Statistical physics of folding and aggregation of amyloid [beta]-protein of Alzheimer's disease

Alzheimer's disease (AD) is neuropathologically characterized by accumulation of amyloid plaques and significant neuronal loss in the cerebral cortex. Amyloid plaques are aggregates of amyloid beta-protein (Abeta). The two most abundant Abeta proteins are 40 (Abeta40) and 42 (Abeta42) amino acids-long. Abeta42 is more strongly associated with severity and onset of AD. Recent experiments indicate that small soluble Abeta aggregates that form prior to amyloid plaque deposition may represent the most toxic structures leading to the onset of AD. To develop therapeutic strategies, it is critical to understand the Abeta aggregation pathways and the structure of Abeta aggregates.; We use a discrete molecular dynamics simulation method to study aggregation of Abeta40 and Abeta42. Our simulations with hydrophobic and hydrophilic interactions show the distributions of Abeta40 and Abeta42 aggregates are significantly different, in agreement with the experimental results. We show that the difference between Abeta40 and Abeta42 occurs already at the folding stage. Abeta42 folded structure is characterized by a turn in the C-terminus that is not present in Abeta40. We show that the amino acids in the same C-terminal region are also responsible for the strongest intermolecular contacts in Abeta42 aggregates, but not in Abeta40 aggregates.; When we include the electrostatic interactions, we observe the formation of larger aggregates for both Abeta40 and Abeta42. We find that in Abeta40 aggregates, the contacts between pairs of amino acids in central hydrophobic clusters, namely from the leucine of the seventeenth amino acid to the alanine of the twenty first amino acid, are the strongest, while in Abeta42, the contacts between pairs of amino acids in C-terminal regions play the vital role. Our research supports the possibility that inhibitors targeting the C-terminal region of Abeta42 may be able to prevent formation of potentially toxic Abeta42 aggregates or structurally modify them to reduce their toxicity.