Department of Psychiatry, Roskamp Institute, University of South Florida, Tampa, Florida 33613, USA
Address for correspondence: D. Paris. Department of Psychiatry, Roskamp Institute, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613. Voice: 813-974-3722; fax: 813-974-3915.
dparis{at}hsc.usf.edu
Ann. N.Y. Acad. Sci. 977: 65-76 (2002).
Aß 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,
Aß 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 Aß
on constrictor responses elicited by endothelin-1 in isolated
human cerebral arteries collected following rapid autopsies.
We report that freshly solubilized Aß potentiates
endothelin-1-induced vasoconstriction in isolated human middle
cerebral and basilar arteries. The vasoconstriction elicited
by Aß 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 Aß vasoactivity
is mediated via the stimulation of a proinflammatory pathway.
In addition, a similar proinflammatory response appears to be
mediated by Aß in isolated human brain microvessels,
resulting in an increased production of prostaglandin E
2 and
F
2
. 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 Aß and the chronic progressive hypoperfusion
seen in AD (and transgenic models thereof) is yet to be elucidated.
