Change search
Refine search result
1 - 10 of 10
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Holback, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gatsinzi, Tom
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jacobsen, Kristin T.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 365, no 2, p. 298-303Article in journal (Refereed)
    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.

  • 2.
    Holback, Sofia
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Koistinen, Niina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jacobsen, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Retinoic acid stimulates maturation of the adaptor protein Fe65 and its binding to the amyloid precursor proteinManuscript (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.

  • 3.
    Jacobsen, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Processing of the APP family by the α-secretases ADAM10 and TACE2010Licentiate 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.

    Download full text (pdf)
    FULLTEXT01
  • 4.
    Jacobsen, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP22013Doctoral 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.

    Download full text (pdf)
    fulltext
  • 5.
    Jacobsen, Kristin
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Adlerz, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Multhaup, Gerd
    Institute for chemistry and biochemistry, Free University of Berlin.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Insulin-like growth factor-1 (IGF-1)-induced processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 14, p. 10223-10231Article in journal (Refereed)
    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.

  • 6.
    Jacobsen, Kristin T
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors.2009In: Cellular and molecular life sciences : CMLS, ISSN 1420-9071, Vol. 66, no 14, p. 2299-2318Article in journal (Refereed)
    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.

  • 7.
    Jacobsen, Kristin T.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    O-GlcNAcylation increases non-amyloidogenic processing of the amyloid-beta precursor protein (APP)2011In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 404, no 3, p. 882-886Article in journal (Refereed)
    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.

  • 8.
    Jacobsen, Kristin T.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The E1 domain of APP and APLP2 determines α-secretase specificityManuscript (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.

  • 9.
    Jacobsen, Kristin T.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Strååt, Ylva
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Koistinen, Niina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    O-GlcNAcylation of the α-secretase ADAM10 selectively affects APP processing in neuron-like cellsManuscript (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.

  • 10.
    Tracy, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bergqvist, Filip
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ivanova, Elena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jacobsen, Kristin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Exposure to the Saturated Free Fatty Acid Palmitate AltersBV-2 Microglia Inflammatory Response2013In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 51, no 3, p. 805-812Article in journal (Refereed)
    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.

1 - 10 of 10
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf