Alzheimer's disease ( AD) has been recently associated with vascular risk factors. beta-amyloid peptides (AbetaP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AbetaP is able to induce endothelial dysfunction, and this effect may represent the link between vascular and neuronal pathophysiological factors involved in AD. We aimed to clarify the molecular mechanisms underlying globular AbetaP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AbetaP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in beta-amyloid toxicity. More important, we have demonstrated that globular AbetaP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AbetaP enhances eNOS phosphorylation on threonine 495 and serine 116 and reduces acetylcholine-induced phosphorylation on serine 1177. Such an effect depends on a PKC signaling pathway, as suggested by its phosphorylation on serine 660. In fact, selective inhibition of the calcium-dependent group of PKC is able to rescue beta-amyloid-induced alteration of eNOS phosphorylation, NO production, and endothelial vasorelaxation. The activation of these Ca2+-dependent pathways is probably due to the ability of AbetaP to evoke Ca2+ leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AbetaP-induced endothelial NO dysfunction can be attributed to an alteration of intracellular Ca2+ homeostasis, which could lead to the activation of calcium-dependent group of PKC with a consequent change of the eNOS phosphorylation pattern. These mechanisms could contribute to shed further light on the toxic effect of beta-amyloid in vascular tissues.
Mechanisms of soluble beta-amyloid impairment of endothelial function / M. T., Gentile; C., Vecchione; A., Maffei; A., Aretini; G., Marino; R., Poulet; L., Capobianco; G., Selvetella; Lembo, Giuseppe. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 279:46(2004), pp. 48135-48142.
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|Titolo:||Mechanisms of soluble beta-amyloid impairment of endothelial function|
|Data di pubblicazione:||2004|
|Citazione:||Mechanisms of soluble beta-amyloid impairment of endothelial function / M. T., Gentile; C., Vecchione; A., Maffei; A., Aretini; G., Marino; R., Poulet; L., Capobianco; G., Selvetella; Lembo, Giuseppe. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 279:46(2004), pp. 48135-48142.|
|Appartiene alla tipologia:||01a Articolo in rivista|