The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42.
Recent studies have demonstrated that amyloid-beta1-42 (Abeta1-42) binds to the nicotinergic alpha7 acetylcholine receptor (alpha7 nAChR) and that the application of Abeta1-42 to cells inhibits the function of the alpha7 nAChR. The in vivo consequences of the pharmacological activation of the alpha7 nAChR have not been examined. The aim of this study has been to evaluate the efficacy of alpha7 nAChR modulators in transgene mice that overexpress human amyloid precursor protein and accumulate Abeta1-40 and Abeta1-42. In accordance with observations in human Alzheimer tissues, we show here through the use of co-immunoprecipitation that human Abeta-immunoreactive peptides bind to mice alpha7 nAChR in vivo. Agonists of the alpha7 nAChR improve memory and attentional properties and increase immediate early gene expression in the prefrontal cortex and the nucleus accumbens. We show that acute systemic administration of the alpha7 nAChR agonist SSR180711 (10 mg/kg) result in a significant increase in Fos protein levels in the shell of nucleus accumbens in wild-type mice, but has no effect in the transgene mice. There were fewer cell bodies expressing Fos in the prefrontal cortex of transgene mice, and in this region no induction was achieved after administration with SSR180711 in either of the two groups. These results suggest that overexpression of human Abeta peptides perhaps via direct interaction with alpha7 nAChR, inhibit alpha7 nAChR-dependent neurotransmission in vivo and emphasize that clinical trials testing alpha7 nAChR agonists should be related to the content of Abeta peptides in the patient's nervous system.
Søderman
Andreas
A
Institute of Anatomy, University of Aarhus, Wilhelm Meyers Allé, 8000 Arhus C, Denmark; NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
Thomsen
Morten S
MS
Hansen
Henrik H
HH
Nielsen
Elsebet Ø
EØ
Jensen
Morten S
MS
West
Mark J
MJ
Mikkelsen
Jens D
JD
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007279:Injections, Subcutaneous; D008032:Limbic System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)