The secretion of amyloid β-peptides is inhibited in the tacrine-treated human neuroblastoma cells

The amyloid beta-protein (A beta) is an approximately 4 kD secreted protein normally found in human plasma and cerebrospinal fluid. A beta is invariably deposited as insoluble amyloid fibrils in the brains of patients with Alzheimer's disease (AD), and there is increasing evidence that A beta deposition plays an important role in AD pathogenesis. A beta is released from the larger beta-amyloid precursor protein (beta APP) through cleavage on the amino and carboxyl side of A beta by proteolytic activities referred to as beta and gamma secretase, respectively. beta APP is also cleaved at A beta 16 by a third protease, alpha secretase, which may prevent amyloid deposition by bisecting the A beta peptide. Tacrine, a cholinesterase inhibitor, has been shown to improve memory and cognitive functions in some patients with AD, and we have previously demonstrated that it significantly reduces the levels of the secretion of soluble beta APP fragments (sAPP) in cultured cells. In this study, we extended our studies by analysis of A beta 40 and A beta 42 and report that in a human neuroblastoma cell line tacrine reduced the levels of total A beta, A beta 40 and A beta 42 in addition to sAPP. These inhibitory results cannot be attributed to a reduction in total beta APP synthesis as tacrine treatment did not cause a significant change in the rate of beta APP synthesis. Furthermore, significant toxicity was not observed in tacrine-treated cultures as determined by analysis of lactate dehydrogenase (LDH) in the conditioned media. Taken together, these results suggest that tacrine affects the processing of beta APP by alterations in beta APP trafficking and/or increased intracellular proteolysis. This study raises the possibility that tacrine may aid in the treatment of AD due to its effects on PAPP processing as well as by its effects on the cholinergic pathway. (C) 1998 Elsevier Science B.V. All rights reserved.