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Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice
Year:
1995
Source of publication :
Current Biology
Authors :
Shani, Moshe
;
.
Volume :
5
Co-Authors:
Beeri, R.
Andres, C., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Lev-Lehman, E., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Timberg, R., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Huberman, T., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Shani, M., Institute of Animal Science, ARO, The Volcani Center, Bet Dagan, 50250, Israel
Soreq, H., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Facilitators :
From page:
1063
To page:
1073
(
Total pages:
11
)
Abstract:
Background: Cognitive deterioration is a characteristic symptom of Alzheimer's disease. This deterioration is notably associated with structural changes and subsequent cell death which occur, primarily, in acetylcholine-producing neurons, progressively damaging cholinergic neurotransmission. We have reported previously that excess acetylcholinesterase (AChE) alters structural features of neuromuscular junctions in transgenic Xenopus tadpoles. However, the potential of cholinergic imbalance to induce progressive decline of memory and learning in mammals has not been explored. Results To approach the molecular mechanisms underlying 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 resistance to the hypothermic effects of the AChE inhibitor, paraoxon. In addition to this improved scavenging capacity for anti-AChEs, however, these transgenic mice also resisted muscarinic, nicotinic and serotonergic agonists, indicating that secondary pharmacological changes had occurred. The transgenic mice also developed progressive learning and memory impairments, although their locomotor activities and open-field behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to training in a spatial learning water maze test, whereas they performed normally in this test at the age of four weeks. This animal model is therefore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. Conclusion We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease. © 1995 Elsevier Science Ltd. All rights reserved.
Note:
Related Files :
Acetylcholinesterase
aging
Animal
Genetics
metabolism
mice
Show More
Related Content
More details
DOI :
10.1016/S0960-9822(95)00211-9
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
28565
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:40
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Scientific Publication
Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice
5
Beeri, R.
Andres, C., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Lev-Lehman, E., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Timberg, R., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Huberman, T., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Shani, M., Institute of Animal Science, ARO, The Volcani Center, Bet Dagan, 50250, Israel
Soreq, H., Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice
Background: Cognitive deterioration is a characteristic symptom of Alzheimer's disease. This deterioration is notably associated with structural changes and subsequent cell death which occur, primarily, in acetylcholine-producing neurons, progressively damaging cholinergic neurotransmission. We have reported previously that excess acetylcholinesterase (AChE) alters structural features of neuromuscular junctions in transgenic Xenopus tadpoles. However, the potential of cholinergic imbalance to induce progressive decline of memory and learning in mammals has not been explored. Results To approach the molecular mechanisms underlying 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 resistance to the hypothermic effects of the AChE inhibitor, paraoxon. In addition to this improved scavenging capacity for anti-AChEs, however, these transgenic mice also resisted muscarinic, nicotinic and serotonergic agonists, indicating that secondary pharmacological changes had occurred. The transgenic mice also developed progressive learning and memory impairments, although their locomotor activities and open-field behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to training in a spatial learning water maze test, whereas they performed normally in this test at the age of four weeks. This animal model is therefore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. Conclusion We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease. © 1995 Elsevier Science Ltd. All rights reserved.
Scientific Publication
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