Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

Kiyoshi Niwa, Ken Kazama, Linda Younkin, Steven G Younkin, George A. Carlson, Costantino Iadecola

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

The amyloid-β (Aβ) 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 Aβ. 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 Aβ concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus Aβ 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume283
Issue number1 52-1
StatePublished - 2002

Fingerprint

Cerebrovascular Circulation
Amyloid beta-Protein Precursor
Homeostasis
Serum Amyloid A Protein
Arterial Pressure
Alzheimer Disease
Exsanguination
Endothelium-Dependent Relaxing Factors
Laser-Doppler Flowmetry
Brain
Phenylephrine
Amyloid
Intravenous Infusions
Vasodilation
Transgenic Mice
Endothelium
Perfusion
Peptides

Keywords

  • Alzheimer's disease
  • Cerebral blood flow
  • Endothelium-dependent vasodilation

ASJC Scopus subject areas

  • Physiology

Cite this

Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. / Niwa, Kiyoshi; Kazama, Ken; Younkin, Linda; Younkin, Steven G; Carlson, George A.; Iadecola, Costantino.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 283, No. 1 52-1, 2002.

Research output: Contribution to journalArticle

Niwa, Kiyoshi ; Kazama, Ken ; Younkin, Linda ; Younkin, Steven G ; Carlson, George A. ; Iadecola, Costantino. / Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. In: American Journal of Physiology - Heart and Circulatory Physiology. 2002 ; Vol. 283, No. 1 52-1.
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