Research reportB2 receptor blockage prevents Aβ-induced cognitive impairment by neuroinflammation inhibition

- B2R activation contributes to Aβ-induced neuroinflammation.
- Aβ1-40 peptide induces B2R expression in the mouse hippocampus and cortex.
- B2R blockage prevents Aβ-induced synaptic loss and memory deficits.
- B2R antagonism inhibits Aβ-induced MAPKs and transcription factors activation.

Background and purposeAβ-induced neuronal toxicity and memory loss is thought to be dependent on neuroinflammation, an important event in Alzheimer's disease (AD). Previously, we demonstrated that the blockage of the kinin B2 receptor (B2R) protects against the memory deficits induced by amyloid β (Aβ) peptide in mice. In this study, we aimed to investigate the role of B2R on Aβ-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations.Experimental approachThe selective kinin B2R antagonist HOE 140 (50 pmol/site) was given by intracerebroventricular (i.c.v.) route to male Swiss mice 2 h prior the i.c.v. injection of Aβ1-40 (400 pmol/site) peptide. Animals were sacrificed, at specific time points after Aβ1-40 injection (6 h, 1 day or 8 days), and the brain was collected in order to perform immunohistochemical analysis. Different groups of animals were submitted to behavioral cognition tests on day 14 after Aβ1-40 administration.Key resultsIn this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited Aβ-induced neuroinflammation in mice. B2R antagonism reduced microglial activation and the levels of pro-inflammatory proteins, including COX-2, iNOS and nNOS. Notably, these phenomena were accompanied by an inhibition of MAPKs (JNK and p38) and transcription factors (c-Jun and p65/NF-κB) activation. Finally, the anti-inflammatory effects of B2R antagonism provided significant protection against Aβ1-40-induced synaptic loss and cognitive impairment in mice.Conclusions and implicationsCollectively, these results suggest that B2R activation may play a critical role in Aβ-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection.