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

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Abstract

The amyloid β-protein (Aβ) is an approximately 4 kD secreted protein normally found in human plasma and cerebrospinal fluid. Aβ is invariably deposited as insoluble amyloid fibrils in the brains of patients with Alzheimer's disease (AD), and there is increasing evidence that Aβ deposition plays an important role in AD pathogenesis. Aβ is released from the larger β-amyloid precursor protein (βAPP) through cleavage on the amino and carboxyl side of Aβ by proteolytic activities referred to as β and γ secretase, respectively. βAPP is also cleaved at Aβ16 by a third protease, α secretase, which may prevent amyloid deposition by bisecting the Aβ 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 βAPP fragments (sAPP) in cultured cells. In this study, we extended our studies by analysis of Aβ40 and Aβ42 and report that in a human neuroblastoma cell line tacrine reduced the levels of total Aβ, Aβ40 and Aβ42 in addition to sAPP. These inhibitory results cannot be attributed to a reduction in total βAPP synthesis as tacrine treatment did not cause a significant change in the rate of βAPP 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 βAPP by alterations in βAPP 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 βAPP processing as well as by its effects on the cholinergic pathway.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalMolecular Brain Research
Volume62
Issue number2
DOIs
StatePublished - Nov 26 1998

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Keywords

  • β- Peptide
  • β-Amyloid precursor protein
  • Alzheimer's disease
  • Anticholinesterase
  • Neuroblastoma cell
  • Protein processing
  • Protein transport
  • THA

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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