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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
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