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 A(4)) in extracellular senile plaques is a pathologic hallmark of Alzheimer's disease (AD). The neu rotoxic effect of beta A(4) has been ascribed to a discrete 11-amino a cid internal sequence (beta A(4)25-35). Substance P (SP) has been foun d to be depleted in the brain of PLD patients while its presence was f ound 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 microvasc ulature and can prevent SP but not calcitonin gene-related peptide (CG RP) 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 mo del of inflammation in the rat hind footpad, we examined the ability o f 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 endoth elium-derived constrictor factor) and protein kinase C (PKC) in the va scular effects of beta A(4)25-35 were examined using the NO synthase i nhibitor, N-G-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 Dopple r flowmetry and the area within the response curve measured. The resul ts showed that beta A(4)25-35 (10 mu M) induced a VC effect and inhibi ted the subsequent VD response to BK (10 mu M) and 5-HT (1 mu M) in a similar fashion to its effect on SP (1 mu M). In the presence of L-NOA RG (100 mu M), the VD effect of SP was reduced and further attenuated after perfusion of beta A(4)25-35. Superfusion of the blister base wit h BQ-123 (10 mu M) or BIM (1 mu M) prior to and during perfusion with beta A(4)25-35 abolished its VC effect and allowed SP to induce a norm al 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 mechanism s involved in the vascular activity of beta A(4)25-35. The relevance o f these mechanisms to those underlying the pathological effects of bet a A(4) and their significance in AD remains to he determined.