Inhibitors of Amyloid Toxicity Based on beta -sheet Packing of A beta 40 and A beta 42

• Published in: Biochemistry (Easton) Vol. 45; no. 17; pp. 5503 - 5516
• Main Authors: Sato, T, Kienlen-Campard, P, Ahmed, M, Liu, W, Li, H, Elliott, JI, Aimoto, S, Constantinescu, S N, Octave, J-N, Smith, SO
• Format: Journal Article
• Language: English
• Published: 02.05.2006
• ISSN: 0006-2960
• DOI: 10.1021/bi052485f

Amyloid fibrils associated with Alzheimer's disease and a wide range of other neurodegenerative diseases have a cross beta -sheet structure, where main chain hydrogen bonding occurs between beta -strands in the direction of the fibril axis. The surface of the beta -sheet has pronounced ridges and grooves when the individual beta -strands have a parallel orientation and the amino acids are in-register with one another. Here we show that in A beta amyloid fibrils, Met35 packs against Gly33 in the C-terminus of A beta 40 and against Gly37 in the C-terminus of A beta 42. These packing interactions suggest that the protofilament subunits are displaced relative to one another in the A beta 40 and A beta 42 fibril structures. We take advantage of this corrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternating glycine and aromatic residues on one face of a beta -strand. We show that peptide inhibitors based on a GxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature A beta fibrils as assayed by thioflavin T fluorescence, electron microscopy, and solid-state NMR spectroscopy. The alternating large and small amino acids in the GxFxGxF sequence are complementary to the corresponding amino acids in the IxGxMxG motif found in the C-terminal sequence of A beta 40 and Ap42. Importantly, the designed peptide inhibitors significantly reduce the toxicity induced by A beta 42 on cultured rat cortical neurons.