The accumulation and aggregation of amyloid-beta (A beta) are critical factors in the pathogenesis of Alzheimer's disease (AD). Several studies have indicated that metal ions such as Cu(2+ )and Zn2+ play a key role in the formation and stabilization of neurotoxic A beta aggregates, however the molecular mechanisms underlying A beta cytotoxicity have not yet been fully elucidated. Previously, we showed that the An-derived fragment peptide (A beta-FrP), A beta 1-19, altered conformation in the presence of Cu2+, inhibiting its digestion by metalloproteinase-7 (MMP-7). In this study we demonstrated that A beta 1-19 did not form aggregates in the presence of Cu2+. Therefore, we synthesized a new A beta-FrP, A beta 1-29, which displayed Cu2+-dependent conformational conversion and aggregate formation. A beta 1-29 was cleaved by MMP-7, however this reaction was inhibited in the presence of Cu2+ in a similar way to A beta 1-19. Interestingly, A beta 1-29 showed conformational conversion and aggregate formation in the presence of Zn2+, however this did not confer resistance against MMP-7 cleavage. Moreover, A beta 1-29 induced the apoptotic cell death of neural SHSY5Y cells in the presence of Cu2+ but not Zn2+. These results suggest that Cu2+, unlike Zn2+, may play an important role in the aggregation mechanism of A beta and thus in the pathology of AD. (C) 2020 Elsevier Inc. All rights reserved.