title: Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer's disease mice.
abstract: 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 (APPSwe,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 Aβ1-42, 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.
  
  
  CONCLUSIONS
  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.
authors: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, QC H3A 2B4, Canada.
authors: Baptiste
authors: B
authors: Lacoste
authors: Xin-Kang
authors: XK
authors: Tong
authors: Karim
authors: K
authors: Lahjouji
authors: Réjean
authors: R
authors: Couture
authors: Edith
authors: E
authors: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D065169:Bradykinin B1 Receptor Antagonists; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D004149:Dioxoles / Q000627:therapeutic use*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D016564:Amyloid beta-Protein Precursor; D065169:Bradykinin B1 Receptor Antagonists; D004149:Dioxoles; D051766:Early Growth Response Protein 1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D020780:Matrix Metalloproteinase 9
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