Processing of the amyloid protein precursor to potentially amyloidogenic derivatives.
The approximately 120-kilodalton amyloid beta protein precursor (beta APP) is processed into a complex set of 8- to 12-kilodalton carboxyl-terminal derivatives that includes potentially amyloidogenic forms with the approximately 4-kilodalton amyloid beta protein (beta AP) at or near their amino terminus. In order to determine if these derivatives are processed in a secretory pathway or by the endosomal-lysosomal system, (i) deletion mutants that produce the normal set of carboxyl-terminal derivatives and shortened secreted derivatives were analyzed and (ii) the effect of inhibitors of endosomal-lysosomal processing was examined. In the secretory pathway, cleavage of the beta APP occurs at a single site within the beta AP to generate one secreted derivative and one nonamyloidogenic carboxyl-terminal fragment, whereas, in the endosomal-lysosomal system, a complex set of carboxyl-terminal derivatives is produced that includes the potentially amyloidogenic forms.
Golde
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TE
Division of Neuropathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
Estus
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S
Younkin
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LH
Selkoe
D J
DJ
Younkin
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SG
D000643:Ammonium Chloride / Q000494:pharmacology; D000682:Amyloid / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010446:Peptide Fragments / Q000378:metabolism*; D014162:Transfection
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D007976:Leupeptins; D010446:Peptide Fragments; D000643:Ammonium Chloride; D010450:Endopeptidases; C032854:leupeptin