Norepinephrine Inhibits Alzheimer's Amyloid-β Peptide Aggregation and Destabilizes Amyloid-β Protofibrils: A...

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 Aβ_1-42 dimer with and without NE molecules. Our results show that without NE molecules, Aβ_1-42 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 30AIIGLMVG37) 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. 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-π interactions synergistically contribute to the binding of NE molecules to Aβ peptides. MD simulations of Aβ_1-42 protofibril show that NE molecules destabilize Aβ protofibril by forming H-bonds with residues D1, A2, D23, and A42. This work reveals the molecular mechanism by which NE molecules inhibit Aβ_1-42 aggregation and disaggregate Aβ protofibrils, providing valuable information for developing new drug candidates and exercise therapy against AD.