Effects of cholinesterase inhibitors on the secretion of beta-amyloid precursor protein in cell cultures.
One of the main characteristics of Alzheimer's disease (AD) is the cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). The majority of beta APP is processed by either a secretory of lysosomal/endosomal pathway. Carboxyl-truncated soluble derivatives of beta APP (sAPP) are generated by the proteolytic processing of full-length beta APP by either alpha- or beta-secretase enzyme. Our objective is to determine whether the processing of beta APP can be regulated by cholinesterase inhibitors, some of which were shown to produce a moderate improvement in memory and cognitive functions in patients with Alzheimer's disease. Here we have analyzed the levels of sAPP derivatives in cultured cells treated with different drugs by immunoblotting samples of conditioned media. The immunoreactive protein bands were developed by probing with the monoclonal antibody 22C11. Treating neuroblastoma, pheochromocytoma and fibroblast cells with high dose of either 3,4-diaminopyridine, metrifonate, or physostigmine did not inhibit the secretion of sAPP. Treating glioblastoma with either 3,4-diaminopyridine or metrifonate showed an increase in secretion of sAPP. However, treatment of cells with tacrine reduced release of sAPP in conditioned media of cell lines studied. The difference in action of metrifonate, physostigmine, and tacrine on beta APP is independent of their anticholinesterase activities. Our results suggests that noncatalytic functions of cholinesterase inhibitors can be utilized to alter the metabolism of beta APP, which might in turn affect the process of deposition of A beta, a key component of the cerebrovascular amyloid detected in AD.
Lahiri
D K
DK
Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA. DLAHIRI@INDYVAX.IUPUI.EDU
Farlow
M R
MR
Nurnberger
J I
JI
Greig
N H
NH
D015761:4-Aminopyridine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077770:Amifampridine; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D016716:PC12 Cells; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D013619:Tacrine / Q000494:pharmacology; D014236:Trichlorfon / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D010830:Physostigmine; D015761:4-Aminopyridine; D014236:Trichlorfon; D000077770:Amifampridine