Effect of ionophores on the processing of the beta-amyloid precursor protein in different cell lines.
1. Alzheimer's disease is characterized by the deposition in the brain of extracellular amyloid plaques and vascular deposits consisting mostly of amyloid beta-peptide (A beta). A beta, a polypeptide of 39-43 amino acids (M(r), approximately 4 kDa), is derived proteolytically from a family of proteins of 695-770 amino acids (M(r), approximately 110-140 kDa) called beta-amyloid precursor protein (beta APP). 2. beta APP, an integral membrane glycoprotein, is extensively posttranslationally modified within the endoplasmic reticulum (ER) and various Golgi compartments. beta APP is cleaved by proteases in either the trans-Golgi network or the post-Golgi apparatus and then secreted as a truncated soluble form into the conditioned media of cultured cells and cerebrospinal fluid samples from human subjects. beta APP can be processed either by an antiamyloidogenic secretory pathway or by an endosomal/lysosomal pathway. 3. I studied the effect of two ionophores on the processing of beta APP in cultured cells. Monensin and, in some cases, ammonium chloride increase the intracellular accumulation of beta APP in several cell lines and may alter its processing. Monensin, which had the most consistent effects, also inhibited secretion of beta APP in a differentiated (growth factor mediated) cell line. Nigericin, with greater K+ selectivity, was less able to alter the accumulation and possible processing of the protein. 4. These results suggest that the increase in the accumulation of intracellular beta APP observed after treating cells with ionophores has some specificity. The selective effect of these ionophores on the metabolism of beta APP may provide a model system to analyze the pathways for studying maturation, secretion, and degradation of beta APP.
Lahiri
D K
DK
Department of Psychiatry, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA.
D000643:Ammonium Chloride / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005910:Glioma / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology*; D008985:Monensin / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D009550:Nigericin / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D007476:Ionophores; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D000643:Ammonium Chloride; D016222:Fibroblast Growth Factor 2; D008985:Monensin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D009550:Nigericin