Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein

Fangyi Zhang, Chris Eckman, Steven Younkin, Karen K. Hsiao, Costantino Iadecola

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We studied the role of the amyloid precursor protein (APP) in ischemic brain damage using transgenic mice overexpressing APR. The middle cerebral artery (MCA) was occluded in FVB/N mice expressing APP695, SWE (Swedish mutation) and in non-transgenic 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 Aβ were present in the brain of the transgenics (Aβ1-40 = 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 Aβ-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.

Original languageEnglish (US)
Pages (from-to)7655-7661
Number of pages7
JournalJournal of Neuroscience
Issue number20
StatePublished - 1997


  • Alzheimer's disease
  • Cerebral blood flow
  • Cerebral ischemia
  • Middle cerebral artery
  • Stroke
  • Transgenic mice


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