Abstract
Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu2+ exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu2+ -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu2+ with a dissociation constant of 5.50μM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu2+ or Cu2+ -Aβ complex, and to inhibit Cu2+ -induced Aβ aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu2+ -mediated Aβ aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aβ40 -Cu2+ complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aβ and Cu2+ -induced Aβ aggregations, in eliminating Cu2+ -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu2+ -mediated Aβ aggregation and cytotoxicity.
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