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

The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic fibrillar aggregates is associated with the pathogenesis of Alzheimer’s disease (AD). The inhibition of β-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 Aβ 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 Aβ1–42 dimer with and without NE molecules. Our results show that without NE molecules, Aβ1–42 dimer transiently adopts a β-hairpin-containing structure, and the β-strand regions of this β-hairpin (residues 15QKLVFFA21 and 33GLMVGGVV40) strongly resemble those of the Aβ fibril structure (residues 15QKLVFFA21 and 30AIIG...