Binding of Cu²⁺ 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 Cu²⁺and Zn²⁺ 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 Cu²⁺, inhibiting its digestion by metalloproteinase-7 (MMP-7). In this study we demonstrated that Aβ1-19 did not form aggregates in the presence of Cu²⁺. Therefore, we synthesized a new Aβ-FrP, Aβ1-29, which displayed Cu²⁺-dependent conformational conversion and aggregate formation. Aβ1-29 was cleaved by MMP-7, however this reaction was inhibited in the presence of Cu²⁺ in a similar way to Aβ1-19. Interestingly, Aβ1-29 showed conformational conversion and aggregate formation in the presence of Zn²⁺, 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 Cu²⁺ but not Zn²⁺. These results suggest that Cu²⁺, unlike Zn²⁺, may play an important role in the aggregation mechanism of Aβ and thus in the pathology of AD.