beta -Amyloid peptides enhance binding of the calcium mobilising second 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-NH sub(2)) 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 sub(3)) and inositol(1,3,4,5)-tetrakisphosphate (Ins(1,3,4,5)P sub(4)) to their receptor sites in rat cerebral cortical membranes. All three peptides gave statistically significant dose-dependent increases in both [ super(3)H]Ins(1,4,5)P sub(3) and [ super(3)H]Ins(1,3,4,5)P sub(4) binding. A beta -(1-40) and A beta -(25-35-NH sub(2)) enhanced [ super(3)H]Ins(1,4,5)P sub(3) and [ super(3)H]Ins(1,3,4,5)P sub(4) binding to a similar extent. In comparison, A beta -(25-35-COOH) gave much greater enhancements of [ super(3)H]Ins(1,4,5)P sub(3) and [ super(3)H]Ins(1,3,4,5)P sub(4) binding. However, a component of the latter appeared to be due to the formation of pelletable A beta -(25-35-COOH)/[ super(3)H]Ins(1,3,4,5)P sub(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 [ super(3)H]Ins(1,4,5)P sub(3) and [ super(3)H]Ins(1,3,4,5)P sub(4) receptor sites.