Alzheimer’s disease (AD) results from the formation of amyloid plaques made of the wild-type (WT) Aβ1-42 peptide and the low molecular weight oligomers. Thus far all drugs have failed. Recent experimental studies have revealed that the A2T mutation is always protective; the A2V variant is protective only when mixed with WT peptide, whereas the A2V mutation in both alleles increases both toxicity and self-aggregation propensity. Further experiments have reported that a quinone-derivative compound, NQTrp, might be a good inhibitor of Aβ aggregation and toxicity, and there is a drastic acceleration of fibril formation for the Aβ1-40 peptides in shear flows. This talk will be divided into three parts. First, we shall try to rationalize how a single-point mutation at the position 2 of Aβ is sufficient to induce protective or potent properties compared to the WT-Aβ using all-atom simulations based on replica exchange MD (REMD) and simulated tempering (ST) of dimers using force fields known to fold correctly non-amyloid proteins. Second, we shall demonstrate that NQTrp is not a very efficient inhibitor based on extensive REMD simulations and new toxicity essays. Third, we shall report the early steps of amyloid aggregation under shear flow as obtained from simulations of 128 Aβ16-22 peptides using the coarse-grained OPEP model coupled to hydrodynamic interactions. We would like to thank support of ANR SIMI7 GRAL 12-BS07-0017, ANR LABEX Grant “DYNAMO” (ANR-11-LABX-0011), ERC (FP7/2007-2013) grant agreement no. 258748, the foundation Pierre Gilles de Gennes and HPC resources from GENCI (CINES and TGCC) and IDRIS.

Alzheimer’s disease: Aggregation of WT and protective Aβ peptides, free or in the presence of inhibitors and under shear flow by all-atom and coarse-grained simulations

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.