Norepinephrine Inhibits Alzheimer's Amyloid-β Peptide Aggregation and Destabilizes Amyloid-β Protofibrils: A Molecular Dynamics Simulation Study

The abnormal self-assembly of amyloid-beta (A beta) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimers disease (AD). The inhibition of beta-sheet-rich oligomer formation is considered as the primary therapeutic strategy for AD. Previous experimental studies reported that norepinephrine (NE), one of the neurotransmitters, is able to inhibit A beta aggregation and disaggregate the preformed fibrils. Moreover, exercise can markedly increase the level of NE. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations to investigate the conformational ensemble of A beta(1-42) dimer with and without NE molecules. Our results show that without NE molecules, A beta(1-42) dimer transiently adopts a beta-hairpin-containing structure, and the beta-strand regions of this beta-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the A beta fibril structure (residues 15QKLVFFA21 and 30AIIGLMVG37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide beta-sheet content and suppress the formation of the above-mentioned beta-hairpin, leading to a more disordered coil-rich A beta dimer. Five dominant binding sites are identified, and the central hydrophobic core 16KLVFFA21 site and C-terminal 31IIGLMV36 hydrophobic site are the two most favorable ones. Our data reveal that hydrophobic, aromatic stacking, hydrogen-bonding and cation-pi interactions synergistically contribute to the binding of NE molecules to A beta peptides. MD simulations of A beta(1-42) protofibril show that NE molecules destabilize A beta protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit A beta(1-42) aggregation and disaggregate A beta protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.