title: Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules.
abstract: Alzheimer's disease is characterized by the extracellular deposition in the brain and its blood vessels of insoluble aggregates of the amyloid beta peptide (A beta). This peptide is derived from a large integral membrane protein, the beta-amyloid precursor protein (beta APP), by proteolytic processing. The A beta has previously been found only in the brains of patients with Alzheimer's disease or advanced aging. We describe here the finding that A beta is produced continuously by normal processing in tissue culture cells. A beta and closely related peptides were identified in the media of cells transfected with cDNAs coding for beta APP in a variety of cell lines and primary tissue cultured cells. The identity of these peptides was confirmed by epitope mapping and radiosequencing. Peptides of a molecular weight of approximately 3 and approximately 4 kDa are described. The 4 kDa range contains mostly the A beta and two related peptides starting N-terminal to the beginning of A beta. In the 3 kDa range, the majority of peptides start at the secretase site; in addition, two longer peptides were found starting at amino acid F(4) and E(11) of the A beta sequence. To identify the processing pathways which lead to the secretion of these peptides, we used a variety of drugs known to interfere with certain cell biological pathways. We conclude that lysosomes may not play a predominant role in the formation of 3 and 4 kDa peptides. We show that an acidic environment is necessary to create the N-terminus of the A beta and postulate that alternative secretory cleavage might result in the formation of the N-terminus of A beta and related peptides. This cleavage takes place either in the late Golgi, at the cell-surface or in early endosomes, but not in lysosomes. The N-terminus of most of the 3 kDa peptides is created by secretory cleavage on the cell surface or within late Golgi.
authors.affiliation: Department of Neurology and Program in Neuroscience, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: C
authors.initials: C
authors.lastname: Haass
authors.forename: A Y
authors.initials: AY
authors.lastname: Hung
authors.forename: M G
authors.initials: MG
authors.lastname: Schlossmacher
authors.forename: T
authors.initials: T
authors.lastname: Oltersdorf
authors.forename: D B
authors.initials: DB
authors.lastname: Teplow
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000595:Amino Acid Sequence; D000643:Ammonium Chloride / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D020126:Brefeldin A; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007668:Kidney; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D008985:Monensin / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003517:Cyclopentanes; D007976:Leupeptins; D000643:Ammonium Chloride; D020126:Brefeldin A; D008985:Monensin; C032854:leupeptin; D015739:Nocodazole; D003078:Colchicine