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  Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

Schilling, S., Pradhan, A., Heesch, A., Helbig, A., Blennow, K., Koch, C., et al. (2023). Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity. Acta Neuropathologica Communications, 11: 87. doi:10.1186/s40478-023-01577-y.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-3A56-2 Version Permalink: https://hdl.handle.net/21.11116/0000-000F-241D-9
Genre: Journal Article
Other : Differential effects of familial Alzheimer's disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity

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 Creators:
Schilling, Sandra, Author
Pradhan, Ajay, Author
Heesch, Amelie, Author
Helbig, Andrea, Author
Blennow, Kaj, Author
Koch, Christian, Author
Bertgen, Lea, Author
Koo, Edward H., Author
Brinkmalm, Gunnar, Author
Zetterberg, Henrik, Author
Kins, Stefan, Author
Eggert, Simone1, Author           
Affiliations:
1External Organizations, ou_persistent22              

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 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 cleavage sites show considerable differences in the underlying pathogenic mechanisms.

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Language(s): eng - English
 Dates: 2023-06-01
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1186/s40478-023-01577-y
 Degree: -

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Project name : -
Grant ID : AFLGBG-71320
Funding program : -
Funding organization : Swedish State Support for Clinical Research
Project name : -
Grant ID : Kl 819/9-1
Funding program : Alzheimer Forschung Initiative
Funding organization : Deutsche Forschungsgemeinschaft (DFG)
Project name : -
Grant ID : 19084
Funding program : -
Funding organization : Alzheimer Forschung Initiative
Project name : -
Grant ID : 2018-02532
Funding program : -
Funding organization : Swedish Research Council
Project name : FLUBIODEM
Grant ID : 101053962
Funding program : Horizon 1.1
Funding organization : European Commission (EC)
Project name : -
Grant ID : 201809-2016862
Funding program : -
Funding organization : Alzheimer's Drug Discovery Foundation
Project name : -
Grant ID : ADSF-21-831376-C
Funding program : -
Funding organization : AD Strategic Fund and the Alzheimer's Association
Project name : -
Grant ID : ADSF-21-831381-C
Funding program : -
Funding organization : AD Strategic Fund and the Alzheimer's Association
Project name : -
Grant ID : ADSF-21-831377-C
Funding program : -
Funding organization : AD Strategic Fund and the Alzheimer's Association
Project name : -
Grant ID : F02022-0270
Funding program : -
Funding organization : Stiftelsen för Gamla Tjänarinnor
Project name : MIRIADE
Grant ID : 860197
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)
Project name : -
Grant ID : UKDRI-1003
Funding program : -
Funding organization : UK Dementia Research Institute

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Title: Acta Neuropathologica Communications
  Other : Acta Neuropathol. Commun.
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: BioMed Central
Pages: - Volume / Issue: 11 Sequence Number: 87 Start / End Page: - Identifier: Other: ISSN
CoNE: https://pure.mpg.de/cone/journals/resource/2051-5960