The membrane-active amphibian peptide caerin 1.8 inhibits fibril formation of amyloid ?1-42

Abstract

The amphibian host-defense peptide caerin 1.8 [1GLFKVLGSV10AKHLLPHVVP20VIAEKL(NH<inf>2</inf>)] inhibits fibril formation of amyloid β 1-42 [1DAEFRHDSG10YEVHHQKLVF20FAEDVGSNKG30AIIGLMVGGV40VIA] [Aβ42] (the major precursor of the extracellular fibrillar deposits of Alzheimer's disease). Some truncated forms of caerin 1.8 also inhibit fibril formation of Aβ42. For example, caerin 1.8 (1-13) [1GLFKVLGSV10AKHL(NH<inf>2</inf>) and caerin 1.8 (22-25) [KVLGSV10AKHLLPHVVP20VIAEKL(NH<inf>2</inf>)] show 85% and 75% respectively of the inhibition activity of the parent caerin 1.8. The synthetic peptide KLVFFKKKKKK is a known inhibitor of Aβ42 fibril formation, and was used as a standard in this study. Caerin 1.8 is the more effective fibril inhibitor. IC<inf>50</inf> values (±15%) are caerin 1.8 (75 μM) and KLVFFKKKKKK (370 μM). MALDI mass spectrometry shows the presence of a small peak corresponding to a protonated 1:1 adduct [caerin 1.8/Aβ42]H+. Molecular dynamics simulation suggests that both hydrogen bonding and hydrophobic interactions between Aβ42 and caerin 1.8 facilitate the formation of a 1:1 complex in water. Fibril formation from Aβ42 has been proposed to be based around the 16KLVF20F region of Aβ42; this region in the 1:1 complex is partially blocked from attachment of a further molecule of Aβ42.