Age-dependent cerebrovascular abnormalities and blood flow disturbances in APP23 mice modeling Alzheimer's disease

Abstract

Neuropathological changes associated with Alzheimer's disease (AD) such as amyloidplaques, cerebral amyloid angiopathy, and related pathologies are reproduced in APP23 transgenic mice overexpressing amyloid precursor protein (APP) with the Swedish mutation. Magnetic resonance angiography (MRA) was applied to probe, in vivo, the cerebral arterial hemodynamics of these mice. Flow voids were detected at the internal carotid artery of 11-month-old APP23 mice. At the age of 20 months, additional flow disturbances were observed in large arteries at the circle of Willis. Vascular corrosion casts obtained from the same mice revealed that vessel elimination, deformation, or both had taken place at the sites where flow voids were detected by MRA. The detailed three-dimensional architecture of the vasculature visible in the casts assisted the identification of smaller vessels most likely formed as substitution or anastomosis within the circle of Willis. Angiograms and corrosion casts from nontransgenic, age-matched mice manifested no major abnormalities in the cerebrovascular arterial flow pattern. Because no transgene overexpression has been found in the cerebrovasculature of APP23 mice and no deposits of amyloid-beta (Abeta) were observed in large arteries in the region of the circle of Willis, the present results suggest that soluble Abeta may exert deleterious effects on the vasculature. Our findings support the idea that cerebral circulatory abnormalities evolving progressively could contribute to AD pathogenesis. The study also shows the power of MRA to identify changes of vascular function in genetically engineered mice. MRA as a noninvasive technique could be applied to test new therapeutic concepts in animal models of AD and in humans.

Figure 1.

Angiogram from a normal 10-month-old C57Bl/6 mouse. The circle of Willis (1, 2, 4) and small vessels emerging from it are well delineated.

Figure 2.

a, Angiogram from a 6-month-old APP23 mouse. No flow disturbances were detected by MRA in the cerebrovascular architecture of transgenic mice at this age. Minor flow voids were seen only at the level of the pterygopalatine arteries (11). b, Corrosion cast from the brain of a 7.5-month-old APP23 mouse. An intact circle of Willis is shown.

Figure 3.

Angiogram from an 11-month-old APP23 mouse. The arrows indicate flow disturbances at the level of the internal carotid arteries (5). Flow disturbances were also detected outside the brain, at the common (7) and external (8) carotid arteries and the pterygopalatine (10, 11).

Figure 4.

Twenty-month-old littermate mouse. a, Coronal MIP image of an angiogram from a 20-month-old wild-type mouse. The arrows indicate flow voids at the level of the left internal carotid artery (5) and the pterygopalatine (10, 11). b, Corresponding corrosion cast showing no abnormalities in the circle of Willis of this animal.

Figure 5.

Twenty-month-old APP23 mouse. a, The arrows in the angiogram indicate flow voids at the level of the middle cerebral artery (3), the posterior cerebral arteries (4), the carotid arteries (5, 7, 8), and the pterygopalatine (10, 11). b, Corresponding corrosion cast demonstrating vessel elimination at the level of the posterior cerebral artery (4) and the carotid arteries (5, 7, 8) on the left side of the circle of Willis. c, d, Details of the cast presented in b showing constrictions at the level of the right middle cerebral (3) and the internal carotid (5) arteries, respectively. e, A constriction (left, opposed arrows) and an inclusion of unknown kind (right, arrow) were detected at the level of the right posterior cerebral artery (4). The picture on the right was taken from the internal side of the circle of Willis. Vessel constrictions and inclusions could be the cause of turbulence resulting in flow voids depicted by the MR angiograms.

Figure 6.

Twenty-month-old APP23 mouse. a, Angiogram showing perturbed flow at the level of the middle cerebral arteries (3), the carotid arteries (5, 7, 8), and the pterygopalatine (10, 11). b, Corrosion cast demonstrating the different diameters of the middle cerebral arteries.