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Effect of ionophores on the processing of theβ-amyloid precursor protein in different cell lines

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Summary

1. Alzheimer's disease is characterized by the deposition in the brain of extracellular amyloid plaques and vascular deposits consisting mostly of amyloidβ-peptide (Aβ). Aβ, a polypeptide of 39–43 amino acids (M r, ∼4 kDa), is derived proteolytically from a family of proteins of 695–770 amino acids (M r, ∼110–140 kDa) calledβ-amyloid precursor protein (βAPP).

2.βAPP, an integral membrane glycoprotein, is extensively posttranslationally modified within the endoplasmic reticulum (ER) and various Golgi compartments.βAPP 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.βAPP 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 ofβAPP in cultured cells. Monensin and, in some cases, ammonium chloride increase the intracellular accumulation ofβAPP in several cell lines and may alter its processing. Monensin, which had the most consistent effects, also inhibited secretion ofβAPP 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 intracellularβAPP observed after treating cells with ionophores has some specificity. The selective effect of these ionophores on the metabolism ofβAPP may provide a model system to analyze the pathways for studying maturation, secretion, and degradation ofβAPP.

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  1. Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of Psychiatry, Medical and Molecular Genetics, Indiana University School of Medicine, 791 Union Drive, 46202, Indianapolis, Indiana

    Debomoy K. Lahiri

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Lahiri, D.K. Effect of ionophores on the processing of theβ-amyloid precursor protein in different cell lines. Cell Mol Neurobiol 14, 297–313 (1994). https://doi.org/10.1007/BF02088713

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