期刊
CNS NEUROSCIENCE & THERAPEUTICS
卷 20, 期 1, 页码 59-66出版社
WILEY
DOI: 10.1111/cns.12161
关键词
Acetylcholinesterase; Alzheimer's disease; Amyloid-beta; Oligomer
资金
- National Basic Research Program of China [2010CB529806]
- National Natural Science Foundation of China [30973509, 81173084]
- International Science AMP
- Technology Cooperation Program of China [2011DFA33180]
- National Innovative Drug Development Project [2009ZX09103-077, 2012ZX09303-003]
- National Basic Research Program of China [2010CB529806]
- National Natural Science Foundation of China [30973509, 81173084]
- International Science AMP
- Technology Cooperation Program of China [2011DFA33180]
- National Innovative Drug Development Project [2009ZX09103-077, 2012ZX09303-003]
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.
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