Vascular response to acetazolamide decreases as a function of age in the arcAβ mouse model of cerebral amyloidosis
Introduction
The function of cerebral vessels is subject to alterations during normal brain aging and in particular in the case of neurodegenerative disorders including Alzheimer's disease (AD) (Kalaria, 1996). β-amyloid deposition along cerebral blood vessels (cerebral amyloid angiopathy, CAA) has been observed in most AD patients, although the extent of the angiopathy may vary significantly among patients with comparable burden of parenchymal β-amyloid plaque deposition (Ellis et al., 1996). Aβ-CAA affects predominantly small- and medium-sized brain vessels including meningeal and cerebral arteries, arterioles, and, less frequently, capillaries and veins of cerebral cortex and subcortical structures (Greenberg, 2002, Greenberg et al., 2004, Jellinger, 2002, Weller et al., 2009). In addition to clinical manifestations of vasculopathy related to the occurrence of microhemorrhages in normal aging and AD, vascular β-amyloid can compromise microvascular compliance resulting in brain hypoperfusion, impaired neurovascular coupling, and neuronal dysfunction that increase the risk for dementia (Greenberg et al., 2004, Weller & Nicoll, 2003, Weller et al., 2008).
A variety of genetically engineered mouse models mimicking aspects of brain β-amyloidosis in AD and CAA, which develop both parenchymal Aβ pathology and, to a varying degree, Aβ-CAA, have been generated. Aβ-CAA has been shown to affect endothelium-dependent vasoactivity in a global manner associated with compromised cerebral circulation (Iadecola et al., 1999, Iadecola, 2003, Shin et al., 2007). To what extent vascular dysfunction is a consequence of soluble Aβ or solid CAA is matter of debate.
Given the progressive nature of CAA, noninvasive methods for quantitative assessment of vascular Aβ deposition or functional consequences thereof, suitable for longitudinal studies are highly desirable. It has been shown that functional MRI (fMRI) probing the vascular adaptation to altered brain function in response to a defined neuronal or vascular stimulus might serve as biomarker for vascular dysfunction (Mueggler et al., 2002, Mueggler et al., 2003). In contrast to established techniques for assessing cerebral blood flow (CBF) in animals such as laser speckle flowmetry, which require cranial window or skull thinning, fMRI is noninvasive and hence translatable into clinics. Reversible hypercapnia induced by acetazolamide, a compound approved for clinical use, might qualify as stimulus for probing the vascular response. Intravenously administered, it selectively inhibits carbonic anhydrase leading to immediate and dose dependent retention of CO2 (Taki et al., 1993) prompting vasodilation of blood vessels and correspondingly increases in CBF (Frankel et al., 1992, Vorstrup et al., 1984, Zhou et al., 2009), blood oxygenation levels (Mukherjee et al., 2005), and cerebral blood volume (CBV). Measurement of dynamic CBV changes caused by acetazolamide revealed a compromised hemodynamic response in aged APP23 mice as compared to age-matched littermates (Mueggler et al., 2002).
In this study, CBV changes on acetazolamide administration were assessed in arcAβ mice, which develop pronounced parenchymal and vascular Αβ pathology in an age-dependent manner (Knobloch et al., 2007). In particular, we were interested in the question whether the rate of onset and the maximal amplitude of the fMRI response to acetazolamide stimulation might serve as diagnostic biomarker for the occurrence of Aβ-CAA in these animals.
Section snippets
Animals
arcAβ mice expressing human APP containing both the Swedish (K670N + M671L) and the Arctic mutation (E693G) under the control of the prion protein promoter (PrP) were generated as described previously (Knobloch et al., 2007). Animals were kept at standard housing conditions with a 12-h dark–light cycle and free access to food and water. For the fMRI experiments, three different age groups of arcAβ (tg) and age-matched control littermates (wild-type: wt) have been used: young animals (10 tg: 2.5 ±
Vascular β-amyloid pathology reduces hypercapnia-induced CBV changes
For the analysis of CBV changes induced by infusion of acetazolamide, five coronal sections of 0.7 mm thickness with an interslice distance of 1.2 mm (center-to-center) covering a large part of the forebrain have been recorded. The center of the most caudal slice was positioned at the fissure between cerebellum and cortex (Fig. 1). Regions of interest (ROIs) for the quantitative analysis were defined on a coronal brain slice located approximately − 0.6 mm caudal to the bregma. Those comprise: (i) a
Discussion
Several genetically engineered mouse lines of cerebral amyloidosis such as APP23 (Stuerchler-Pierrat et al., 1997), APPDutch (Herzig et al., 2004), and arcAβ (Knobloch et al., 2007) display significant CAA and constitute attractive models to study the mechanistic aspects associated with the vascular pathology and to evaluate potential biomarkers of CAA. Two strategies for assessing the hemodynamic status of affected vessels can be pursued: (i) analysis of potential effects of CAA on resting
Conflicts of interest
No duality of interest has to be declared for any of the authors.
Acknowledgments
The authors thank Dr. Christof Baltes for providing the high-resolution MR image displayed in Fig. 1, Rudolf Fischer for help with curve fitting procedures, and Dr. Aileen Schröter for help with blood pressure experiments. The authors thank the laboratory of Prof. Carsten Wagner (Institute of Physiology, University of Zurich) for providing access to the blood pressure analysis system and for assistance with the BP measurements. This work was supported by the Swiss National Science Foundation
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