TRANSGENIC EXPRESSION OF HUMAN ACETYLCHOLINESTERASE INDUCES PROGRESSIVE COGNITIVE DETERIORATION IN MICE

Background: Cognitive deterioration is a characteristic symptom of Alz heimer's disease. This deterioration is notably associated with struct ural changes and subsequent cell death which occur, primarily, in acet ylcholine-producing neurons, progressively damaging cholinergic neurot ransmission. We have reported previously that excess acetylcholinester ase (AChE) alters structural features of neuromuscular junctions in tr ansgenic Xenopus tadpoles. However, the potential of cholinergic imbal ance to induce progressive decline of memory and learning in mammals h as not been explored. Results: To approach the molecular mechanisms un derlying the progressive memory deficiencies associated with impaired cholinergic neurotransmission, we created transgenic mice that express human AChE in brain neurons. With enzyme levels up to two-fold higher than in control mice, transgenic mice displayed an age-independent re sistance to the hypothermic effects of the AChE inhibitor, paraoxon. I n addition to this improved scavenging capacity for anti-AChEs, howeve r, these transgenic mice also resisted muscarinic, nicotinic and serot onergic agonists, indicating that secondary pharmacological changes ha d occurred. The transgenic mice also developed progressive learning an d memory impairments, although their locomotor activities and open-fie ld behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to train ing in a spatial learning water maze test, whereas they performed norm ally in this test at the age of four weeks. This animal model is there fore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. Conclusion: We conclude that upsetting cholinergi c balance may by itself cause progressive memory decline in mammals, s uggesting that congenital and/or acquired changes in this vulnerable b alance may contribute to the physiopathology of Alzheimer's disease.