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 (Aβ) 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 (Aβ1-42) 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 Aβ1-42 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 Aβ toxicity, the involvement of endoplasmic reticulum (ER) calcium (Ca2+) release in oligomer-induced apoptosis was evaluated. We observed that oligomeric Aβ1-42 depletes ER Ca2+ levels leading to intracellular Ca2+ dyshomeostasis involving phospholipase C activation. Moreover, in the presence of dantrolene, an inhibitor of ER Ca2+ release through ryanodine receptors, the oligomer-induced apoptosis was prevented demonstrating the involvement of ER Ca2+ release.