Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein.
The amyloid-beta (A beta) 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 beta. 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 beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta 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.
Niwa
Kiyoshi
K
Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Kazama
Ken
K
Younkin
Linda
L
Younkin
Steven G
SG
Carlson
George A
GA
Iadecola
Costantino
C
D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D006470:Hemorrhage / Q000503:physiopathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000098:blood supply / Q000503:physiopathology*; D019076:Transgenes; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology*
D016564:Amyloid beta-Protein Precursor; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D001920:Bradykinin