Membrane charge dependent states of the β-amyloid fragment Aβ (16–35) with differently charged micelle aggregates

Abstract

Abeta (16-35) is the hydrophobic central core of beta-amyloid peptide, the main component of plaques found in the brain tissue of Alzheimer's disease patients. Depending on the conditions present, beta-amyloid peptides undergo a conformational transition from random coil or alpha-helical monomers, to highly toxic beta-sheet oligomers and aggregate fibrils. The behavior of beta-amyloid peptide at plasma membrane level has been extensively investigated, and membrane charge has been proved to be a key factor modulating its conformational properties. In the present work we probed the conformational behavior of Abeta (16-35) in response to negative charge modifications of the micelle surface. CD and NMR conformational analyses were performed in negatively charged pure SDS micelles and in zwitterionic DPC micelles "doped" with small amounts of SDS. To analyze the tendency of Abeta (16-35) to interact with these micellar systems, we performed EPR experiments on three spin-labeled analogues of Abeta (16-35), bearing the methyl 3-(2,2,5,5-tetramethyl-1-oxypyrrolinyl) methanethiolsulfonate spin label at the N-terminus, in the middle of the sequence and at the C-terminus, respectively. Our conformational data show that, by varying the negative charge of the membrane, Abeta (16-35) undergoes a conformational transition from a soluble helical-kink-helical structure, to a U-turn shaped conformation that resembles protofibril models.

Conformation and EPR characterization of rigid, 310‐helical peptides with TOAC spin labels: Models for short distances

“…The ratios of the integrated bands associated with the H‐bonded vs free NH groups point clearly to almost fully developed (≥ 90%) 3 10 ‐helical structures for all peptides examined . These findings are in full agreement with the spectroscopic and X‐ray diffraction literature data of peptides rich in the known helicogenic TOAC and Aib residues in CDCl 3 solution and in the crystal state.…”

“…More specifically, we analyze a series of peptides consisting of stretches of the non‐coded, host α‐amino acid α‐aminoisobutyric acid (Aib), combined with one or two 4‐amino‐1‐oxyl‐2,2,6,6‐tetramethylpiperidine‐4‐carboxylic acid (TOAC) guest residues. Both TOAC and Aib are known to strongly stabilize regular 3 10 ‐helices . The backbone and side‐chain conformations of TOAC are remarkably constrained, providing well‐defined distances between the stable nitroxide free radicals of two TOAC residues.…”

Application of the Fuzzy Oil Drop Model Describes Amyloid as a Ribbonlike Micelle

“…Experimental studies concerning amyloidogenesis point to the special role of hydrophobic residues [55][56][57]. If interactions between residues forming the sequence do not promote the formation of a common, central hydrophobic core, a different type of ordering may take hold-one in which local peaks and troughs aggregate linearly.…”

Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease

“…In such a model, cell membranes appear to act as two-dimensional aggregation templates. For example, complementary CD, NMR, and electron paramagnetic resonance analyses (Grimaldi et al, 2010) performed in SDS and DPC (dodecyl phosphocholine) micelles showed that A␤ 16 -35 undergoes a conformational transition from a soluble helical structure, to a U-turn-shaped conformation, and fluorescence and CD spectra at varied temperatures (Yoda et al, 2008) show that the flat surface of tightly packed PC (phosphatidylcholine) membranes (a major component of neuronal cell membranes) appears to serve as a platform for nonelectrostatic interactions and self-association. Furthermore, at near-physiological concentrations of A␤ only the small oligomeric A␤ species of ϳ46 Å are relevant, they are capable of attaching to the PC12 cell membrane, and they assemble in situ to form much larger complexes (Nag et al, 2010).…”