Ann N Y Acad Sci. 2002 Nov;977:65-76.
Proinflammatory and vasoactive
effects of Abeta in the cerebrovasculature.
Townsend KP, Obregon
D, Quadros
A, Patel N, Volmar
Ch, Paris D, Mullan
M.
Department of Psychiatry, Roskamp Institute, University of South Florida, 3515
Fletcher Avenue, Tampa, FL 33613, USA.
Abeta peptides are thought to be critical molecules
in the pathophysiology of Alzheimer's disease (AD)
and are the major protein constituents of senile plaques. In most AD cases, Abeta peptides also form some deposits in the cerebrovasculature, leading to cerebral amyloid
angiopathy and hemorrhagic stroke. Regional cerebral hypoperfusion is one of the earlier clinical manifestations
in both the sporadic and familial forms of AD. In addition, a variety of
vascular risk factors of different etiologies (for instance, diabetes,
hypertension, high cholesterol level, atherosclerosis, and smoking) constitute
risk factors for AD as well, suggesting that functional vascular abnormalities
may contribute to AD pathology. We studied the effect of Abeta
on constrictor responses elicited by endothelin-1 in isolated human cerebral
arteries collected following rapid autopsies. We report that freshly solubilized Abeta potentiates endothelin-1-induced vasoconstriction in
isolated human middle cerebral and basilar arteries. The vasoconstriction
elicited by Abeta in these large human cerebral
arteries appears to be completely antagonized by NS-398, a selective
cyclooxygenase-2 inhibitor, or by SB202190, a specific p38 mitogen-activated
protein kinase inhibitor, suggesting that Abeta vasoactivity is mediated
via the stimulation of a proinflammatory pathway. In
addition, a similar proinflammatory response appears
to be mediated by Abeta in isolated human brain microvessels, resulting in an increased production of
prostaglandin E(2) and F(2alpha). Using a scanner
laser Doppler imager, we show a progressive decline with aging in cortical
perfusion level in transgenic APPsw mice (line 2576)
compared with age-matched control littermates. The relation between the acute proinflammatory and vasoactive
properties of Abeta and the chronic progressive hypoperfusion seen in AD (and transgenic models thereof) is
yet to be elucidated.
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Keywords: Proinflammatory, vasoactive, Abeta, cerebrovasculature, Annals of the New York Academy of Sciences