Amyloid beta-peptides A beta(1-40) and A beta(1-42) induce cerebrovascularendothelial dysfunction

Citation
T. Thomas et al., Amyloid beta-peptides A beta(1-40) and A beta(1-42) induce cerebrovascularendothelial dysfunction, ALZHEIM REP, 1(1), 1998, pp. 17-24
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurology
Journal title
ALZHEIMERS REPORTS
ISSN journal
1461-6130 → ACNP
Volume
1
Issue
1
Year of publication
1998
Pages
17 - 24
Database
ISI
SICI code
1461-6130(199801)1:1<17:ABABAA>2.0.ZU;2-R
Abstract
Cerebrovascular deposits of amyloid beta-peptides (A beta) leading to amylo id angiopathy is a prominent feature of Alzheimer's disease (AD). But cereb rovascular lesions in AD are usually neglected and the focus of most recent research efforts has been on genetic factors and the neurotoxicity of A be ta. Recently we demonstrated that in vitro or in vivo application of A beta produced vascular endothelial damage and an inflammatory response through the production of free radicals. To probe the differential cerebrovascular actions of the major A beta-peptides used in AD research, we used an in vit ro paradigm in which low concentrations of soluble A beta-peptides were int roduced into a medium containing physiologically viable bovine cerebral art eries. The major endogenous C-terminal variants of A beta (A beta(1-40) or A beta(1-42)) induced characteristic features of endothelial dysfunction su ch as enhanced vasoconstriction and diminished vasodilation. The synthetic neurotoxic peptide A beta(25-35) had no significant effect on the vascular endothelium. This illustrates that the vascular actions of A beta are disti nct from the previously reported neurotoxic properties of these peptides. T he antioxidants superoxide dismutase and n-tertiary-butyl-alpha-phenylnitro ne (PBN) protected the endothelium from A beta toxicity suggestive of an ox ygen radical mediated phenomenon. If uncontrolled, the endothelial damage c an trigger neurodegeneration in circumscribed regions by ischemic or inflam matory mechanisms. Drugs specifically targeting A beta(1-42) may not accord the desired protection against amyloid toxicity as A beta(1-40) of cerebra l or peripheral origin can still induce deleterious effects of A beta. The possibility that A beta-induced vascular dysfunction may be an early event in the neurodegenerative process offers new avenues for therapy.