TY - JOUR T1 - Increased Susceptibility to Ischemic Brain Damage in Transgenic Mice Overexpressing the Amyloid Precursor Protein JF - The Journal of Neuroscience JO - J. Neurosci. SP - 7655 LP - 7661 DO - 10.1523/JNEUROSCI.17-20-07655.1997 VL - 17 IS - 20 AU - Fangyi Zhang AU - Chris Eckman AU - Steven Younkin AU - Karen K. Hsiao AU - Costantino Iadecola Y1 - 1997/10/15 UR - http://www.jneurosci.org/content/17/20/7655.abstract N2 - 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 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. ER -