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Jacobsen, Kristin
Alternative names
Publications (10 of 10) Show all publications
Tracy, L., Bergqvist, F., Ivanova, E., Jacobsen, K. & Iverfeldt, K. (2013). Exposure to the Saturated Free Fatty Acid Palmitate AltersBV-2 Microglia Inflammatory Response. Journal of Molecular Neuroscience, 51(3), 805-812
Open this publication in new window or tab >>Exposure to the Saturated Free Fatty Acid Palmitate AltersBV-2 Microglia Inflammatory Response
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2013 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 3, p. 805-812Article in journal (Refereed) Published
Abstract [en]

Elevated levels of free fatty acids (FFAs) in plasma and increased incidence of chronic systemic inflammation are associated with obesity. In the brain, activated microglia are believed to play different roles during inflammation that may either be neuroprotective or promote neurodegeneration. Here, we have investigated the effects of FFAs on microglial response to inflammatory stimuli. Our results indicate that the saturated FFA palmitate on its own induces alternative activation of BV-2 microglia cells. Further, pre-exposure to palmitate changed the response of microglia to lipopolysaccharide (LPS). We show that palmitate affects the mRNA levels of the pro-inflammatory cytokines interleukin-1β and interleukin-6. The transcription factor CCAAT/enhancer-binding protein δ is also affected by pre-exposure to palmitate. Furthermore, the phagocytic activity of microglia was investigated using fluorescent beads. By analyzing the bead uptake by fluorescence-activated cell sorting, we found that palmitate alone, as well as together with LPS, stimulated the phagocytic activity of microglia. Taken together, our results suggest that exposure of microglia to increased levels of free fatty acids may alter the consequences of classical inflammatory stimuli.

National Category
Biochemistry and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:su:diva-95103 (URN)10.1007/s12031-013-0068-7 (DOI)000325710500021 ()
Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2022-02-24Bibliographically approved
Jacobsen, K. (2013). α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP2. (Doctoral dissertation). Stockholm: Department of Neurochemistry, Stockholm University
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. p. 57
Keywords
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: 2022-02-24Bibliographically approved
Jacobsen, K. T. & Iverfeldt, K. (2011). O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-beta precursor protein (APP). Biochemical and Biophysical Research Communications - BBRC, 404(3), 882-886
Open this publication in new window or tab >>O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-beta precursor protein (APP)
2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 404, no 3, p. 882-886Article 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.

Keywords
Alzheimer's disease, Amyloid-beta, APP processing, O-linked glycosylation, alpha-Secretase
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-67334 (URN)10.1016/j.bbrc.2010.12.080 (DOI)000286848100023 ()
Note

authorCount :2

Available from: 2011-12-28 Created: 2011-12-28 Last updated: 2022-02-24Bibliographically approved
Jacobsen, K., Adlerz, L., Multhaup, G. & Iverfeldt, K. (2010). 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. Journal of Biological Chemistry, 285(14), 10223-10231
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, p. 10223-10231Article 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
Keywords
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: 2022-02-24Bibliographically approved
Jacobsen, K. (2010). Processing of the APP family by the α-secretases ADAM10 and TACE. (Licentiate dissertation). Stockholm: Universitetsservice US-AB
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. p. 51
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: 2022-02-24Bibliographically approved
Jacobsen, K. T. & Iverfeldt, K. (2009). Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors.. Cellular and molecular life sciences : CMLS, 66(14), 2299-2318
Open this publication in new window or tab >>Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors.
2009 (English)In: Cellular and molecular life sciences : CMLS, ISSN 1420-9071, Vol. 66, no 14, p. 2299-2318Article in journal (Refereed) Published
Abstract [en]

The Alzheimer's amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1 and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding partners, and regulated processing.

Identifiers
urn:nbn:se:su:diva-34358 (URN)10.1007/s00018-009-0020-8 (DOI)000267886500008 ()19333550 (PubMedID)
Available from: 2010-01-07 Created: 2010-01-07 Last updated: 2022-02-25Bibliographically approved
Holback, S., Adlerz, L., Gatsinzi, T., Jacobsen, K. T. & Iverfeldt, K. (2008). PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid. Biochemical and Biophysical Research Communications - BBRC, 365(2), 298-303
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, p. 298-303Article 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.

Keywords
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: 2022-02-25Bibliographically approved
Jacobsen, K. T., Strååt, Y., Koistinen, N. & Iverfeldt, K.O-GlcNAcylation of the α-secretase ADAM10 selectively affects APP processing in neuron-like cells.
Open this publication in new window or tab >>O-GlcNAcylation of the α-secretase ADAM10 selectively affects APP processing in neuron-like cells
(English)Manuscript (preprint) (Other academic)
Abstract [en]

α-Secretase processing of APP has recently gained more interest, highlighting its potential as a therapeutic target to prevent Alzheimer’s disease (AD). We have previously shown that O-GlcNAcylation stimulates α-secretase processing of APP, concomitantly with decreased Aβ secretion. O-GlcNAcylation has previously been linked to AD since the levels of O-GlcNAcylated proteins are decreased in AD brains. Here, we have further investigated the mechanism behind α-secretase processing of APP in response to increased O-GlcNAcylation. Our results shown that APP is not O-GlcNAcylated during the conditions used in this study. Instead, we demonstrate that the α-secretase ADAM10 is O-GlcNAcylated and that APP cell surface localization is enhanced in response to increased O-GlcNAcylation. Furthermore, the effects of O-GlcNAcylation on APP processing are cell-type specific, only affecting sAPPα secretion in neuroblastoma cell-lines.

Keywords
APP, ADAM10, O-GlcNAcylation
National Category
Biological Sciences Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-95071 (URN)
Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2022-02-24Bibliographically approved
Holback, S., Koistinen, N., Jacobsen, K. & Iverfeldt, K.Retinoic acid stimulates maturation of the adaptor protein Fe65 and its binding to the amyloid precursor protein.
Open this publication in new window or tab >>Retinoic acid stimulates maturation of the adaptor protein Fe65 and its binding to the amyloid precursor protein
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Retinoic acid (RA) stimulates both synthesis and processing of the amyloid precursor protein (APP) and its mammalian paralogues, the APP-like proteins 1 and 2 (APLP1 and APLP2). Previously, we have detected increased levels of the APP and APLP1 intracellular dolmans, AICD and ALID1 respectively, concomitant with RA-induced neuronal differentiation. Here we used Western blot analysis to show increased levels of the mature form of the adaptor protein Fe65 during RA- as well as nerve growth factor-induced differentiation. Co-immunoprecipitation studies also revealed that increased binding of Fe65 to APP and APLP1 occurred during neuronal differentiation. Furthermore, exposure to RA decreased the phosphorylation of Thr668 located in the cytoplasmic domain of APP.

Keywords
Fe65, retinoic acid, amyloid precursor protein, neuronal differentiation
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-32579 (URN)
Available from: 2009-12-14 Created: 2009-12-14 Last updated: 2022-02-25Bibliographically approved
Jacobsen, K. T. & Iverfeldt, K.The E1 domain of APP and APLP2 determines α-secretase specificity.
Open this publication in new window or tab >>The E1 domain of APP and APLP2 determines α-secretase specificity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The α-secretase cleavage of the amyloid-β precursor protein (APP) precludes the formation of amyloid-β (Aβ), the main constituent of senile plaques in Alzheimer´s disease (AD). Stimulation of α-secretase processing may thereby constitute an important therapeutical strategy. APP belongs to a conserved protein family including the APP-like protein 2 (APLP2). Although the proteins are sequentially processed in a similar way, we have previously shown that insulin-like factor-1 (IGF-1) - and retinoic acid (RA)-induced α-secretase processing of APP and APLP2 is mediated by different enzymes. APP was shown to be cleaved by the α-secretase ADAM10 in a PI3K-dependent manner, whereas APLP2 was cleaved by the α-secretase TACE in a PKC-dependent manner. To better understand the mechanism underlying this difference in α-secretase processing between these two homologous proteins, we aimed to determine which part of APP that was essential for making it a better substrate for ADAM10 than for TACE during stimulated conditions. We constructed a chimeric protein, were the E1 domain of APP was substituted with the corresponding domain of APLP2. Our results demonstrate that the APP/E1/APLP2 chimer is successfully expressed and secreted into the cell medium of transiently transfected SH-SY5Y cells. Pharmacological inhibition demonstrate that the IGF-1-induced processing of the chimer is PI3K-independent but dependent on PKC, as previously shown for the APLP2 processing. Our result indicates that the E1 domain in APP determines its specificity towards ADAM10 over TACE.

Keywords
APP, APLP2, ADAM10, TACE
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-95072 (URN)
Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2022-02-24Bibliographically approved
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