Mechanisms underlying the vascular activity of beta-amyloid protein fragment (beta A(4)25-35) at the level of skin microvasculature.
Deposition of beta-amyloid protein (beta A4) in extracellular senile plaques is a pathologic hallmark of Alzheimer's disease (AD). The neurotoxic effect of beta A4 has been ascribed to a discrete 11-amino acid internal sequence (beta A(4)25-35). 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 beta A(4)25-35. Our previous studies, in vivo, in aged rats showed that beta A(4)25-35 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 beta A(4)25-35 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 beta A(4)25-35 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 beta A(4)25-35 were examined using the NO synthase inhibitor, NG-nitro-L-arginine (L-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 beta A(4)25-35 (10 microM) induced a VC effect and inhibited the subsequent VD response to BK (10 microM) and 5-HT (1 microM) in a similar fashion to its effect on SP (1 microM). In the presence of L-NOARG (100 microM), the VD effect of SP was reduced and further attenuated after perfusion of beta A(4)25-35. Superfusion of the blister base with BQ-123 (10 microM) or BIM (1 microM) prior to and during perfusion with beta A(4)25-35 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, beta A(4)25-35, 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 beta A(4)25-35. The relevance of these mechanisms to those underlying the pathological effects of beta A4 and their significance in AD remains to be determined.
Khalil
Z
Z
National Ageing Research Institute, North West hospital, Parkville, Vic., Australia.
Chen
H
H
Helme
R D
RD
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001768:Blister; D001920:Bradykinin / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D017078:Laser-Doppler Flowmetry; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C074636:amyloid beta-protein (25-35); D019335:Nitroarginine; D012701:Serotonin; D011493:Protein Kinase C; C088060:bisindolylmaleimide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D001920:Bradykinin