RGD Reference Report - Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer's disease mice. - Rat Genome Database

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

Authors: Lacoste, B  Tong, XK  Lahjouji, K  Couture, R  Hamel, E 
Citation: Lacoste B, etal., J Neuroinflammation. 2013 May 4;10:57. doi: 10.1186/1742-2094-10-57.
RGD ID: 10395279
Pubmed: PMID:23642031   (View Abstract at PubMed)
PMCID: PMC3710240   (View Article at PubMed Central)
DOI: DOI:10.1186/1742-2094-10-57   (Journal Full-text)

BACKGROUND: Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Abeta) 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. Abeta 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 Abeta 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 Abeta1-42, diffuse and dense-core Abeta plaques, and it increased protein levels of the Abeta 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease treatmentISOEgr1 (Mus musculus)10395279; 10395279 RGD 
Alzheimer's disease treatmentIEP 10395279 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Egr1  (early growth response 1)

Genes (Mus musculus)
Egr1  (early growth response 1)

Genes (Homo sapiens)
EGR1  (early growth response 1)


Additional Information