Cholinesterases are found in senile plaques and neurofibrillary tangles. In different cell groups in the brain tissue where lesions occur, AChE has been found. It is inhibition of these enzymes that may lead to a treatment for Alzheimer's. Inhibition can either be competitive or non-competetive. Hence, an inhibitor may completely block the substarte from reaching the active site or it may inactivate the catalytic activity of the enzyme by binding to to the peripheral site. (Giles)
In one study, two experiments were conducted to examine the effects of two separate manipulations that reduce cholinergic function on visual attentional performance in rats. In the first part, experimenters administered a choline uptake blocker either alone or with an AChE inhibitor. The results indicated that the choline uptake blocker decreased the ability of the rats to localize visual stimuli. However, when combined with the acetylcholinesterase inhibitor, physostigmine, these visual impairments were reversed. In the second, researchers produced lesions in the basal forebrain. These lesions produced behavioral effects similar to those of the choline uptake blocker. Embryonic basal forebrain cells were transplanted into the cortex of the lesioned animals to restore the cholinergic innervation. After recovery, impairments in visual performance were no longer present. This indicates that cholinergic dysfunction produces visual impairment and attention deficits, and that these dysfunctions can be reversed by administering an AChE inhibitor or performing transplants of tissue. (Dunnett, 1992)
Muscarinic and nicotinic ACh systems have been implicated in cognitive performance. Research was conducted on choice accuracy and how it was affected by both muscarinic and nicotinic agonists and antagonists. Injections of muscarinic and nicotinic agonists were given to female rats that had been trained on a short term memory task in a maze. The nicotinic agonist caused a significant improvement in choice accuracy compared to a control and the muscarinic agonist produced a smaller improvement in accuracy. The coupling of these agonists did not lead to an additive effect. However, when combined with antagonists, the improvement was reversed. This indicates not only the usefulness of such agonists in treating Alzheimer's, but it also suggests that the two ACh systems work together and that this should be considered when searching for other treatments associated with cholinergic hypofunction. (Levin & Rose, 1991)
In another study, researchers investigated the effects of two non-cholinergic drugs on the release of acetylcholine. By examining the effects of a GABA transamase inhibitor and altanserin, a serotonergic antagonist, in a primate brain, the researchers detected high levels of regional changes in acetylcholine release. This points to the use of such drugs in prevention of disease progression. (Brodie et al, 1993)
A drug that has been gaining attention lately is the competitive AChE inhibitor tacrine.
Because the lack of Ach in the brain leads to damaged learning processes, and because AchE has been found in the plaques of Alzheimer's patients brain tissue, AchE inhibitor and cholinergic agonists may make very successful treatments.