What can be Learned from the use of HuAChE Mutants for Evaluation of Potential Alzheimer’s Drugs

Abstract

Senile dementia of the Alzheimer’s type (SDAT) is characterised by loss of cholinergic neuronal markers like the enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), in selected brain regions (Bierer et al., 1995). These indications of progressive depletion of cholinergic synapses led to the hypothesis that increasing the central nervous system (CNS) levels of acetylcholine (ACh), through inhibition of AChE, will improve cognition in SDAT (Court & Perry, 1991). This approach is theoretically preferable to other means of cholinergic augmentation since it may amplify the natural temporal pattern of ACh release, rather than globally stimulating the cholinergic system. Yet up to the present most of these agents show only mild to moderate ameliorating effects on memory deficits (Schneider & Tariot, 1994; Kan, 1992). To further optimize the therapeutic efficacy of these agents, a better understanding is needed of the structural features determining their interactions with AChE. The recent progress in the elucidation of structure-function characteristics of AChE, is therefore of considerable importance for these efforts.KeywordsActive CenterHydrophobic PocketAromatic MoietyPeripheral Anionic SiteAnticholinesterase AgentThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.