Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein
Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid β-protein (Aβ42) at an early age and develop severe Alzheimer's disease. Aβ42is selectively elevated in the conditioned media of cells expressing mutant but not w...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
1998-08-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996198901838 |
| _version_ | 1818862544778952704 |
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| author | Martin Citron Christopher B. Eckman Thekla S. Diehl Chris Corcoran Beth L. Ostaszewski Weiming Xia Georges Levesque Peter St. George Hyslop Steven G. Younkin Dennis J. Selkoe |
| author_facet | Martin Citron Christopher B. Eckman Thekla S. Diehl Chris Corcoran Beth L. Ostaszewski Weiming Xia Georges Levesque Peter St. George Hyslop Steven G. Younkin Dennis J. Selkoe |
| author_sort | Martin Citron |
| collection | DOAJ |
| description | Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid β-protein (Aβ42) at an early age and develop severe Alzheimer's disease. Aβ42is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of Aβ42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in Aβ42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter γ-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in Aβ42. When a PS1 mutation was expressed in cells carrying the APPV717Imutation, Aβ42rose dramatically to become the predominant secreted Aβ species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by γ-secretases. |
| first_indexed | 2024-12-19T10:01:34Z |
| format | Article |
| id | doaj.art-d13b14d33e2349ccba03e130bdbc9f3b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T10:01:34Z |
| publishDate | 1998-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-d13b14d33e2349ccba03e130bdbc9f3b2022-12-21T20:26:38ZengElsevierNeurobiology of Disease1095-953X1998-08-0152107116Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-ProteinMartin Citron0Christopher B. Eckman1Thekla S. Diehl2Chris Corcoran3Beth L. Ostaszewski4Weiming Xia5Georges Levesque6Peter St. George Hyslop7Steven G. Younkin8Dennis J. Selkoe9Center for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaCenter for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, 02115; Department of Neuroscience, Amgen Inc. Thousand Oaks, California, 91320; Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, Florida, 32224; Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, 02115; Centre for Research into Neurodegenerative Disease, University of Toronto, Toronto, Ontario, CanadaHumans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid β-protein (Aβ42) at an early age and develop severe Alzheimer's disease. Aβ42is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of Aβ42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in Aβ42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter γ-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in Aβ42. When a PS1 mutation was expressed in cells carrying the APPV717Imutation, Aβ42rose dramatically to become the predominant secreted Aβ species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by γ-secretases.http://www.sciencedirect.com/science/article/pii/S0969996198901838 |
| spellingShingle | Martin Citron Christopher B. Eckman Thekla S. Diehl Chris Corcoran Beth L. Ostaszewski Weiming Xia Georges Levesque Peter St. George Hyslop Steven G. Younkin Dennis J. Selkoe Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein Neurobiology of Disease |
| title | Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein |
| title_full | Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein |
| title_fullStr | Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein |
| title_full_unstemmed | Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein |
| title_short | Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein |
| title_sort | additive effects of ps1 and app mutations on secretion of the 42 residue amyloid β protein |
| url | http://www.sciencedirect.com/science/article/pii/S0969996198901838 |
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