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Volume 17, Number 20, Issue of October 15, 1997 pp. 7655-7661
Copyright ©1997 Society for Neuroscience

Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein

Received June 13, 1997; revised July 22, 1997; accepted Aug. 5, 1997.

Fangyi Zhang1, Chris Eckman2, Steven Younkin2, Karen K. Hsiao1, and Costantino Iadecola1

1 Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, and 2 Mayo Clinic Jacksonville, Jacksonville, Florida 32224

We studied the role of the amyloid precursor protein (APP) in ischemic brain damage using transgenic mice overexpressing APP. The middle cerebral artery (MCA) was occluded in FVB/N mice expressing APP695.SWE (Swedish mutation) and in nontransgenic littermates. Infarct volume (cubic millimeters) was assessed 24 hr later in thionin-stained brain sections. The infarct produced by MCA occlusion was enlarged in the transgenics (+32 ± 6%; n = 12; p < 0.05; t test). Measurement of APP by ELISA revealed that, although relatively high levels of Abeta were present in the brain of the transgenics (Abeta 1-40 = 80 ± 19 pmol/g; n = 6), there were no differences between ischemic and nonischemic hemispheres (p > 0.05). The reduction in cerebral blood flow produced by MCA occlusion at the periphery of the ischemic territory was more pronounced in APP transgenics (-42 ± 8%; n = 9) than in controls (-20 ± 8%; n = 9). Furthermore, the vasodilatation produced by neocortical application of the endothelium-dependent vasodilator acetylcholine (10 µM) was reduced by 82 ± 5% (n = 8; p < 0.05) in APP transgenics. The data demonstrate that APP overexpression increases the susceptibility of the brain to ischemic injury. The effect is likely to involve the Abeta -induced disturbance in endothelium-dependent vascular reactivity that leads to more severe ischemia in regions at risk for infarction. The cerebral vascular actions of peptides deriving from APP metabolism may play a role in the pathogenic effects of APP.

Key words: middle cerebral artery; Alzheimer's disease; cerebral ischemia; stroke; cerebral blood flow; transgenic mice




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