Deposition of β-amyloid protein (βA4) in extracellular senile plaques is a pathologic hallmark of Alzheimer's disease (AD). The neurotoxic effect of βA4has been ascribed to a discrete 11-amino acid internal sequence (βA425-35). Substance P (SP) has been found to be depleted in the brain of AD patients while its presence was found to protect against the neurodegenerative effect of βA425-35. Our previous studies, in vivo, in aged rats showed that βA425-35 exhibits a potent vasoconstrictor (VC) effect in rat skin microvasculature and can prevent SP but not calcitonin gene-related peptide (CGRP) from inducing a vasodilator (VD) response. It was postulated that βA425-35 might be interacting with SP at the level of the second messenger system via the phosphoinositide pathway. Using a blister model of inflammation in the rat hind footpad, we examined the ability of βA425-35 to modulate the vascular activity of bradykinin (BK) and serotonin (5-HT) which also activate the phosphoinositide pathway. In addition, the role of nitric oxide (NO), endothelin (ET, an endothelium-derived constrictor factor) and protein kinase C (PKC) in the vascular effects of βA425-35 were examined using the NO synthase inhibitor. N(G)-nitro-L-arginine (t-NOARG), the ET-receptor antagonist. BQ-123, and the PKC inhibitor, bisindolylmaleimide (BIM) respectively. Changes in microvascular blood flow were monitored using laser Doppler flowmetry and the area within the response curve measured. The results showed that βA425-35 (10 μM) induced a VC effect and inhibited the subsequent VD response to BK (10 μM) and 5-HT (1 μM) in a similar fashion to its effect on SP (1 μM). In the presence of L-NOARG (100 μM), the VD effect of SP was reduced and further attenuated after perfusion of βA425-35. Superfusion of the blister base with BQ-123 (10 μM) or BIM (1 μM) prior to and during perfusion with βA425-35 abolished its VC effect and allowed SP to induce a normal VD response in both young and old rats. Based on these results, we suggest that the vascular activity of the active fragment, βA425-35, is mediated by ET via activation of PKC. This study provides new findings which may help to elucidate the signal transduction mechanisms involved in the vascular activity of βA425-35. The relevance of these mechanisms to those underlying the pathological effects of βA4and their significance in AD remains to be determined.
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