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 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.

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

“…Studies in animal models of cerebral amyloidosis have reported age-dependent reductions in rCBF ( Fig. 3b) [46,[49][50][51][82][83][84]. Interestingly, hyperperfusion was found in the rTG4510 mouse model of tauopathy [85], but have so far not been reported for models of cerebral amyloidosis.…”

“…Vascular remodelling has been also described to occur in animal models of cerebral amyloidosis [46][47][48], where some of the strains also display CAA [24,31,47,[49][50][51]. A recent study described changes in vessel den-sity and morphology in a transgenic model of tauopathy [52].…”

Transcranialin vivodetection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopy

“…Severe cerebral amyloid angiopathy is also present by 9 to 15 months of age, with dense Aβ aggregates accumulating in the walls of blood vessels (42). Cerebral amyloid angiopathy leads to hypoperfusion, impaired vascular reactivity, decreased vessel density, blood-brain barrier 6 impairment and occurrence of cerebral microbleeds (36,(43)(44)(45)(46). Animals were housed in ventilated cages inside a temperature-controlled room, under a 12-hour dark/light cycle.…”

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

“…MRI was performed as described previously [27,44]. To reduce field inhomogeneities, global 1 st -order followed by fieldmap-based local shimming on the mouse brain was performed.…”