Cognitive and cerebrovascular improvements following kinin B(1) receptor blockade in Alzheimer’s disease mice

BACKGROUND: Recent evidence suggests that the inducible kinin B(1) receptor (B(1)R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aβ) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B(1)R on cognitive and cerebrovascular functions in a mouse model of Alzheimer’s disease (AD). METHODS: Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APP(Swe,Ind), line J20) were treated with a selective and brain penetrant B(1)R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B(1)R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Aβ burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry. RESULTS: B(1)R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aβ plaques. In APP mice, B(1)R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B(1)R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B(2)R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Aβ(1-42), diffuse and dense-core Aβ plaques, and it increased protein levels of the Aβ brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels. CONCLUSION: These findings show a selective upregulation of astroglial B(1)R in the APP mouse brain, and the capacity of the B(1)R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B(1)R in AD pathogenesis.