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Processing of the APP family by the α-secretases ADAM10 and TACE
Stockholm University, Faculty of Science, Department of Neurochemistry. (Kerstin Iverfeldt)
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: urn:nbn:se:su:diva-41996ISBN: 978-91-7447-000-0 (print)OAI: oai:DiVA.org:su-41996DiVA: diva2:343433
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
List of papers
1. PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid
Open this publication in new window or tab >>PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid
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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.

Keyword
ADAM10, APP, BACE1, BDNF, PI3-kinase, Protein kinase C, Retinoic acid, TACE
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-19985 (URN)10.1016/j.bbrc.2007.10.167 (DOI)000251494000015 ()
Available from: 2009-01-23 Created: 2009-01-23 Last updated: 2015-01-30Bibliographically approved
2. Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases
Open this publication in new window or tab >>Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases
2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 14, 10223-10231 p.Article in journal (Refereed) Published
Abstract [en]

α-Secretase cleavage of the amyloid precursor protein (APP) is of great interest since it prevents the formation of the Alzheimer-linked amyloid-β peptide. APP belongs to a conserved gene family including the two paralogues APP-like protein (APLP) 1 and 2. Insulin-like growth factor-1 (IGF-1) stimulates the shedding of all three proteins. IGF-1-induced shedding of both APP and APLP1 is dependent on phosphatidylinositol 3-kinase (PI3-K), whereas sAPLP2 secretion is independent of this signaling pathway. Here, we used human neuroblastoma SH-SY5Y cells to investigate the involvement of protein kinase C (PKC) in the proteolytic processing of endogenously expressed members of the APP family. Processing was induced by IGF-1 or retinoic acid, another known stimulator of APP a-secretase shedding. Our results show that stimulation of APP and APLP1 processing involves multiple signaling pathways, whereas APLP2 processing is mainly dependent on PKC. Next, we wanted to investigate if the difference in the regulation of APLP2 shedding compared to APP shedding could be due to involvement of different processing enzymes. We focused on the two major a-secretase candidates ADAM10 and TACE, which both are members of the ADAM (a disintegrin and metalloprotease) family. Shedding was analyzed in the presence of the ADAM10 inhibitor GI254023X, or after transfection with siRNA targeted against TACE. The results clearly demonstrate that different α-secretases are involved in IGF-1-induced processing. APP is mainly cleaved by ADAM10, whereas APLP2 processing is mediated by TACE. Finally, we also show that IGF-1 induces PKC-dependent phosphorylation of TACE.

Place, publisher, year, edition, pages
Bethesda: ASBMB, 2010
Keyword
Alzheimer disease, Amyloid, IGF-1, ADAM10, TACE
National Category
Physiology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-38487 (URN)10.1074/jbc.M109.038224 (DOI)000276264600006 ()
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2015-01-30Bibliographically approved

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