Search

Abstract: Recent studies have demonstrated that amyloid-β1–42 (Aβ1–42) binds to the nicotinergic α7 acetylcholine receptor (α7 nAChR) and that the application of Aβ1–42 to cells inhibits the function of the α7 nAChR. The in vivo consequences of the pharmacological activation of the α7 nAChR have not been examined. The aim of this study has been to evaluate the efficacy of α7 nAChR modulators in transgene mice that overexpress human amyloid precursor protein and accumulate Aβ1–40 and Aβ1–42. In accordance with observations in human Alzheimer tissues, we show here through the use of co-immunoprecipitation that human Aβ-immunoreactive peptides bind to mice α7 nAChR in vivo. Agonists of the α7 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 α7 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 Aβ peptides perhaps via direct interaction with α7 nAChR, inhibit α7 nAChR-dependent neurotransmission in vivo and emphasize that clinical trials testing α7 nAChR agonists should be related to the content of Aβ peptides in the patient''s nervous system. [Copyright &y& Elsevier]