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Articles in PresS, published online ahead of print March 7, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00022.2002
Submitted on January 14, 2002
Accepted on March 4, 2002
1 Neurology, University of Minnesota, Minneapolis, MN, USA
2 Mayo Clinic Jacksonville, Jacksonville, FL, USA
3 McLaughlin Reseach Insitute, Great Falls, MT, USA
* To whom correspondence should be addressed. E-mail: iadec001{at}umn.edu.
The Aß peptide, 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 overexpressing APP and Aß. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP+ and APP- mice. MAP was elevated by i.v. infusion of phenylephrine and reduced by controlled exanguination. In APP- mice autoregulation was preserved. However, in APP+ mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain Aß concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus, Aß 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.
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