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-?-peptide (A?) 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 A? neurotoxocity. Congo Red dye stabilizes the A? monomer, is able to inhibit oligomerization, and inhibits the binding of AChE to A?. However no effect of Congo Red on the binding of AChE to the A? preformed fibrils was observed. These studies suggest that different interactions between A? soluble-AChE and A? fibrils-AChE take place during the association between them. Docking studies were performed to evaluate the binding of Congo Red to A? in order to identify putative binding sites in the A? 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 ?-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-A? neurotoxicity and the Wnt signal transduction pathway. ©2005 Bentham Science Publishers Ltd."