Genetic deletion or antagonism of kinin B1 and B2 receptors improves cognitive deficits in a mouse model of Alzheimer's disease

Increased brain deposition of amyloid β protein (Aβ) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated β-amyloid peptide-(1–40) (Aβ1–40) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. In the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the Aβ1–40 cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Aβ1–40 treatment were significantly reduced by the i.c.v. administration of the selective kinin B2 receptor antagonist d-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe 140). A similar effect was found in mice lacking kinin B2 receptor. On the other hand, genetic deletion of the inducible kinin B1 receptor or its blockage by i.c.v. injection of des-Arg9-[Leu8]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by Aβ1–40. Moreover, treatment with Aβ1–40 resulted in a sustained increase in the expression of the kinin B1 receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B2 receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B1 and B2 receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by Aβ peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD.