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Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879340/ https://www.ncbi.nlm.nih.gov/pubmed/31604820 http://dx.doi.org/10.1074/jbc.RA119.008310 |
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author | Menon, Preeti Kumaran Koistinen, Niina Anneli Iverfeldt, Kerstin Ström, Anna-Lena |
author_facet | Menon, Preeti Kumaran Koistinen, Niina Anneli Iverfeldt, Kerstin Ström, Anna-Lena |
author_sort | Menon, Preeti Kumaran |
collection | PubMed |
description | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP(695) numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), even though the total plasma membrane level of APP was unchanged compared with APP levels in cells expressing APPwt or APP-S675A. Moreover, the level of an alternative larger C-terminal fragment (CTF) increased in the APP-S675E cells, whereas the CTF form that was most abundant in cells expressing APPwt or APP-S675A decreased in the APP-S675E cells. Upon siRNA-mediated knockdown of the astacin metalloprotease meprin β, the levels of the alternative CTF decreased and the CTF ratio was restored back to APPwt levels. Our findings suggest that APP–Ser-675 phosphorylation alters the balance of APP processing, increasing meprin β–mediated and decreasing α-secretase–mediated processing of APP at the plasma membrane. As meprin β cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Aβ2–40/42 peptides, enhanced APP processing by this enzyme could contribute to AD pathology. We propose that it would be of interest to clarify in future studies how APP–Ser-675 phosphorylation promotes meprin β–mediated APP cleavage. |
format | Online Article Text |
id | pubmed-6879340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-68793402019-11-27 Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β Menon, Preeti Kumaran Koistinen, Niina Anneli Iverfeldt, Kerstin Ström, Anna-Lena J Biol Chem Neurobiology Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP(695) numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), even though the total plasma membrane level of APP was unchanged compared with APP levels in cells expressing APPwt or APP-S675A. Moreover, the level of an alternative larger C-terminal fragment (CTF) increased in the APP-S675E cells, whereas the CTF form that was most abundant in cells expressing APPwt or APP-S675A decreased in the APP-S675E cells. Upon siRNA-mediated knockdown of the astacin metalloprotease meprin β, the levels of the alternative CTF decreased and the CTF ratio was restored back to APPwt levels. Our findings suggest that APP–Ser-675 phosphorylation alters the balance of APP processing, increasing meprin β–mediated and decreasing α-secretase–mediated processing of APP at the plasma membrane. As meprin β cleavage of APP has been shown to result in formation of highly aggregation-prone, truncated Aβ2–40/42 peptides, enhanced APP processing by this enzyme could contribute to AD pathology. We propose that it would be of interest to clarify in future studies how APP–Ser-675 phosphorylation promotes meprin β–mediated APP cleavage. American Society for Biochemistry and Molecular Biology 2019-11-22 2019-10-11 /pmc/articles/PMC6879340/ /pubmed/31604820 http://dx.doi.org/10.1074/jbc.RA119.008310 Text en © 2019 Menon et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) . |
spellingShingle | Neurobiology Menon, Preeti Kumaran Koistinen, Niina Anneli Iverfeldt, Kerstin Ström, Anna-Lena Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title | Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title_full | Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title_fullStr | Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title_full_unstemmed | Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title_short | Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin β |
title_sort | phosphorylation of the amyloid precursor protein (app) at ser-675 promotes app processing involving meprin β |
topic | Neurobiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879340/ https://www.ncbi.nlm.nih.gov/pubmed/31604820 http://dx.doi.org/10.1074/jbc.RA119.008310 |
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