Non-electrostatic binding and self-association of amyloid β-peptide on the surface of tightly packed phosphatidylcholine membranes

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).…”

β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels

“…Its fluidity increases the probability of proteins and peptides to get incorporated into the bilayer during reconstitution, and the absence of phase-separated domains provides flat and uniform lipid supported bilayers on mica surfaces such that the incorporated peptides can be readily distinguished during imaging. 27,29 Although some amyloids prefer to interact with anionic bilayers 86-89 as compared with the zwitterionic phosphatidylcholine lipids, 43,90 anionic lipids interact repulsively with the negatively charged mica surface used as substrate in AFM experiments, thus complicating the formation of a supported bilayer. In our previous simulations, Aβ channels were modeled in both the zwitterionic DOPC bilayer and the anionic bilayer containing POPC and POPG.…”

Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation

“…If a compound can be identified that binds to this region, it could in principle prevent unwanted interactions that lead to protein misfolding. 5,6 We devised an in silico screening strategy to identify compounds capable of binding to the HHQK domain. The HHQK receptor consists of 3 positively charged basic residues in a 1-2-4 arrangement within a tetrapeptide motif.…”

“…S1, available at cma.ca/jpn), has been identified as a region that plays a mechanistic role in the conversion of β-amyloid from a nontoxic α-helical or random coil con formation to the β-sheet conformation that leads to aggregation and neurotoxicity. 5,6 The aggregation of β-amyloid is a nucleation process whereby the misfolding of 1 protein initiates the misfolding of another, with the misfolded monomers forming into oligomeric species. 7 The small, soluble oligomeric forms of β-amyloid are neurotoxic; 8 thus, preventing their aggregation is therapeutically desirable.…”