Binding of Cu to Aβ1-29 causes aggregation and toxicity in SH-SY5Y cells

The accumulation and aggregation of amyloid-β (Aβ) are critical factors in the pathogenesis of Alzheimer's disease (AD). Several studies have indicated that metal ions such as Cuand Zn play a key role in the formation and stabilization of neurotoxic Aβ aggregates, however the molecular mechanisms underlying Aβ cytotoxicity have not yet been fully elucidated. Previously, we showed that the Aβ-derived fragment peptide (Aβ-FrP), Aβ1-19, altered conformation in the presence of Cu, inhibiting its digestion by metalloproteinase-7 (MMP-7). In this study we demonstrated that Aβ1-19 did not form aggregates in the presence of Cu. Therefore, we synthesized a new Aβ-FrP, Aβ1-29, which displayed Cu-dependent conformational conversion and aggregate formation. Aβ1-29 was cleaved by MMP-7, however this reaction was inhibited in the presence of Cu in a similar way to Aβ1-19. Interestingly, Aβ1-29 showed conformational conversion and aggregate formation in the presence of Zn, however this did not confer resistance against MMP-7 cleavage. Moreover, Aβ1-29 induced the apoptotic cell death of neural SH-SY5Y cells in the presence of Cu but not Zn. These results suggest that Cu, unlike Zn, may play an important role in the aggregation mechanism of Aβ and thus in the pathology of AD.