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

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.

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

“…Vascular dysregulation in AD includes deficiencies in cerebrovascular reactivity, CBF, and neurovascular coupling responses (Girouard and Iadecola 2006;Gorelick et al 2011;Hock et al 1997;Rombouts et al 2000). Neurovascular coupling dysfunction of AD has been replicated in experimental studies showing that in mouse models of AD, neurovascular coupling is also significantly impaired (Rancillac et al 2012;Shin et al 2007;Royea et al 2017), at least in part, due to enhanced oxidative stress (Nicolakakis et al 2008;Park et al 2008;Park et al 2005) arising from mitochondrial dysfunction and inflammation (Lacoste et al 2013;Ongali et al 2014). Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008).…”

“…Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008). Due to the increased realization that understanding of the mechanisms underlying neurovascular dysfunction is critical for developing novel therapeutic interventions to prevent or treat AD, there is an increasing need in many laboratories to adapt methodologies to investigate neurovascular coupling responses in mouse models of aging and AD (Lacoste et al 2013;Ongali et al 2014;Papadopoulos et al 2016;Hamel et al 2016;Nicolakakis and Hamel 2011;Papadopoulos et al 2014). In this paper, published as part of the BMethods for Geroscience^series in the BTranslational Geroscience^initiative of the journal (Callisaya et al 2017;Kane et al 2017;Kim et al 2017;Liu et al 2017;Meschiari et al 2017;Perrott et al 2017;Shobin et al 2017;Ashpole et al 2017;Bennis et al 2017;Deepa et al 2017;Grimmig et al 2017;Hancock et al 2017;Konopka et al 2017;Podlutsky et al 2017;Sierra and Kohanski 2017;Tenk et al 2017;Ungvari et al 2017a;Ungvari et al 2017b;Urfer et al 2017a;Urfer et al 2017b), we present an easy-to-adapt protocol for assessment of neurovascular coupling responses in mice in both geroscience and AD research.…”

A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes

“…Specificity of our anti-B1R and -B2R antibodies was further determined using mouse kidney extracts from wild-type (WT), B1R and B2R knockout (KO) mice. 14,15 Flow cytometry B1R and B2R expression in isolated platelets was measured by flow cytometry. Briefly, platelets (250 × 10 6 /mL) were fixed with paraformaldehyde for 30 min, washed, and permeabilized with PBS containing 0.01% Triton X-100 and 1% BSA for 10 min.…”

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

“…administration of the kinin B1R agonist Sar-[D-Phe 8 ]-des-Arg 9 -BK in glucose-fed rats. The widespread distribution of B1R in the brain may suggest its presence on microglia and/or astrocytes as evidenced in models of pain and Alzheimer's disease [33,46,47]. Nitric oxide (NO) could also derive from iNOS based on findings showing an upregulation of iNOS by B1R in this model [16,18] and the ability of B1R to activate iNOS through G␣i and the Src-dependent activation of the ERK/MAP kinase pathway [5].…”

“…In the brain, endogenous NO plays a role in the effect of SP on motor behavior [36]. This is keeping with the presence of all components of the kallikrein-kinin system in normal brain and the upregulation of B1R in pathologic brain [4,11,33,37].…”