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O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-beta precursor protein (APP)
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-0308-1964
2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 404, no 3, 882-886 p.Article in journal (Refereed) Published
Abstract [en]

The amyloid-beta precursor protein (APP) was shown to be O-GlcNAcylated 15 years ago, but the effect of this modification on APP processing and formation of the Alzheimer's disease associated amyloid-beta (A beta) peptide has so far not been investigated. Here, we demonstrate with pharmacological tools or siRNA that O-GlcNAcase and O-GlcNAc transferase regulate the level of O-GlcNAcylated APP. We also show that O-GlcNAcylation increases non-amyloidogenic alpha-secretase processing, resulting in increased levels of the neuroprotective sAPP alpha fragment and decreased A beta secretion. Our results implicate O-GlcNAcylation as a potential therapeutic target for Alzheimer's disease.

Place, publisher, year, edition, pages
2011. Vol. 404, no 3, 882-886 p.
Keyword [en]
Alzheimer's disease, Amyloid-beta, APP processing, O-linked glycosylation, alpha-Secretase
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-67334DOI: 10.1016/j.bbrc.2010.12.080ISI: 000286848100023OAI: diva2:470316

authorCount :2

Available from: 2011-12-28 Created: 2011-12-28 Last updated: 2015-01-30Bibliographically approved
In thesis
1. α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP2
Open this publication in new window or tab >>α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP2
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The amyloid-β precursor protein (APP) has been widely studied due to its role in Alzheimer´s disease (AD). When APP is sequentially cleaved by β- and γ-secretase, amyloid-β (Aβ) is formed. Aβ is prone to aggregate and is toxic to neurons. However, the main processing pathway for APP involves initial cleavage at the α-site, within the Aβ region, instead generating a neuroprotective soluble fragment, sAPPα. APP is a member of a protein family, also including the proteins APLP1 and APLP2, which are processed in a similar way as APP. In addition, K/O studies in mice have shown that the three proteins have overlapping functions where APLP2 play a key physiological role. The aim of this thesis was to study mechanisms underlying the α-secretase processing of APP and APLP2. We have used the human neuroblastoma cell-line SH-SY5Y as a model system and stimulated α-secretase processing with insulin-like growth factor-1 (IGF-1) or retinoic acid (RA). Our results show that the stimulated α-site cleavage of APP and APLP2 is regulated by different signaling pathways and that the cleavage is mediated by different enzymes. APP was shown to be cleaved by ADAM10 in a PI3K-dependent manner, whereas APLP2 was cleaved by TACE in a PKC-dependent manner. We further show that protein levels and maturation of ADAM10 and TACE is increased in response to RA, mediated by a PI3K- or PKC-dependent signaling pathway, respectively. Another focus of our research has been O-GlcNAcylation, a dynamic post-translational modification regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase (OGA). We show that decreased OGA activity stimulates sAPPα secretion, without affecting APLP2 processing. We further show that ADAM10 is O-GlcNAcylated. Lastly, we show that APP can be manipulated to be cleaved in a similar way as APLP2 during IGF-1 stimulation by substituting the E1 domain in APP with the E1 domain in APLP2. Together our results show distinct α-site processing mechanisms of APP and APLP2.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2013. 57 p.
APP, APLP2, ADAM10, TACE, Alzheimer's Disease
National Category
Research subject
Neurochemistry with Molecular Neurobiology
urn:nbn:se:su:diva-95114 (URN)978-91-7447-732-0 (ISBN)
Public defence
2013-12-06, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 13:00 (English)

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 4: Manuscript; Paper 5: Manuscript.

Available from: 2013-11-14 Created: 2013-10-21 Last updated: 2015-03-09Bibliographically approved

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Jacobsen, Kristin T.Iverfeldt, Kerstin
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