Mechanisms of soluble β-amyloid impairment of endothelial function

Maria Teresa Gentile, Carmine Vecchione, Angelo Maffei, Alessandra Aretini, Gennaro Marino, Roberta Poulet, Loredana Capobianco, Giulio Selvetella, Giuseppe Lembot

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Alzheimer's disease (AD) has been recently associated with vascular risk factors. β-amyloid peptides (AβP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AβP 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 AβP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AβP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in β-amyloid toxicity. More important, we have demonstrated that globular AβP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AβP 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 β-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 AβP to evoke Ca2+ leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AβP-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 β-amyloid in vascular tissues.

Original languageEnglish
Pages (from-to)48135-48142
Number of pages8
JournalJournal of Biological Chemistry
Issue number46
Publication statusPublished - Nov 12 2004

ASJC Scopus subject areas

  • Biochemistry


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