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PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
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2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 365, no 2, 298-303 p.Article in journal (Refereed) Published
Abstract [en]

Retinoic acid stimulates α-secretase processing of amyloid precursor protein (APP) and decreases β-secretase cleavage that leads to amyloid-β formation. Here, we investigated the effect of retinoic acid on the two putative α-secretases, the disintegrin metalloproteinases ADAM10 and TACE, and the β-site cleaving enzyme BACE1, in human neuroblastoma SH-SY5Y cells. Western blot analysis showed that exposure to retinoic acid resulted in significantly increased levels of ADAM10 and TACE, suggesting that regulation of α-secretases causes the effects on APP processing. The presence of the phosphatidylinositol 3-kinase inhibitor LY 294002 selectively reduced the effect on ADAM10 protein levels but not on ADAM10 mRNA levels as determined by RT-PCR. On the other hand, the effect on TACE was shown to be dependent on protein kinase C, since it was completely blocked in the presence of the inhibitor bisindolylmaleimide XI. Our data indicate that different signalling pathways are involved in retinoic acid-induced up-regulation of the secretases.

Place, publisher, year, edition, pages
2008. Vol. 365, no 2, 298-303 p.
Keyword [en]
ADAM10, APP, BACE1, BDNF, PI3-kinase, Protein kinase C, Retinoic acid, TACE
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-19985DOI: 10.1016/j.bbrc.2007.10.167ISI: 000251494000015OAI: oai:DiVA.org:su-19985DiVA: diva2:186510
Available from: 2009-01-23 Created: 2009-01-23 Last updated: 2015-01-30Bibliographically approved
In thesis
1. Proteolytic processing of the Alzheimer APP protein family during neuronal differentiation
Open this publication in new window or tab >>Proteolytic processing of the Alzheimer APP protein family during neuronal differentiation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increased amyloid-β (Aβ) load in the brain, neurite degeneration, neuronal loss, and decreased levels of several neurotrophins are among the characteristics of Alzheimer’s disease (AD). Generation of Aβ occurs when the amyloid precursor protein (APP) is proteolytically processed by β- and γ-secretases in the amyloidogenic pathway. However, Aβ formation is prevented if APP is cleaved by α- and γ- secretases in the non-amyloidogenic pathway. The normal function of APP is still not fully known. It seems clear that the different fragments that are produced during proteolytic processing have different bioactive properties. APP and its metabolites have been implicated in neurite outgrowth, synaptogenesis, cell adhesion, neuroprotection and apoptosis.

The aim of this thesis was to investigate how neurotrophic factors affect the synthesis and processing of APP and its two mammalian paralogues the APP-like protein-1 and-2 (APLP1 and APLP2). We also wanted to determine how the expression levels of α- and β- secretases were affected in response to these factors. In addition, we wanted to analyze if the levels and function of the most well characterized APP adaptor protein, Fe65, was regulated during neuronal differentiation.

Our results show that retinoic acid (RA), insulin-like growth factor-1 (IGF-1), and brain derived neurotrophic factor (BDNF) all regulate expression levels and processing of the APP protein family. Interestingly, the increased processing of the APP family involves different signaling pathways. The PI3-K/Akt pathway is involved in IGF-1-induced APP and APLP1, but not APLP2, processing. In addition, RA-induced expression of the α-secretase, a disintegrin and metalloproteinase (ADAM) 10 is dependent on PI3-K, whereas PKC is involved in RA-induced expression of another α-secretase, ADAM17/TACE. Furthermore, we present evidence that maturation of the adaptor protein Fe65, as well as its docking to APP, increases concomitant with neuronal differentiation.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2009. 82 p.
Keyword
APP, APLP1, APLP2, differentiation, processing, retinoic acid, secretase
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-31301 (URN)978-91-7155-942-5 (ISBN)
Public defence
2009-12-18, Magnélisalen, Kemiska övningslaboratioriet, 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 4: Manuscript.Available from: 2009-11-26 Created: 2009-11-10 Last updated: 2015-03-09Bibliographically approved
2. Processing of the APP family by the α-secretases ADAM10 and TACE
Open this publication in new window or tab >>Processing of the APP family by the α-secretases ADAM10 and TACE
2010 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is characterized by formation of amyloid plaques in the brain. The major constituent of these plaques is the hydrophobic peptide Aβ. Aβ accumulation is considered to be the main cause of the pathology seen in AD brains. Aβ is produced through sequential cleavage of the amyloid precursor protein (APP). APP can be processed by two different enzymatic pathways. Formation of Aβ requires cleavage of APP by β- and γ-secretase. However, most proteolytic processing of APP does not result in Aβ formation. Instead, APP is mainly cleaved by α-secretase, which not only precludes formation of the toxic Aβ peptide but also generates the neuroprotective sAPPα fragment. Increasing the α-secretase processing of APP is thereby a potential therapeutic strategy for AD. APP is a member of a conserved gene family, also including the APP-like proteins-1 and -2 (APLP1 and APLP2). The APP family members have essential and overlapping functions and have been reported to be processed in a similar way by the same enzymes. The processing of all APP family members is increased in response to several stimuli, including retinoic acid (RA) and insulin-like growth factor-1 (IGF-1), which also induce a shift towards α-secretase processing. The aim of this thesis was to investigate the mechanisms and signaling involved in induced α-secretase processing of the APP family. The main α-secretase candidates are ADAM10 and TACE. In this thesis we wanted to study the effects on expression levels of ADAM10 and TACE during RA treatment. We also wanted to investigate the mechanism behind IGF-1-induced processing of APP and APLP2. We found that both ADAM10 and TACE are up-regulated in response to RA, but that the signaling pathways involved differed between the two enzymes. Similarly, we showed that IGF-1-induced processing of APLP2, but not of APP, is dependent on PKC. Furthermore, we showed that ADAM10 is the main α-secretase for APP, whereas TACE cleaves APLP2 in response to IGF-1. We conclude that although APP and APLP2 proteolytic processing are induced by the same stimuli, the processing is dependent on different signaling pathways and processing enzymes, which in turn are differentially regulated.

Place, publisher, year, edition, pages
Stockholm: Universitetsservice US-AB, 2010. 51 p.
National Category
Neurosciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-41996 (URN)978-91-7447-000-0 (ISBN)
Presentation
2010-01-22, Heilbronnsalen, Svante Arrhenius väg 21A, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2011-01-14 Created: 2010-08-13 Last updated: 2015-03-09Bibliographically approved
3. Neuroblastoma cells: in vitro studies on childhood cancer and amyloid precursor protein processing enzymes
Open this publication in new window or tab >>Neuroblastoma cells: in vitro studies on childhood cancer and amyloid precursor protein processing enzymes
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Stockholm: Universitetsservice AB, 2009. 54 p.
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-79162 (URN)ISBN 978-91-7155-848-0 (ISBN)
Presentation
2009-03-31, Heilbronnsalen, Svante Arrhenius väg 21A, 106 91 Stockholm, 16:50 (English)
Opponent
Supervisors
Available from: 2012-10-30 Created: 2012-08-28 Last updated: 2015-03-09Bibliographically approved
4. 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.
Keyword
APP, APLP2, ADAM10, TACE, Alzheimer's Disease
National Category
Neurosciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
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)
Opponent
Supervisors
Note

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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