Abstract
BackgroundRecent 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).MethodsTransgenic 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.ResultsB1R 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.ConclusionThese 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.
Highlights
Alzheimer’s disease (AD) is characterized by cognitive and cerebrovascular deficits [1], and by neuroinflammation that may involve the kallikrein-kinin system (KKS) [2] known to be widely distributed in brain [3]
Upregulation of B1 receptor (B1R) in the Amyloid precursor protein (APP) mouse brain Since localization and expression of BK receptors in the rodent brain has been described by autoradiography of radioligand binding sites and by western blot [9,17,18], we first investigated the immunohistochemical distribution of the B1R protein in WT and APP mice using highly selective primary antibodies
In APP mice, B1R immunostaining was increased in the hippocampus (Figure 2B, arrows), primarily in the dentate gyrus (DG) that displayed abundant immunopositive cells in the hilus region (Figure 2B, inset), whereas only few B1R-positive cells were found in cortex (Figure 2B, arrowhead)
Summary
Alzheimer’s disease (AD) is characterized by cognitive and cerebrovascular deficits [1], and by neuroinflammation that may involve the kallikrein-kinin system (KKS) [2] known to be widely distributed in brain [3]. In agreement with our preliminary studies [12,13], growing evidence suggests a role for the KKS in AD [2], as reflected by the cleavage of high-molecular-weight kininogens observed in the cerebrospinal fluid (CSF) of AD patients [14]. Consistent with this observation, a single dose of BK infused into the rat hippocampus led to learning and memory deficits [15]. 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)
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