APPI-Derived Cyclic Peptide Enhances Aß42 Aggregation and Reduces Aß42-Mediated Membrane Destabilization and Cytotoxicity.

ABSTRACT

An amyloid precursor protein inhibitor (APPI) and amyloid beta 42 (Aß42) are both subdomains of the human transmembrane amyloid precursor protein (APP). In the brains of patients with Alzheimer's disease (AD), Aß42 oligomerizes into aggregates of various sizes, with intermediate, low-molecular-weight Aß42 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 Aß42 oligomeric species include the use of short, Aß42-interacting peptides that either inhibit the formation of the Aß42 oligomeric species or promote their conversion to high-molecular-weight aggregates. We therefore designed such an Aß42-interacting peptide that is based on the ß-hairpin amino acid sequence of the APPI, which exhibits high similarity to the ß-sheet-like aggregation site of Aß42. Upon tight binding of this 20-mer cyclic peptide to Aß42 (in a 11 molar ratio), the formation of Aß42 aggregates was enhanced, and consequently, Aß42-mediated cell toxicity was ameliorated. We showed that in the presence of the cyclic peptide, interactions of Aß42 with both plasma and mitochondrial membranes and with phospholipid vesicles that mimic these membranes were inhibited. Specifically, the cyclic peptide inhibited Aß42-mediated mitochondrial membrane depolarization and reduced Aß42-mediated apoptosis and cell death. We suggest that the cyclic peptide modulates Aß42 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.