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 pho sphoinositide derived, calcium mobilising, second messengers inositol( 1,4,5)-trisphosphate (Ins(1,4,5)P-3) and inositol(1,3,4,5)-tetrakispho sphate (Ins(1,3,4,5)P-4) to their receptor sites in rat cerebral corti cal 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 compari son, 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 o f membranes. These results raise the possibility that A beta affects c alcium homeostasis by a direct action on [H-3]Ins(1,4,5)P-3 and [H-3]I ns(1,3,4,5)P-4 receptor sites.