APPI-Derived Cyclic Peptide Enhances A42 Aggregation and Reduces A42-Mediated Membrane Destabilization and Cytotoxicity

An amyloid precursor protein inhibitor (APPI) and amyloid beta 42 (A beta 42) are both subdomains of the human transmembrane amyloid precursor protein (APP). In the brains of patients with Alzheimer's disease (AD), A beta 42 oligomerizes into aggregates of various sizes, with intermediate, low-molecular-weight A beta 42 oligomers currently being held to be the species responsible for the most neurotoxic effects associated with the disease. Strategies to ameliorate the toxicity of these intermediate A beta 42 oligomeric species include the use of short, A beta 42-interacting peptides that either inhibit the formation of the A beta 42 oligomeric species or promote their conversion to high-molecular-weight aggregates. We therefore designed such an A beta 42-interacting peptide that is based on the beta-hairpin amino acid sequence of the APPI, which exhibits high similarity to the beta-sheet-like aggregation site of A beta 42. Upon tight binding of this 20-mer cyclic peptide to A beta 42 (in a 1:1 molar ratio), the formation of A beta 42 aggregates was enhanced, and consequently, A beta 42-mediated cell toxicity was ameliorated. We showed that in the presence of the cyclic peptide, interactions of A beta 42 with both plasma and mitochondrial membranes and with phospholipid vesicles that mimic these membranes were inhibited. Specifically, the cyclic peptide inhibited A beta 42-mediated mitochondrial membrane depolarization and reduced A beta 42-mediated apoptosis and cell death. We suggest that the cyclic peptide modulates A beta 42 aggregation by enhancing the formation of large aggregates-as opposed to low-molecular-weight intermediates- and as such has the potential for further development as an AD therapeutic.