparations suggested that oligomeric species are more toxic to cortical neurons in culture than fibrillar forms, which was confirmed by using isolated oligomers and fibrils. In order to further elucidate the mechanisms involved in soluble Abeta toxicity, the involvement of endoplasmic reticulum (ER) calcium (Ca(2+)) release in oligomer-induced apoptosis was evaluated. We observed that oligomeric Abeta1-42 depletes ER Ca(2+) levels leading to intracellular Ca(2+) dyshomeostasis involving phospholipase C activation. Moreover, in the presence of dantrolene, an inhibitor of ER Ca(2+) release through ryanodine receptors, the oligomer-induced apoptosis was prevented demonstrating the involvement of ER Ca(2+) release.
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Institute of Biochemistry, Faculty of Medicine and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
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D000682:Amyloid / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D009498:Neurotoxins / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015544:Inositol 1,4,5-Trisphosphate; D053148:Caspase 3; D002118:Calcium