TY - JOUR

T1 - The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42

AU - Søderman, Andreas

AU - Thomsen, Morten Skøtt

AU - Hansen, Henrik H

AU - Nielsen, Elsebet Ø

AU - Jensen, Morten S

AU - West, Mark J.

AU - Mikkelsen, Jens D

PY - 2008/8/28

Y1 - 2008/8/28

N2 - 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.

AB - 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.

KW - Amyloid beta-Peptides

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Attention

KW - Bicyclo Compounds, Heterocyclic

KW - Blotting, Western

KW - Dose-Response Relationship, Drug

KW - Female

KW - Humans

KW - Immunohistochemistry

KW - Immunoprecipitation

KW - Injections, Subcutaneous

KW - Limbic System

KW - Memory

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Neurons

KW - Nucleus Accumbens

KW - Peptide Fragments

KW - Prefrontal Cortex

KW - Proto-Oncogene Proteins c-fos

KW - Receptors, Nicotinic

KW - alpha7 Nicotinic Acetylcholine Receptor

U2 - 10.1016/j.brainres.2008.06.062

DO - 10.1016/j.brainres.2008.06.062

M3 - Journal article

C2 - 18619425

VL - 1227

SP - 240

EP - 247

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -