Differential effect of tacrine and physostigmine on the secretion of the β-amyloid precursor protein in cell lines

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Abstract

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid β-peptide (Aβ) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (βAPP). Soluble derivatives of βAPP generated by the proteolytic processing of full-length βAPP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of βAPP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of βAPP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble βAPP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of βAPP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of βAPP compared to untreated cells. The effect of tacrine on the secretion of βAPP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of βAPP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.

Original languageEnglish
Pages (from-to)41-49
Number of pages9
JournalJournal of Molecular Neuroscience
Volume7
Issue number1
DOIs
StatePublished - Mar 1996

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Tacrine
Physostigmine
Amyloid beta-Protein Precursor
Cells
Cell Line
Conditioned Culture Medium
Cholinesterase Inhibitors
Alzheimer Disease
Derivatives
Staurosporine
Calcium Ionophores
Membrane Glycoproteins
Amyloid Plaques
Pheochromocytoma
Processing
Neuroblastoma
Immunoblotting
Amyloid
Neuroglia
Cognition

Keywords

  • β-amyloid precursor proteins
  • Alzheimer's disease
  • cholinergic agents
  • cholinesterase inhibitors
  • lysosomes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neuroscience(all)
  • Biochemistry
  • Genetics

Cite this

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title = "Differential effect of tacrine and physostigmine on the secretion of the β-amyloid precursor protein in cell lines",
abstract = "The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid β-peptide (Aβ) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (βAPP). Soluble derivatives of βAPP generated by the proteolytic processing of full-length βAPP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of βAPP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of βAPP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble βAPP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of βAPP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of βAPP compared to untreated cells. The effect of tacrine on the secretion of βAPP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of βAPP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.",
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N2 - The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid β-peptide (Aβ) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (βAPP). Soluble derivatives of βAPP generated by the proteolytic processing of full-length βAPP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of βAPP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of βAPP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble βAPP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of βAPP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of βAPP compared to untreated cells. The effect of tacrine on the secretion of βAPP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of βAPP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.

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