Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice.
ABSTRACT Amyloid-β (Aβ) deposition in the cerebral vasculature is accompanied by remodeling which has a profound influence on vascular integrity and function. In the current study we have quantitatively assessed the age-dependent changes of the cortical vasculature in the arcAβ model of cerebral amyloidosis. To estimate the density of the cortical microvasculature in vivo, we used contrast-enhanced magnetic resonance microangiography (CE-μMRA). Three-dimensional gradient echo datasets with 60 μm isotropic resolution were acquired in 4- and 24-month-old arcAβ mice and compared with wild-type (wt) control mice of the same age before and after administration of superparamagnetic iron oxide nanoparticles. After segmentation of the cortical vasculature from difference images, an automated algorithm was applied for assessing the number and size distribution of intracortical vessels. With CE-μMRA, cerebral arteries and veins with a diameter of less than the nominal pixel resolution (60 μm) can be visualized. A significant age-dependent reduction in the number of functional intracortical microvessels (radii of 20-80 μm) has been observed in 24-month-old arcAβ mice compared with age-matched wt mice, whereas there was no difference between transgenic and wt mice of 4 months of age. Immunohistochemistry demonstrated strong fibrinogen and Aβ deposition in small- and medium-sized vessels, but not in large cerebral arteries, of 24-month-old arcAβ mice. The reduced density of transcortical vessels may thus be attributed to impaired perfusion and vascular occlusion caused by deposition of Aβ and fibrin. The study demonstrated that remodeling of the cerebrovasculature can be monitored noninvasively with CE-μMRA in mice.
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ABSTRACT: Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction. RU-505 restored Aβ-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.Journal of Experimental Medicine 05/2014; · 13.21 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Aβ with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Aβ in the brain parenchyma and cerebral blood vessels. We found that Aβ and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Aβ fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Aβ-fibrin(ogen) binding and altered hemostasis and could thus contribute to Aβ deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Aβ may be a promising therapeutic target for AD.Journal of Alzheimer's disease: JAD 08/2012; · 4.17 Impact Factor
- The Lancet Neurology 08/2013; 12(8):735-6. · 23.92 Impact Factor