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The Journal of Neuroscience, September 17, 2003, 23(24):8453-8459

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Age-Dependent Cerebrovascular Abnormalities and Blood Flow Disturbances in APP23 Mice Modeling Alzheimer's Disease

Nicolau Beckmann,¹ Alexandra Schuler,³ Thomas Mueggler,¹ Eric P. Meyer,³ Karl-Heinz Wiederhold,² Matthias Staufenbiel,² and Thomas Krucker⁴

¹Discovery Technologies Center and ²Nervous System Department, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland, ³Department of Zoology, University of Zurich, CH-8002 Zurich, Switzerland, and ⁴Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

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- (A) were observed in large arteries in the region of the circle of Willis, the present results suggest that soluble A 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.

Key words: Alzheimer's disease; amyloid precursor protein (APP); angiography; angiopathy; cerebral amyloid angiopathy (CAA); circle of Willis; magnetic resonance angiography (MRA); magnetic resonance imaging (MRI); soluble amyloid; transgenic mice; vascular corrosion cast

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Received May 12, 2003; revised July 28, 2003; accepted July 28, 2003.

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