Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

1 Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; 2 Mayo Clinic, Jacksonville, Florida 32224; and 3 McLaughlin Research Institute, Great Falls, Montana 59405 The amyloid- (A ) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A . Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP( ) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP( ) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia. Alzheimer's disease; cerebral blood flow; endothelium-dependent vasodilation