Carboxyl-terminal fragments of Alzheimer beta-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells
| Autor: | D. M. Zhang, G. Levesque, David Westaway, Gang Yu, Anurag Tandon, Ekaterina Rogaeva, Peter St George-Hyslop, Toshitaka Kawarai, Lyne Levesque, Masaki Nishimura, Paul E. Fraser, Fusheng Chen, Howard T.J. Mount, Richard Rozmahel, S.E. Gandy, Dun-Sheng Yang, Suzana Petanceska, Austin J. Yang, Jorge Ghiso, Julia Mills, You-Qiang Song |
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| Rok vydání: | 2000 |
| Předmět: |
Endosome
Mutant Biology Biochemistry Presenilin symbols.namesake Amyloid beta-Protein Precursor Mice Alzheimer Disease mental disorders Endopeptidases Amyloid precursor protein Presenilin-1 Animals Aspartic Acid Endopeptidases Molecular Biology Mice Knockout Amyloid beta-Peptides Activator (genetics) Endoplasmic reticulum Brain Membrane Proteins Cell Biology Golgi apparatus Peptide Fragments Cell biology Cell Compartmentation Microscopy Electron nervous system symbols biology.protein Electrophoresis Polyacrylamide Gel Amyloid Precursor Protein Secretases Intracellular Biomarkers |
| Zdroj: | The Journal of biological chemistry. 275(47) |
| ISSN: | 0021-9258 |
| Popis: | Absence of functional presenilin 1 (PS1) protein leads to loss of gamma-secretase cleavage of the amyloid precursor protein (betaAPP), resulting in a dramatic reduction in amyloid beta peptide (Abeta) production and accumulation of alpha- or beta-secretase-cleaved COOH-terminal fragments of betaAPP (alpha- or beta-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as betaAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Abeta-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length betaAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of betaAPP to the Golgi compartment is necessary before alpha- and beta-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual gamma-secretase catalytic activity or in other functions indirectly related to gamma-secretase catalysis (e.g. an activator of gamma-secretase, a substrate adaptor for gamma-secretase, or delivery of gamma-secretase to betaAPP-containing compartments). |
| Databáze: | OpenAIRE |
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