| Title: |
Increased Generation of Alternatively Cleaved β‐Amyloid Peptides in Cells Expressing Mutants of the Amyloid Precursor Protein Defective in Endocytosis |
| Authors: |
Cescato, Renzo; Dumermuth, Eric; Spiess, Martin; Paganetti, Paolo A. |
| Source: |
Journal of Neurochemistry ; volume 74, issue 3, page 1131-1139 ; ISSN 0022-3042 1471-4159 |
| Publisher Information: |
Wiley |
| Publication Year: |
2000 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
The subcellular location of the secretases processing the β‐amyloid precursor protein (APP) is not established yet. We analyzed the generation of the β‐amyloid peptide (Aβ) in human embryonic kidney 293 cell lines stably expressing wild‐type and noninternalizing mutants of human APP. APP lacking the entire cytoplasmic domain or with both tyrosine residues of the motif GYENPTY mutated to alanine showed at least fivefold reduced endocytosis. In these cell lines, the production of Aβ 1‐40 was substantially reduced, but accompanied by the appearance of two prominent alternative Aβ peptides differing at the amino‐termini. Based on antibody reactivity and mobility in high‐resolution gels in comparison with defined Aβ fragments, these peptides were identified as Aβ 3‐40 and Aβ 5‐40 . Notably, these alternative Aβ peptides were not generated when the APP mutants were retained in the early secretory pathway by treatment with brefeldin A. These results indicate that the alternative processing is the result of APP accumulation at the plasma membrane and provide evidence of distinct β‐secretase activities. Cleavage amino‐terminal to position 1 of Aβ occurs predominantly in endosomes, whereas the processing at positions 3 or 5 takes place at the plasma membrane. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1046/j.1471-4159.2000.741131.x |
| Availability: |
http://dx.doi.org/10.1046/j.1471-4159.2000.741131.x; https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2000.741131.x |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| Accession Number: |
edsbas.6F6DE7A5 |
| Database: |
BASE |