Reversibility of the effect of tacrine on the secretion of the beta-amyloid precursor protein in cultured cells.

The amyloid beta-protein (A beta) of Alzheimer's disease is derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Two secretory proteolytic pathways are involved in the metabolism of beta APP. The major pathway involves cleavage within the A beta sequence and generates carboxyl-truncated derivatives of beta APP which are secreted into the conditioned medium of cells. The minor 'amyloidogenic' pathway results in the production of A beta. Here, cell cultures were used to examine the metabolism of beta APP by tacrine, a centrally active cholinesterase inhibitor reported to improve cognitive deficits. Treatment with tacrine in cells resulted in the drastic inhibition of secretion of the major isoforms of beta APP into the medium. The effect of tacrine can be reversed by washing away the drug from the cells. Treatment with tacrine did not change the level of either HSP-70 or LDH. Thus, the inhibitory effect of tacrine on the secretion of beta APP was not due to the permanent damage or loss of cells as normal release of beta APP could be restored when the drug was washed away.