Dataset Information

A new motif in the N-terminal of acetylcholinesterase triggers amyloid-β 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-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.

SUBMITTER: Hou LN

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

REPOSITORIES: biostudies-literature

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Publications

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

Hou Li-Na LN Xu Jian-Rong JR Zhao Qing-Nan QN Gao Xiao-Ling XL Cui Yong-Yao YY Xu Jun J Wang Hao H Chen Hong-Zhuan HZ

CNS neuroscience & therapeutics 20130824 1

<h4>Background and purpose</h4>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.<h4>Methods and results</h4>The β-hairpin in monomeric Aβ is the key motif of nucleation-dependent Aβ self-aggregation. As AChE co ...[more]

PMID: 23981668

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

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

Background and purpose

Methods and results

Conclusions

Publications

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

Similar Datasets

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