CARBOXYL-TERMINAL PEPTIDE OF BETA-AMYLOID PRECURSOR PROTEIN BLOCKS INOSITOL 1,4,5-TRISPHOSPHATE-SENSITIVE CA2+ RELEASE IN XENOPUS LAEVIS OOCYTES.

Abstract

The effects of Alzheimer's disease-related amyloidogenic peptides on inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization were examined in Xenopus laevis oocytes. Intracellular Ca2+ was monitored by electrophysiological measurement of the endogenous Ca2+-activated Cl- current. Application of a hyperpolarizing pulse released intracellular Ca2+ in oocytes primed by pre-injection of a non-metabolizable inositol 1,4,5-trisphosphate analogue. The carboxyl terminus of the amyloid precursor protein inhibited inositol 1,4,5-trisphosphate receptor-mediated intracellular Ca2+ release in a dose-dependent manner. Equimolar beta-amyloid peptides Abeta(1-40) or Abeta(1-42) had no effect, and whereas a truncated carboxyl terminus lacking the Abeta domain was equipotent to the full-length one, a carboxyl terminus fragment lacking the NPTY sequence was less effective than the full-length fragment. The inhibition induced by the carboxyl terminus was not associated with the block of the Ca2+-dependent Cl- channel itself or compromised Ca2+ influx. We conclude that the carboxyl terminus of the amyloid precursor protein inhibits inositol 1,4,5-trisphosphate-sensitive Ca2+ release and could thus disrupt Ca2+ homeostasis and that the carboxyl terminus is much more effective than the P-amyloid fragments used. By perturbing the coupling of inositol 1,4,5-trisphosphate and Ca2+ release, the carboxyl terminus of the amyloid precursor protein can potentially be involved in inducing the neural toxicity characteristic of Alzheimer's disease.