Carboxyl-terminal Peptide of β-Amyloid Precursor Protein Blocks Inositol 1,4,5-Trisphosphate-sensitive Ca2+ Release in Xenopus laevis Oocytes

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 β-amyloid peptides Aβ1–40 or Aβ1–42 had no effect, and whereas a truncated carboxyl terminus lacking the Aβ 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 β-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.