Acetylcholinesterase-amyloid-β-peptide interaction: Effect of Congo Red and the role of the Wnt pathway

Nibaldo C. Inestrosa, Alejandra Alvarez, Margarita C. Dinamarca, Tomás Pérez-Acle, Marcela Colombres

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

The cholinergic system impairment observed in Alzheimer's disease (AD) patients leads to the cognitive, global and behavioral dysfunction commonly associated with dementia. The only treatment for AD has been the use of inhibitors of acetylcholinesterase (AChE) (E.G. 3.1.1.7), which is one of the several proteins associated with amyloid plaque deposits. Recently, novel dual inhibitors of AChE have been developed that target both the active site of the enzyme as well as the peripheral anionic site (PAS). Such inhibitors prevent the aggregation of amyloid-β-peptide (Aβ) into Alzheimer's fibrils. The incorporation of AChE, as a "chaperone" into amyloid aggregates results in the modification of the biochemical properties of the enzyme, including: sensitivity to low pH, inhibition at high substrate concentration, and increases of the Aβ neurotoxocity. Congo Red dye stabilizes the Aβ monomer, is able to inhibit oligomerization, and inhibits the binding of AChE to Aβ. However no effect of Congo Red on the binding of AChE to the Aβ preformed fibrils was observed. These studies suggest that different interactions between Aβ soluble-AChE and Aβ fibrils-AChE take place during the association between them. Docking studies were performed to evaluate the binding of Congo Red to Aβ in order to identify putative binding sites in the Aβ monomer that might interact with AChE. The binding site involves a region between residues 12 and 16. Finally, recent studies are consistent with the idea that a attenuating β-catenin loss of function of Wnt signaling components may play a role in the progression of neurodegenerative disease, such as AD, providing a connection between AChE-Aβ neurotoxicity and the Wnt signal transduction pathway.

Original languageEnglish
Pages (from-to)301-306
Number of pages6
JournalCurrent Alzheimer Research
Volume2
Issue number3
DOIs
Publication statusPublished - Jul 2005

Keywords

  • Acetylcholinesterase
  • Alzheimer's disease
  • Amyloid β-peptide
  • Congo Red
  • Peripheral anionic site

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry
  • Neurology

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