AN AMYLOID PEPTIDE, BETA-A4 25-35, MIMICS THE FUNCTION OF SUBSTANCE-P ON MODULATION OF NICOTINE-EVOKED SECRETION AND DESENSITIZATION IN CULTURED BOVINE ADRENAL CHROMAFFIN CELLS

The amyloid protein (betaA4) is found in the CNS of patients with Alzheimer's disease; however, the pathogenic role of this protein is not known. In the present study, a peptide fragment of betaA4 (betaA4 25-35; Gly-Ser-Asn-Lys-Gly-Ala-Ile-Ile-Gly-Leu-Met-NH2), which contains the conserved C-terminal sequence of substance P (X-Gly-Leu-Met-NH2), and the neuropeptide substance P (SP) were examined for their ability to modulate nicotine-evoked secretion from cultured bovine adrenal chromaffin cells. Secretion of the released endogenous catecholamines was monitored by electrochemical detection after separation by HPLC. Secretion induced by 10(-5) M nicotine was inhibited by SP and betaA4 25-35. The IC50 of SP and betaA4 25-35 was 3 x 10(-6) and 3 x 10(-5) M, respectively. SP and betaA4 25-35 both protected against nicotinic receptor desensitization. However, betaA4 25-35 was approximately 10-fold less effective than SP in its protective effect. The present work shows that betaA4 25-35 can mimic the modulatory actions of SP on the nicotinic response of cultured bovine chromaffin cells, i.e., inhibition of the nicotinic response and protection against nicotinic desensitization. These modulatory actions may be associated with changes in nicotinic receptor levels reported to occur in Alzheimer's disease.