A New Motif in the N-Terminal of Acetylcholinesterase Triggers Amyloid-β Aggregation and Deposition

Background and purposeAs 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- (A) binding domain. The goal of this study was to determine other motifs in AChE involved in A aggregation and deposition. Methods and resultsThe -hairpin in monomeric A is the key motif of nucleation-dependent A self-aggregation. As AChE could induce A aggregation and deposition, we searched AChE for -hairpin structures. In A11-specific dot blot assay, AChE was detected by an oligomer-specific antibody A11, implying the existence of -hairpin structures in AChE as -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 -hairpin domain in A. The results of further dot blot assays, thioflavin T fluorescence assays, and electron microscopy imaging experiments, indicated that the N-terminal synthetic peptide AChE(7-20) had nearly the same ability as AChE with regard to triggering A aggregation and deposition. ConclusionsAChE 7-20, a -hairpin region in AChE, might be a new motif in AChE capable of triggering A aggregation and deposition. This finding will be helpful to design new and more effective A aggregation inhibitors for AD treatment.