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| NORMAL CELLULAR PROCESSING OF THE BETA-AMYLOID PRECURSOR PROTEIN RESULTS IN THE SECRETION OF THE AMYLOID-BETA PEPTIDE AND RELATED MOLECULES |
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| Author(s): HAASS C, HUNG AY, SCHLOSSMACHER MG, OLTERSDORF T, TEPLOW DB, SELKOE DJ |
| Editor(s): Nitsch RM; Growdon JH; Corkin S; Wurtman RJ |
| Source: ALZHEIMERS DISEASE: AMYLOID PRECUSOR PROTEINS, SIGNAL TRANSDUCTION, AND NEURONAL TRANSPLANTATION Book Series: ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Volume: 695 Pages: 109-116 Published: 1993 |
| Times Cited: 38 References: 19 |
| 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 previousIy 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 similar to 3 and similar to 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 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. |
| Document Type: Proceedings Paper |
| Language: English |
| Reprint Address: HAASS, C (reprint author), HARVARD UNIV, SCH MED, DEPT NEUROL, BOSTON, MA 02115 USA |
Addresses:
1. HARVARD UNIV, SCH MED, PROGRAM NEUROSCI, BOSTON, MA 02115 USA
2. BRIGHAM & WOMENS HOSP, CTR NEUROL DIS, BOSTON, MA 02115 USA
3. ATHENA NEUROSCI INC, S SAN FRANCISCO, CA 94090 USA |
| Publisher: NEW YORK ACAD SCIENCES, 2 EAST 63RD ST, NEW YORK, NY 10021 |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: BZ92T |
| ISSN: 0077-8923 |
| ISBN: 0-89766-853-7 |
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