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

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

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
Volume17
Issue number20
DOIs
StatePublished - 1997

Keywords

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

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