RT Journal Article
SR Electronic
T1 Deletion of the α7 Nicotinic Acetylcholine Receptor Gene Improves Cognitive Deficits and Synaptic Pathology in a Mouse Model of Alzheimer's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8805
OP 8815
DO 10.1523/JNEUROSCI.6159-08.2009
VO 29
IS 27
A1 Gustavo Dziewczapolski
A1 Carolina M. Glogowski
A1 Eliezer Masliah
A1 Stephen F. Heinemann
YR 2009
UL http://www.jneurosci.org/content/29/27/8805.abstract
AB It has been recently shown that the Alzheimer's disease (AD) pathogenic peptide amyloid β1–42 (Aβ1–42) binds to the α7 nicotinic acetylcholine receptor (α7nAChR) with high affinity and the α7nAChR and Aβ1–42 are both found colocalized in neuritic plaques of human brains with AD. Moreover, the intraneuronal accumulation of Aβ1–42 was shown to be facilitated by its high-affinity binding to the α7nAChR, and α7nAChR activation mediates Aβ-induced tau protein phosphorylation. To test the hypothesis that α7nAChRs 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 α7nAChR gene (APPα7KO). We have shown that, despite the presence of high amounts of APP and amyloid deposits, deleting the α7nAChR 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, APPα7KO 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 α7nAChR 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 α7nAChR plays a role in AD and suggest that interrupting α7nAChR function could be beneficial in the treatment of AD.