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

作者：Hou, Li-Na; Xu, Jian-Rong; Zhao, Qing-Nan; Gao, Xiao-Ling; Cui, Yong-Yao; Xu, Jun; Wang, Hao; Chen, Hong-Zhuan^*

来源：CNS Neuroscience & Therapeutics, 2014, 20(1): 59-66.

DOI：10.1111/cns.12161

• Acetylcholinesterase
• Alzheimer's disease
• Amyloid-beta
• Oligomer

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.

• 出版日期2014-1
• 单位中山大学; 上海交通大学; 河北医科大学