Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity
Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage...
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ftsubgoettingen:oai:publications.goettingen-research-online.de:2/129245 2023-09-05T13:17:20+02:00 Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity Schilling, Sandra Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Eggert, Simone 2023 https://resolver.sub.uni-goettingen.de/purl?gro-2/129245 https://doi.org/10.1186/s40478-023-01577-y en eng 2051-5960 https://resolver.sub.uni-goettingen.de/purl?gro-2/129245 doi:10.1186/s40478-023-01577-y 1577 https://creativecommons.org/licenses/by/4.0 journal_article yes 2023 ftsubgoettingen https://doi.org/10.1186/s40478-023-01577-y 2023-08-20T22:17:19Z Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase ... Article in Journal/Newspaper Arctic Georg-August-Universität Göttingen: GoeScholar Arctic Acta Neuropathologica Communications 11 1 |
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Georg-August-Universität Göttingen: GoeScholar |
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ftsubgoettingen |
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English |
description |
Abstract The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer’s disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation–mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation–mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1–17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase ... |
format |
Article in Journal/Newspaper |
author |
Schilling, Sandra Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Eggert, Simone |
spellingShingle |
Schilling, Sandra Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Eggert, Simone Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
author_facet |
Schilling, Sandra Pradhan, Ajay Heesch, Amelie Helbig, Andrea Blennow, Kaj Koch, Christian Bertgen, Lea Koo, Edward H. Brinkmalm, Gunnar Zetterberg, Henrik Eggert, Simone |
author_sort |
Schilling, Sandra |
title |
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
title_short |
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
title_full |
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
title_fullStr |
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
title_full_unstemmed |
Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity |
title_sort |
differential effects of familial alzheimer’s disease-causing mutations on amyloid precursor protein (app) trafficking, proteolytic conversion, and synaptogenic activity |
publishDate |
2023 |
url |
https://resolver.sub.uni-goettingen.de/purl?gro-2/129245 https://doi.org/10.1186/s40478-023-01577-y |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
2051-5960 https://resolver.sub.uni-goettingen.de/purl?gro-2/129245 doi:10.1186/s40478-023-01577-y 1577 |
op_rights |
https://creativecommons.org/licenses/by/4.0 |
op_doi |
https://doi.org/10.1186/s40478-023-01577-y |
container_title |
Acta Neuropathologica Communications |
container_volume |
11 |
container_issue |
1 |
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1776198542637924352 |