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J. Biol. Chem., Vol. 279, Issue 46, 48135-48142, November 12, 2004

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Mechanisms of Soluble -Amyloid Impairment of Endothelial Function^*

Maria Teresa Gentile||, Carmine Vecchione, Angelo Maffei, Alessandra Aretini, Gennaro Marino, Roberta Poulet, Loredana Capobianco, Giulio Selvetella, and Giuseppe Lembo¶||

From the Department of Angio-Cardio-Neurology, IRCCS "NEUROMED," Pozzilli (IS) and the Department of Experimental Medicine and Pathology, "La Sapienza" University, Rome 86077, Italy and the ^||Excellence Centre for Cardiovascular Disease, Second University of Naples, Naples 80100, Rome

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

Received for publication, July 1, 2004 , and in revised form, July 29, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: IRCCS Neuromed, Località Camerelle, 86077 Pozzilli (IS), Italy. Tel.: 39-0865-915244; Fax: 39-0865-927575; E-mail: lembo{at}neuromed.it.

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