Inhibitors of Amyloid Toxicity Based on β-sheet Packing of Aβ40 and Aβ42

• DOI: 10.1021/bi052485f
• Publication Date: 2006-04-25T05:04:42Z
• Authors: Takeshi Sato; Pascal Kienlen-Ca...; Mahiuddin Ahmed; Wei Liu; Huilin Li; James I. Elliott; Saburo Aimoto; Stefan N. Constan...; Jean-Noel Octave; Steven O. Smith
• Keywords: Beta sheet; Thioflavin; Amyloid (mycology); Congo red; Sequence (biology)

Amyloid fibrils associated with Alzheimer's disease and a wide range of other neurodegenerative diseases have cross β-sheet structure, where main chain hydrogen bonding occurs between β-strands in the direction fibril axis. The surface has pronounced ridges grooves when individual parallel orientation amino acids are in-register one another. Here we show that Aβ amyloid fibrils, Met35 packs against Gly33 C-terminus Aβ40 Gly37 Aβ42. These packing interactions suggest protofilament subunits displaced relative to another Aβ42 structures. We take advantage this corrugated structure design new class inhibitors prevent formation by placing alternating glycine aromatic residues on face β-strand. peptide based GxFxGxF framework disrupt sheet-to-sheet inhibit mature as assayed thioflavin T fluorescence, electron microscopy, solid-state NMR spectroscopy. large small sequence complementary corresponding IxGxMxG motif found C-terminal Importantly, designed significantly reduce toxicity induced cultured rat cortical neurons.