1. A new motif in the N-terminal of acetylcholinesterase triggers amyloid-β aggregation and deposition.
- Author
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Hou LN, Xu JR, Zhao QN, Gao XL, Cui YY, Xu J, Wang H, and Chen HZ
- Subjects
- Acetylcholinesterase genetics, Amino Acid Motifs, Circular Dichroism, Fluorometry, GPI-Linked Proteins chemistry, GPI-Linked Proteins genetics, Humans, Immunoblotting, Microscopy, Electron, Models, Molecular, Protein Structure, Secondary, Structure-Activity Relationship, Acetylcholinesterase chemistry, Amyloid beta-Peptides chemistry, Plaque, Amyloid chemistry
- 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-β (Aβ) binding domain. The goal of this study was to determine other motifs in AChE involved in Aβ aggregation and deposition., Methods and Results: The β-hairpin in monomeric Aβ is the key motif of nucleation-dependent Aβ self-aggregation. As AChE could induce Aβ aggregation and deposition, we searched AChE for β-hairpin structures. In A11-specific dot blot assay, AChE was detected by an oligomer-specific antibody A11, implying the existence of β-hairpin structures in AChE as β-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 β-hairpin domain in Aβ. 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 Aβ aggregation and deposition., Conclusions: AChE 7-20, a β-hairpin region in AChE, might be a new motif in AChE capable of triggering Aβ aggregation and deposition. This finding will be helpful to design new and more effective Aβ aggregation inhibitors for AD treatment., (© 2013 John Wiley & Sons Ltd.)
- Published
- 2014
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