An early specific cell-cell interaction occurs in the production of beta-amyloid in cell cultures.

We have earlier proposed that a cell-cell interaction, mediated by the specific binding of molecules of the beta-amyloid precursor protein (beta-APP) on one cell surface with molecules of presenilin (PS) on the other cell surface, is a required initial step in the ultimate production of beta-amyloid (Abeta) from beta-APP. Abeta is widely believed to be the neurotoxic agent in Alzheimer's disease. In this paper, we test this proposal by modifying cells to express surface beta-APP but no PS, and other cells to express surface PS but no beta-APP. Coculturing these two cell populations at appropriate cell densities produces substantial amounts of Abeta that appear both in cell extracts and culture media. Such Abeta production could occur only if the two cell types interacted with one another to provide the beta-APP and the PS required for the generation of Abeta. The addition to the coculture, from the start, of the soluble specific N-terminal domain of the appropriate PS significantly reduces the amount of Abeta produced. These and related experiments, therefore, suggest a very different mechanism for Abeta production than the one that is currently widely accepted.