The Norepinephrine Inhibits Alzheimer's Amyloid-β Peptide Aggregation by Binding to the C-Terminal Hydrophobic Region

Abstract

The abnormal self-assembly of amyloid-β (Aβ) peptides into toxic prefibrillar aggregates is associated with the pathogenesis of Alzheimer's disease (AD). The inhibition of β-sheet-rich oligomers 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. However, the underlying inhibitory and disruptive mechanisms remain elusive. In this work, we performed extensive replica-exchange molecular dynamic (REMD) simulations on the conformational ensemble of Aβ1-42 dimer with and without NE molecules. Our results show that in the absence of NE molecules, Aβ1-42 dimer transiently adopts a β-hairpin involving two β-strands of residues 15QKLVFFA21 and residues 33GLMVGGVV40, whose β-strand regions strongly resemble those of the Aβ fibril structure (β1: residues Q15-A21, β2: residues I30-G37) reported in an electron paramagnetic resonance spectroscopy study. NE molecules greatly reduce the interpeptide β-sheet content and suppress the formation of the above-mentioned β-hairpin, leading to a more disordered coil-rich Aβ dimer. Four dominant binding sites are identified via contact probability and binding energy analyses, among which the C-terminal I31-V36 hydrophobic region is the most favorable one. Our data reveal that hydrophobic, aromatic stacking, cation-π and hydrogen-bonding interactions synergistically contribute to the NE-induced conformational shift. This work reveals the molecular mechanism of NE molecules against Aβ1-42 aggregation and provides valuable information for the development of new drug candidates against AD.