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The Journal of Neuroscience, July 8, 2009, 29(27):8805-8815; doi:10.1523/JNEUROSCI.6159-08.2009

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Neurobiology of Disease
Deletion of the 7 Nicotinic Acetylcholine Receptor Gene Improves Cognitive Deficits and Synaptic Pathology in a Mouse Model of Alzheimer's Disease

Gustavo Dziewczapolski,¹ Carolina M. Glogowski,¹ Eliezer Masliah,^2,3 and Stephen F. Heinemann¹

¹Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, and Departments of ²Neurosciences and ³Pathology, University of California at San Diego, La Jolla, California 92037

Correspondence should be addressed to Dr. Gustavo Dziewczapolski, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: gustavo{at}salk.edu

It has been recently shown that the Alzheimer's disease (AD) pathogenic peptide amyloid β_1–42 (Aβ_1–42) binds to the 7 nicotinic acetylcholine receptor (7nAChR) with high affinity and the 7nAChR and Aβ_1–42 are both found colocalized in neuritic plaques of human brains with AD. Moreover, the intraneuronal accumulation of Aβ_1–42 was shown to be facilitated by its high-affinity binding to the 7nAChR, and 7nAChR activation mediates Aβ-induced tau protein phosphorylation. To test the hypothesis that 7nAChRs are involved in AD pathogenesis, we used a transgenic mouse model of AD overexpressing a mutated form of the human amyloid precursor protein (APP) and lacking the 7nAChR gene (APP7KO). We have shown that, despite the presence of high amounts of APP and amyloid deposits, deleting the 7nAChR subunit in the mouse model of AD leads to a protection from the dysfunction in synaptic integrity (pathology and plasticity) and learning and memory behavior. Specifically, APP7KO mice express APP and Aβ at levels similar to APP mice, and yet they were able to solve a cognitive challenge such as the Morris water maze test significantly better than APP, with performances comparable to control groups. Moreover, deleting the 7nAChR subunit protected the brain from loss of the synaptic markers synaptophysin and MAP2, reduced the gliosis, and preserved the capacity to elicit long-term potentiation otherwise deficient in APP mice. These results are consistent with the hypothesis that the 7nAChR plays a role in AD and suggest that interrupting 7nAChR function could be beneficial in the treatment of AD.

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Received Dec. 26, 2008; revised May 6, 2009; accepted June 1, 2009.

Correspondence should be addressed to Dr. Gustavo Dziewczapolski, Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: gustavo{at}salk.edu

This article has been cited by other articles:

				H.-Y. Wang, A. Stucky, J. Liu, C. Shen, C. Trocme-Thibierge, and P. Morain Dissociating {beta}-Amyloid from {alpha}7 Nicotinic Acetylcholine Receptor by a Novel Therapeutic Agent, S 24795, Normalizes {alpha}7 Nicotinic Acetylcholine and NMDA Receptor Function in Alzheimer's Disease Brain J. Neurosci., September 2, 2009; 29(35): 10961 - 10973. [Abstract] [Full Text] [PDF]

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