BETA-AMYLOID PEPTIDES ENHANCE BINDING OF THE CALCIUM MOBILIZING 2ND MESSENGERS, INOSITOL(1,4,5)TRISPHOSPHATE AND INOSITOL(1,3,4,5)TETRAKISPHOSPHATE TO THEIR RECEPTOR-SITES IN RAT CORTICAL MEMBRANES

We studied the effects of the beta-amyloid (A beta) peptides A beta-(1-40), A beta-(25-35-NH2) and A beta-(25-35-COOH) on binding of the phosphoinositide derived, calcium mobilising, second messengers inositol(1,4,5)-trisphosphate (Ins(1,4,5)P-3) and inositol(1,3,4,5)-tetrakisphosphate (Ins(1,3,4,5)P-4) to their receptor sites in rat cerebral cortical membranes. All three peptides gave statistically significant dose-dependent increases in both [H-3]Ins(1,4,5)P-3 and [H-3]Ins(1,3,4,5)P-4 binding. A beta-(1-40) and A beta-(25-35-NH2) enhanced [H-3]Ins(1,4,5)P-3 and [H-3]Ins(1,3,4,5)P-4 binding to a similar extent. In comparison, A beta-(25-35-COOH) gave much greater enhancements of [H-3]Ins(1,4,5)P-3 and [H-3]Ins(1,3,4,5)P-4 binding. However, a component of the latter appeared to be due to the formation of pelletable A beta-(25-35-COOH)/[H-3]Ins(1,3,4,5)P-4 aggregates, that occurred in the absence of membranes. These results raise the possibility that A beta affects calcium homeostasis by a direct action on [H-3]Ins(1,4,5)P-3 and [H-3]Ins(1,3,4,5)P-4 receptor sites.