A new motif in the N-terminal of acetylcholinesterase triggers amyloid-? aggregation and deposition.

ABSTRACT: 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-? (A?) binding domain. The goal of this study was to determine other motifs in AChE involved in A? aggregation and deposition. METHODS AND RESULTS:The ?-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 AChE7-20 had nearly the same ability as AChE with regard to triggering A? aggregation and deposition. CONCLUSIONS:AChE 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.

SUBMITTER: Hou LN 

PROVIDER: S-EPMC6493010 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature