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APP Ser675 phosphorylation affects α-secretase processing resulting in decreased secretion of the neuroprotective ectodomain sAPPα
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-8268-3006
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-8630-2127
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of the amyloid-β (Aβ) peptide. Aβ is produced after amyloidogenic (β-secretase) processing of the transmembrane amyloid precursor protein (APP). However, APP can also be processed by α-secretases, instead resulting in release of neuroprotective sAPPα.  Growing evidence indicate that aberrant post-translational modifications of APP may play a pivotal role in AD pathogenesis by dysregulating APP processing. APP Ser675 phosphorylation occurs in AD brains and here we for the first time show that this phosphorylation decreases the release of sAPPα, while the level of an alternative APP-C83-CTF fragment is increased. Moreover, we found that while APP Ser675 phosphorylation increased the APP-Fe65 interaction, the level of APP at the plasma membrane were unaltered. Taken together these results suggest that APP Ser675 phosphorylation alters the α-secretase processing of APP at the plasma membrane. As α-secretase processing of APP is an essential step in decreasing the generation of Aβ these results suggest that Ser675 phosphorylation could contribute to AD pathology.

Keyword [en]
Alzheimer's disease, Amyloid precursor protein
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-149903OAI: oai:DiVA.org:su-149903DiVA: diva2:1164619
Available from: 2017-12-11 Created: 2017-12-11 Last updated: 2017-12-14Bibliographically approved
In thesis
1. The amyloid-β precursor protein (APP)-binding protein Fe65 and APP processing
Open this publication in new window or tab >>The amyloid-β precursor protein (APP)-binding protein Fe65 and APP processing
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of neurotoxic amyloid-β (Aβ) peptide. Aβ is generated by sequential cleavage of the amyloid-β precursor protein (APP) by β- and then γ-secretase. However, APP can also be processed by α- and γ-secretase, instead resulting in generation of neuroprotective sAPPα. Increased APP phosphorylation and altered expression levels of the brain enriched Fe65 protein have been observed in the brains of AD patients. Fe65 can not only interact with membrane tethered APP, but can also localized into the nucleus and act as a transcriptional regulator together with the APP intracellular domain (AICD), generated after γ-secretase processing. How APP processing, APP/Fe65 interaction, and the nuclear AICD/Fe65 complex is regulated has not yet been fully understood. The aim of this thesis was therefore to further elucidate how Fe65 is regulated and how APP Ser675 phosphorylation affects APP processing.

We could identify several factors regulating Fe65. First, we identified that neuronal differentiation induces Fe65 phosphorylation (paper I), and that phosphorylated forms of Fe65 were preferentially localized outside the nucleus (paper II). Second, we found that the APP binding PTB2 domain of Fe65, rather than the previously proposed N-terminal WW domain, is important for the nuclear localization of Fe65 (paper II). In addition, we surprisingly found that mutation of S228 in the Fe65 N-terminus could increase the APP/Fe65 interaction (paper III). Third, both α- and γ-secretase inhibitors decreased Fe65 nuclear localization similarly, indicating an important role of α-secretase in regulating Fe65 nuclear localization (papers II and III). Lastly, we could in paper IV for the first time show that phosphorylation of APP at Ser675 regulates APP processing at the plasma membrane, resulting in reduced levels of sAPPα. These results, together with the observation that APP Ser675 phosphorylation occur in AD brains, suggest that Ser675 phosphorylation could contribute to AD pathology by decreasing α-secretase processing and instead increasing the levels of Aβ.

In summary these studies have contributed to understanding of APP processing and the interplay between Fe65 and APP, two suggested key players in AD. 

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2018. 89 p.
Keyword
APP, Fe65, ADAM10, Alzheimer's disease
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-149906 (URN)978-91-7797-112-2 (ISBN)978-91-7797-113-9 (ISBN)
Public defence
2018-02-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2018-01-10 Created: 2017-12-11 Last updated: 2018-01-11Bibliographically approved

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Koistinen, NiinaMenon, PreetiIverfeldt, KerstinStröm, Anna-Lena
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