INCREASED SUSCEPTIBILITY TO ISCHEMIC BRAIN-DAMAGE IN TRANSGENIC MICE OVEREXPRESSING THE AMYLOID PRECURSOR PROTEIN

We studied the role of the amyloid precursor protein (APP) in ischemic brain damage using transgenic mice overexpressing APP. The middle cer ebral artery (MCA) was occluded in FVB/N mice expressing APP(695)SWE ( Swedish mutation) and in nontransgenic littermates. Infarct volume (cu bic millimeters) was assessed 24 hr later in thionin-stained brain sec tions. The infarct produced by MCA occlusion was enlarged in the trans genics (+32 +/- 6%; n = 12; p < 0.05; ttest). Measurement of APP by EL ISA revealed that, although relatively high revels of A beta were pres ent in the brain of the transgenics (A beta(1-40) = 80 +/- 19 pmol/g; n = 6), there were no differences between ischemic and nonischemic hem ispheres (p > 0.05). The reduction in cerebral blood flow produced by MCA occlusion at the periphery of the ischemic territory was more pron ounced 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 mu M) was reduced by 82 +/- 5% (n = 8; p < 0.05) in APP transgenics. The data demonstrate that APP overexpression increases the susceptibil ity of the brain to ischemic injury. The effect is likely to involve t he A beta-induced disturbance in endothelium-dependent vascular reacti vity that leads to more severe ischemia in regions at risk for infarct ion. The cerebral vascular actions of peptides deriving from APP metab olism may play a role in the pathogenic effects of APP.