Neurol Res. 2003 Sep;25(6):642-51.
Vasoactive effects of A beta in
isolated human cerebrovessels and in a transgenic
mouse model of Alzheimer's disease: role of inflammation.
Paris D, Humphrey J, Quadros A, Patel N, Crescentini R,
Crawford F, Mullan M.
Roskamp Institute,
A beta peptides are the major protein constituents of Alzheimer's disease (AD)
senile plaques and also form some deposits in the cerebrovasculature
leading to cerebral amyloid angiopathy
and hemorrhagic stroke. Functional vascular abnormalities are one of the earlier
clinical manifestations in both sporadic and familial forms of AD. Most of the
cardiovascular risk factors (for instance, diabetes, hypertension, high
cholesterol levels, 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 A beta on
endothelin-1 induced vasoconstriction in isolated human cerebral arteries
collected following rapid autopsies. We report that freshly solubilized
A beta enhances endothelin-1 induced vasoconstriction in isolated human middle
cerebral and basilar arteries. The vasoactive effect
of A beta in these large human cerebral arteries is
inhibited by NS-398, a selective cyclooxygenase-2 inhibitor and by SB202190, a
specific p38 Mitogen Activated Protein Kinase inhibitor suggesting the involvement of a
pro-inflammatory pathway. Using a scanner laser Doppler imager, we observed
that cerebral blood flow is decreased in the double transgenic APPsw Alzheimer mouse (PS1/APPsw) compared to PS1
littermates and can be improved by chronic treatment with either NS-398 or
SB202190. Altogether, our data suggest a link between inflammation and the
compromised cerebral hemodynamics in AD.
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Keywords: Vasoactive, ABeta, cerebrovessels, Alzheimer’s disease, transgenic mouse, inflammation, Neurol Res