Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice

Journal of Neuroinflammation

Edith Hamel²  Réjean Couture¹  Karim Lahjouji¹  Xin-Kang Tong²  Baptiste Lacoste² 

[1] Department of Physiology, Faculty of Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC, H3T 1J4, Canada;Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, QC, H3A 2B4, Canada

关键词: Neuropeptide;    Neuroinflammation;    Cerebral circulation;    Amyloid;    Brain kinins;   

Others  :  1159985
DOI  :  10.1186/1742-2094-10-57

 received in 2013-03-03, accepted in 2013-04-20,  发布年份 2013

【 摘 要 】

Background

Recent evidence suggests that the inducible kinin B₁ receptor (B₁R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aβ) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B₁R 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 B₁R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B₁R 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

B₁R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aβ plaques. In APP mice, B₁R 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. B₁R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B₂R. 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 B₁R in the APP mouse brain, and the capacity of the B₁R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B₁R in AD pathogenesis.

【 授权许可】

   
2013 Lacoste et al.; licensee BioMed Central Ltd.

【 图 表 】

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