title: Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein.
abstract: 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 (Abeta1-40 = 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 microM) 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.
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Eckman
authors.forename: S
authors.initials: S
authors.lastname: Younkin
authors.forename: K K
authors.initials: KK
authors.lastname: Hsiao
authors.forename: C
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001925:Brain Damage, Chronic / Q000209:etiology*; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor