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Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production
Amyloid-β peptides (Aβs) are produced via cleavage of the transmembrane region of the amyloid precursor protein (APP) by γ-secretase and are responsible for Alzheimer’s disease. Familial Alzheimer’s disease (FAD) is associated with APP mutations that disrupt the cleavage reaction and increase the pr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959964/ https://www.ncbi.nlm.nih.gov/pubmed/36835396 http://dx.doi.org/10.3390/ijms24043970 |
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author | Suzuki, Ryota Takahashi, Haruka Yoshida, Chika Hidaka, Masafumi Ogawa, Tomohisa Futai, Eugene |
author_facet | Suzuki, Ryota Takahashi, Haruka Yoshida, Chika Hidaka, Masafumi Ogawa, Tomohisa Futai, Eugene |
author_sort | Suzuki, Ryota |
collection | PubMed |
description | Amyloid-β peptides (Aβs) are produced via cleavage of the transmembrane region of the amyloid precursor protein (APP) by γ-secretase and are responsible for Alzheimer’s disease. Familial Alzheimer’s disease (FAD) is associated with APP mutations that disrupt the cleavage reaction and increase the production of neurotoxic Aβs, i.e., Aβ42 and Aβ43. Study of the mutations that activate and restore the cleavage of FAD mutants is necessary to understand the mechanism of Aβ production. In this study, using a yeast reconstruction system, we revealed that one of the APP FAD mutations, T714I, severely reduced the cleavage, and identified secondary APP mutations that restored the cleavage of APP T714I. Some mutants were able to modulate Aβ production by changing the proportions of Aβ species when introduced into mammalian cells. Secondary mutations include proline and aspartate residues; proline mutations are thought to act through helical structural destabilization, while aspartate mutations are thought to promote interactions in the substrate binding pocket. Our results elucidate the APP cleavage mechanism and could facilitate drug discovery. |
format | Online Article Text |
id | pubmed-9959964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99599642023-02-26 Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production Suzuki, Ryota Takahashi, Haruka Yoshida, Chika Hidaka, Masafumi Ogawa, Tomohisa Futai, Eugene Int J Mol Sci Article Amyloid-β peptides (Aβs) are produced via cleavage of the transmembrane region of the amyloid precursor protein (APP) by γ-secretase and are responsible for Alzheimer’s disease. Familial Alzheimer’s disease (FAD) is associated with APP mutations that disrupt the cleavage reaction and increase the production of neurotoxic Aβs, i.e., Aβ42 and Aβ43. Study of the mutations that activate and restore the cleavage of FAD mutants is necessary to understand the mechanism of Aβ production. In this study, using a yeast reconstruction system, we revealed that one of the APP FAD mutations, T714I, severely reduced the cleavage, and identified secondary APP mutations that restored the cleavage of APP T714I. Some mutants were able to modulate Aβ production by changing the proportions of Aβ species when introduced into mammalian cells. Secondary mutations include proline and aspartate residues; proline mutations are thought to act through helical structural destabilization, while aspartate mutations are thought to promote interactions in the substrate binding pocket. Our results elucidate the APP cleavage mechanism and could facilitate drug discovery. MDPI 2023-02-16 /pmc/articles/PMC9959964/ /pubmed/36835396 http://dx.doi.org/10.3390/ijms24043970 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Suzuki, Ryota Takahashi, Haruka Yoshida, Chika Hidaka, Masafumi Ogawa, Tomohisa Futai, Eugene Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title | Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title_full | Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title_fullStr | Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title_full_unstemmed | Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title_short | Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-β Production |
title_sort | specific mutations near the amyloid precursor protein cleavage site increase γ-secretase sensitivity and modulate amyloid-β production |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959964/ https://www.ncbi.nlm.nih.gov/pubmed/36835396 http://dx.doi.org/10.3390/ijms24043970 |
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