THE SECRETION OF AMYLOID BETA-PEPTIDES IS INHIBITED IN THE TACRINE-TREATED HUMAN NEUROBLASTOMA-CELLS

The amyloid beta-protein (A beta) is an approximately 4 kD secreted pr otein normally found in human plasma and cerebrospinal fluid. A beta i s invariably deposited as insoluble amyloid fibrils in the brains of p atients with Alzheimer's disease (AD), and there is increasing evidenc e 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 pro teolytic activities referred to as beta and gamma secretase, respectiv ely. beta APP is also cleaved at A beta 16 by a third protease, alpha secretase, which may prevent amyloid deposition by bisecting the A bet a peptide. Tacrine, a cholinesterase inhibitor, has been shown to impr ove memory and cognitive functions in some patients with AD, and we ha ve 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 re duced 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 signi ficant change in the rate of beta APP synthesis. Furthermore, signific ant toxicity was not observed in tacrine-treated cultures as determine d by analysis of lactate dehydrogenase (LDH) in the conditioned media. Taken together, these results suggest that tacrine affects the proces sing of beta APP by alterations in beta APP trafficking and/or increas ed intracellular proteolysis. This study raises the possibility that t acrine may aid in the treatment of AD due to its effects on PAPP proce ssing as well as by its effects on the cholinergic pathway. (C) 1998 E lsevier Science B.V. All rights reserved.