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 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 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 arcAβ 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 arcAβ mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (Aβ) and inflammation levels in brain sections. Immunohistological stainings for Aβ deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcAβ mice. In addition, levels of soluble and insoluble Aβ38, Aβ40, Aβ42 were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcAβ 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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and represents a complex and multi-factorial disorder
We investigated the effect of bradykinin receptors (BRs) blockade by noscapine on cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) in arcAβ mice using Functional magnetic resonance imaging (fMRI) techniques
We showed that arcAβ mice of amyloidosis have increased plasma bradykinin levels as compared to non-transgenic littermates (NTLs) at the endpoint of the study
Summary
Alzheimer’s disease (AD) is the most common form of dementia and represents a complex and multi-factorial disorder. Functional MRI (fMRI) techniques have been implemented to evaluate cerebrovascular abnormality in patients with AD, which has been shown to occur early during the disease course (IturriaMedina et al, 2016). These comprise regional changes in CBF (Maier et al, 2014) and microvessel density (Klohs et al, 2012), disturbances of blood–brain barrier integrity (Montagne et al, 2017), impairment of vascular reactivity (Stoppe et al, 1995; Mueggler et al, 2002; Princz-Kranz et al, 2010; Dumas et al, 2012), and vascular remodeling (Dumas et al, 2012; Klohs et al, 2016)
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