Hou_2014_CNS.Neurosci.Ther_20_59

BACKGROUND AND PURPOSE: As a molecular chaperone, acetylcholinesterase (AChE; EC 3.1.1.7) plays a critical role in the pathogenesis of Alzheimer's disease (AD). The peripheral anionic site (PAS) of AChE has been indicated as the amyloid-beta (Abeta) binding domain. The goal of this study was to determine other motifs in AChE involved in Abeta aggregation and deposition. METHODS AND
RESULTS: The beta-hairpin in monomeric Abeta is the key motif of nucleation-dependent Abeta self-aggregation. As AChE could induce Abeta aggregation and deposition, we searched AChE for beta-hairpin structures. In A11-specific dot blot assay, AChE was detected by an oligomer-specific antibody A11, implying the existence of beta-hairpin structures in AChE as beta-hairpin was the core motif of oligomers. A molecular superimposing approach further revealed that the N-terminal region, from Glu7 to Ile20, in AChE (AChE 7-20) was similar to the beta-hairpin domain in Abeta. The results of further dot blot assays, thioflavin T fluorescence assays, and electron microscopy imaging experiments, indicated that the N-terminal synthetic peptide AChE7-20 had nearly the same ability as AChE with regard to triggering Abeta aggregation and deposition.
CONCLUSIONS: AChE 7-20, a beta-hairpin region in AChE, might be a new motif in AChE capable of triggering Abeta aggregation and deposition. This finding will be helpful to design new and more effective Abeta aggregation inhibitors for AD treatment.