Dataset Information

FMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis.

ABSTRACT: Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer's disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcA? mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcA? mice, and non-transgenic littermates of 14 months-of-age were either treated with the bradykinin receptors 1 and 2 blocker noscapine or received normal drinking water as control over 3 months (n = 8-11/group) and all mice were assessed using fMRI at the end of the treatment period. Perfusion MRI using an arterial spin labeling technique showed regional hypoperfusion in arcA? compared to non-transgenic controls, which was alleviated by noscapine treatment. Similarly, measuring cerebral blood volume changes upon pharmacological stimulation using vessel dilator acetazolamide revealed recovery of regional impairment of cerebral vascular reactivity in arcA? mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (A?) and inflammation levels in brain sections. Immunohistological stainings for A? deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcA? mice. In addition, levels of soluble and insoluble A?38, A?40, A?42 were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcA? mice using electro-chemiluminescent based immunoassay. In summary, bradykinin receptors blockade recovered cerebral vascular dysfunction in a mouse model of cerebral amyloidosis. fMRI methods revealed the functional deficit in disease condition and were useful tools to monitor the treatment response.

SUBMITTER: Ni R

PROVIDER: S-EPMC6413713 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis.

Ni Ruiqing R Kindler Diana Rita DR Waag Rebecca R Rouault Marie M Ravikumar Priyanka P Nitsch Roger R Rudin Markus M Camici Giovanni G GG Liberale Luca L Kulic Luka L Klohs Jan J

Frontiers in aging neuroscience 20190215

Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer's disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcAβ mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcAβ mice, and non-transgenic littermates of 14 months-of-age were either treated with the ...[more]

PMID: 30890928

Similar Datasets

Project description:Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid ? (A?) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.[(18)F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain A? levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1?, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [(18)F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary A?, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) A?1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.Epistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p???10-5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (A?1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.Certain allele combinations involving IL6r and C9 genes are associated with A? burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.

Dataset Information

FMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis.

Publications

fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets