(376bq) Effects of Coexisting Familial Mutants on Wild Type Amyloid?21-30 Assembly | AIChE

(376bq) Effects of Coexisting Familial Mutants on Wild Type Amyloid?21-30 Assembly


Chakraborty, M. - Presenter, University of Rochester
White, A., University of Rochester
Gandhi, H., University of Rochester
Amirkulova, D., University of Rochester
We present a comprehensive study using simulation and experiments to understand the co-assembly of wild type (WT) Amyloidβ (Aβ) peptide and its familial mutants. Aβ peptide has been identified to play a major role in the progression of the debilitating neurodegenerative Alzheimer's disease (AD). Aβ monomers first aggregate into soluble oligomers which further aggregates to insoluble fibrils that are deposited as senile plaques. The fibrillar structures of familial mutants of Aβ have been reported to be different than that obtained from Aβ. In heterozygous carrier patients where both WT Aβ and one of its familial mutants coexist, WT Aβ structure shows stark phenotypic difference compared to fibrils found in homozygous AD patients where only WT Aβ is present. This suggests possible differences in aggregation pathways. Here we studied the 21-30 sub-sequence of WT-Aβ (Aβ21−30) in the presence of two of its familial mutants, E22G and E22Q. Nuclear magnetic resonance (NMR) spectroscopy and circular dichroism (CD) were used to examine both homogeneous and heterogeneous solutions of WT and familial mutants of Aβ21−30 monomers. NMR diffusion experiments and coarse-grained molecular dynamics simulations for both pure (WT, E22G, E22Q) and mixed (WT + E22G, WT + E22Q) systems were performed. Contact maps were used to study the relative frequency of interactions between the two types of monomers in a 1:1 mixture of WT and familial mutant Aβ21−30. The combined multiscale simulation and experimental approach allows us to understand factors which might affect the co-assembly process.