Acetylcholinesterase-amyloid-beta-peptide interaction: effect of Congo Red and the role of the Wnt pathway.
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.C. 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-beta-peptide (Abeta) 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 Abeta neurotoxicity. Congo Red dye stabilizes the Abeta monomer, is able to inhibit oligomerization, and inhibits the binding of AChE to Abeta. However no effect of Congo Red on the binding of AChE to the Abeta preformed fibrils was observed. These studies suggest that different interactions between Abeta soluble-AChE and Abeta fibrils-AChE take place during the association between them. Docking studies were performed to evaluate the binding of Congo Red to Abeta in order to identify putative binding sites in the Abeta 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 beta-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-Abeta neurotoxicity and the Wnt signal transduction pathway.
FONDAP-Biomedical Center, P. Catholic University of Chile, P.O. Box 114-D, Santiago, Chile. ninestr@bio.puc.cl
Nibaldo C
NC
Inestrosa
Alejandra
A
Alvarez
Margarita C
MC
Dinamarca
Tomás
T
Pérez-Acle
Marcela
M
Colombres
D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004396:Coloring Agents / Q000494:pharmacology*; D003224:Congo Red / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051153:Wnt Proteins
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D003224:Congo Red; D000110:Acetylcholinesterase