Greet Vanhoutte

Intraneuronal amyloid β and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease

Transgenic mouse models of Alzheimers disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.

Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

Background— Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results— Here, we report that VEGF∂/∂ mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions— These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

Quantification of tumor microvascular permeability in human glioma xenografts using dynamic T1 MRI with Gadomer-17

Dynamic Magnetic Resonance Imaging (T1-mapping) using the Gadolinium complex Gadomer-17, was applied to characterize the vascular permeability of human glioma xenografts implanted in nude mice. We aimed at measuring permeability differences in two types of glioma xenograft lines with a known difference in perfusion status. The T1-data could be analyzed according to the Tofts-Kermode compartmental model for modeling tracer kinetics to vascular permeability. This vascular permeability was mapped as the permeability surface area product per unit of leakage volume (k). The two tumor types displayed different k-maps. For the fast growing E102 tumor, we observed a homogeneous distribution of the vascular permeability across the tumor with a mean k-value of (0.207 plus or minus 0.027) min-1. However, for the slowly growing E106 tumor, we could distinguish four different regions with different permeability characteristics: a well-perfused rim [k equals (0.30 plus or minus 0.09) min-1], regions at the inner side of the tumor with lower permeability [k equals (0.130 plus or minus 0.019) min-1], regions at the inner side of the tumor around necrotic regions demonstrating locally increased permeability [k equals (0.33 plus or minus 0.11) min-1], and necrotic regions.

In-vivo study of the thermoregulation of the rat tail using magnetic resonance angiography (MRA)

In the rat, almost 20% of the total body heat-loss occurs by sympathetically mediated increases in blood flow through a system of arteriovenous anastomoses (AVAs) in the skin of the tail which are absent at the base and abundant at the tip. To study the mechanisms of thermoregulation in the rat tail we monitored online the blood vessel temperature and the arterial and venous vessel size and their mutual vascular volume interactions using in vivo MRA. During a gradual rise in rectal temperature from 36 degrees Celsius to 40 degrees Celsius, tail surface temperatures were measured at ventral (Ta) and lateral (Tv) sits overlying the respective vascular bundles. At the base, middle and tip, diameter of the ventral artery and the lateral veins of the heat-loaded animal increased clearly upon rising body temperature. Calculation of (Ta - Tv) in function of the rectal temperature during heating showed that at the tail base (Ta - Tv) was maximum at rectal temperature of 38 degrees Celsius and minimum at 39 degrees Celsius. At the middle and the tip of the tail, a steady rise of (Ta - Tv) was observed. If we assume that vasodilatation is a synchronical process along the length of the tail, then the difference in (Ta - Tv) is due to the presence of AVAs.