Proinflammatory and vasoactive effects of Abeta in the cerebrovasculature.
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.
Townsend
K P
KP
Department of Psychiatry, Roskamp Institute, University of South Florida, 3515 Fletcher Avenue, Tampa, FL 33613, USA.
Obregon
D
D
Quadros
A
A
Patel
N
N
Volmar
Ch
Ch
Paris
D
D
Mullan
M
M
D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D012307:Risk Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D005609:Free Radicals