On the lack of polymorphism in Aβ-peptide aggregates derived from patient brains.
The amyloid beta (Aβ) oligomers and fibrils that are found in neural tissues of patients suffering from Alzheimer's disease may either cause or contribute to the pathology of the disease. In vitro, these Aβ-aggregates are characterized by structural polymorphism. However, recent solid state NMR data of fibrils acquired post mortem from the brains of two Alzheimer's patients indicate presence of only a single, patient-specific structure. Using enhanced molecular dynamic simulations we investigate the factors that modulate the stability of Aβ-fibrils. We find characteristic differences in molecular flexibility, dynamics of interactions, and structural behavior between the brain-derived Aβ-fibril structure and in vitro models. These differences may help to explain the lack of polymorphism in fibrils collected from patient brains, and have to be taken into account when designing aggregation inhibitors and imaging agents for Alzheimer's disease.
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
Erik J
EJ
Alred
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
Malachi
M
Phillips
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
Workalemahu M
WM
Berhanu
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019.
Ulrich H E
UH
Hansmann
D000544:Alzheimer Disease / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D055550:Protein Stability
D000682:Amyloid; D016229:Amyloid beta-Peptides
amyloid diseases; hydration channel; molecular dynamics; polymorphism