Nibaldo C. Inestrosa, Alejandra Alvarez, Margarita C. Dinamarca, Tomas Perez-Acle and Marcela Colombres Pages 301 - 306 ( 6 )
The cholinergic system impairment observed in Alzheimers 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. 18.104.22.168), 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 Alzheimers 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 Ab 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 Ab 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.
acetylcholinesterase, alzheimers disease, amyloid peptide, congo red, peripheral anionic site
FONDAP-Biomedical Center, P. Catholic University of Chile, P.O. Box 114-D, Santiago, Chile.