Change search
Refine search result
1 - 11 of 11
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.
    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.

  • 2.
    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.

  • 3.
    Koistinen, Niina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The adaptor protein Fe65 and APP processing2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The amyloid precursor protein (APP) protein has been in the limelight of research on Alzheimer´s disease (AD) pathogenesis because its proteolytic processing gives rise to the neurotoxic amyloid β (Aβ) peptide, the main constituent of amyloid plaques in the brains of AD patients. APP is sequentially processed by at least three different proteases termed α-, β-, and γ-secretases. The proteolytic processing of APP can be divided into two different pathways, the non-amyloidogenic and the amyloidogenic. Whether APP is processed by the non-amyloidogenic or the amyloidogenic pathway is highly dependent on colocalization of APP with the different processing enzymes. Hence, understanding the mechanism underlying regulation of APP trafficking and its related secretases is of great importance in our understanding of AD and AD pathogenesis. The aim of this thesis was to study the processing and trafficking of APP, how it may be regulated by the interaction with the adaptor protein, Fe65, and by a novel type of posttranslational modification, O-GlcNAcylation. We have used the human neuroblastoma cell line SH-SY5Y as a modell system to investigate the effect of Fe65 knock-down on APP processing. Our results showed that Fe65 knockdown did not have any effect on sAPPα secretion. However, decreased levels of C83 and C99 were observed, suggesting that Fe65 has a stabilizing effect on the C-terminal fragments. Furthermore, we investigated the effects of RA-induced neronal differentiation on Fe65 expression. We observed increased protein levels of Fe65 and an electrophoretic mobility shift due to increased phosphorylation of Fe65. O-GlcNAcylation is a dynamic posttranslational modification regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). To investigate the effect of O-GlcNAcylation on APP trafficking and processing, SH-SY5Y cells were treated with PUGNAc, an OGA inhibitor, to increase the cellular levels of O-GlcNAc. The results revealed that cell surface localization of mature APP was significantly enhanced without any affect on the total levels of APP. We further show evidence that ADAM10 is O-GlcNAcylated and that the effect of O-GlcNAcylation on APP processing is neuron-specific.

  • 4.
    Koistinen, Niina
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The amyloid-β precursor protein (APP)-binding protein Fe65 and APP processing2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of neurotoxic amyloid-β (Aβ) peptide. Aβ is generated by sequential cleavage of the amyloid-β precursor protein (APP) by β- and then γ-secretase. However, APP can also be processed by α- and γ-secretase, instead resulting in generation of neuroprotective sAPPα. Increased APP phosphorylation and altered expression levels of the brain enriched Fe65 protein have been observed in the brains of AD patients. Fe65 can not only interact with membrane tethered APP, but can also localized into the nucleus and act as a transcriptional regulator together with the APP intracellular domain (AICD), generated after γ-secretase processing. How APP processing, APP/Fe65 interaction, and the nuclear AICD/Fe65 complex is regulated has not yet been fully understood. The aim of this thesis was therefore to further elucidate how Fe65 is regulated and how APP Ser675 phosphorylation affects APP processing.

    We could identify several factors regulating Fe65. First, we identified that neuronal differentiation induces Fe65 phosphorylation (paper I), and that phosphorylated forms of Fe65 were preferentially localized outside the nucleus (paper II). Second, we found that the APP binding PTB2 domain of Fe65, rather than the previously proposed N-terminal WW domain, is important for the nuclear localization of Fe65 (paper II). In addition, we surprisingly found that mutation of S228 in the Fe65 N-terminus could increase the APP/Fe65 interaction (paper III). Third, both α- and γ-secretase inhibitors decreased Fe65 nuclear localization similarly, indicating an important role of α-secretase in regulating Fe65 nuclear localization (papers II and III). Lastly, we could in paper IV for the first time show that phosphorylation of APP at Ser675 regulates APP processing at the plasma membrane, resulting in reduced levels of sAPPα. These results, together with the observation that APP Ser675 phosphorylation occur in AD brains, suggest that Ser675 phosphorylation could contribute to AD pathology by decreasing α-secretase processing and instead increasing the levels of Aβ.

    In summary these studies have contributed to understanding of APP processing and the interplay between Fe65 and APP, two suggested key players in AD. 

    Download full text (pdf)
    fulltext
    Download (png)
    Omslagsframsida
  • 5.
    Koistinen, Niina A.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bacanu, Smaranda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Phosphorylation of Fe65 amyloid precursor protein-binding protein in response to neuronal differentiation2016In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 613, p. 54-59Article in journal (Refereed)
    Abstract [en]

    Fe65 is a brain enriched multi domain adaptor protein involved in diverse cellular functions. One of its binding partners is the amyloid-beta (A beta) precursor protein (APP), which after sequential proteolytic processing by secretases gives rise to the Alzheimer's A beta peptide. Fe65 binds to the APP intracellular domain (AICD). Several studies have indicated that Fe65 binding promotes the amyloidogenic processing of APP. It has previously been shown that expression of APP increases concomitantly with a shift of its processing to the non-amyloidogenic pathway during neuronal differentiation. In this study we wanted to investigate the effects of neuronal differentiation on Fe65 expression. We observed that differentiation of SH-SY5Y human neuroblastoma cells induced by retinoic acid (RA), the phorbol ester PMA, or the gamma-secretase inhibitor DAPT resulted in an electrophoretic mobility shift of Fe65. Similar effects were observed in rat PC6.3 cells treated with nerve growth factor. The electrophoretic mobility shift was shown to be due to phosphorylation. Previous studies have shown that Fe65 phosphorylation can prevent the APP-Fe65 interaction. We propose that phosphorylation is a way to modify the functions of Fe65 and to promote the non-amyloidogenic processing of APP during neuronal differentiation.

  • 6.
    Koistinen, Niina A.
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Edlund, Anna K.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Menon, Preeti K.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ivanova, Elena V.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Bacanu, Smaranda
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Nuclear localization of amyloid-beta precursor protein-binding protein Fe65 is dependent on regulated intramembrane proteolysis2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 3, article id e0173888Article in journal (Refereed)
    Abstract [en]

    Fe65 is an adaptor protein involved in both processing and signaling of the Alzheimer-associated amyloid-beta precursor protein, APP. Here, the subcellular localization was further investigated using TAP-tagged Fe65 constructs expressed in human neuroblastoma cells. Our results indicate that PTB2 rather than theWWdomain is important for the nuclear localization of Fe65. Electrophoretic mobility shift of Fe65 caused by phosphorylation was not detected in the nuclear fraction, suggesting that phosphorylation could restrict nuclear localization of Fe65. Furthermore, both ADAM10 and gamma-secretase inhibitors decreased nuclear Fe65 in a similar way indicating an important role also of alpha-secretase in regulating nuclear translocation.

  • 7.
    Koistinen, Niina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holback, Sofia
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    siRNA knock-down of Fe65 in SH-SY5Y cells decreases the levels of C-terminal fragments of APP without any effect on sAPPα secretionManuscript (preprint) (Other academic)
    Abstract [en]

    Fe65 is an adaptor protein that binds to the amyloid precursor protein (APP) within the 82YENPTY687 motif of APP which is important for amyloid β (Aβ) production. Considering that Fe65 binds to this motif, it can be hypothesized that Fe65 may influence the trafficking of APP and hence its processing by α- and/or β-secretase. Therefore in this study we wanted to determine how knock-down of Fe65 effects the processing of endogenous APP in human SH-SY5Y neuroblastoma cells. Our results showed that Fe65 knock-down did not have any effect on sAPPα secretion in SH-SY5Y cells. However, decreased levels of membrane-bound APP stubs C83 and C99 were observed, suggesting that Fe65 has a stabilizing effect on the C-terminal fragments. Furthermore, we wanted to investigate effects of retinoic acid (RA)-induced neronal differentiation on Fe65 expression. It has previously been shown that under these conditions mRNA and protein levels of APP increase concomitant with increased secretion of sAPPα, shifting the processing of APP to the more non-amyloidogenic pathway. We observed that RA-induced neuronal differentiation increases the protein levels of Fe65 in SH-SY5Y cells and gives rise to an electrophoretic mobility shift due to increased phosphorylation. The increased expression levels of Fe65 during neuronal differentiation concomitant with the increase of Fe65 phosphorylation, suggest that Fe65 and its phosphorylation may play a role during neuronal differentiation.

  • 8.
    Koistinen, Niina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Menon, Preeti
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ivanova, Elena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kumcu, Michael
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    ADAM10 dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 is attenuated in neuronally differentiated SH-SY5Y cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Fe65 is a brain enriched adaptor protein involved in various cellular processes. These processes may include regulated intramembrane proteolysis (RIP) of the amyloid-β precursor protein (APP) and transcriptional activation. However, much still needs to be learned regarding the regulation of Fe65 functions throughout the cell. In this study we therefore investigated the role of Fe65 Ser228 phosphorylation and α-secretase processing of proteins like APP undergoing RIP, in the regulation of Fe65 nuclear localization. We found that although Ser228 phosphorylation is not a major regulator of Fe65 nuclear localization, mutation of Ser228 results in an increased interaction with APP, suggesting that the N-terminal domain of Fe65 may have a more prominent role in mediating the Fe65-APP interaction than previously thought.  Moreover, we found that α-secretase processing play a key role in promoting Fe65 nuclear localization, but while ADAM10 play a considerable role in undifferentiated cells, other α-secretases take a more prominent part in releasing Fe65 from the plasma membrane in differentiated cells.      

  • 9.
    Koistinen, Niina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Menon, Preeti
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    APP Ser675 phosphorylation affects α-secretase processing resulting in decreased secretion of the neuroprotective ectodomain sAPPαManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of the amyloid-β (Aβ) peptide. Aβ is produced after amyloidogenic (β-secretase) processing of the transmembrane amyloid precursor protein (APP). However, APP can also be processed by α-secretases, instead resulting in release of neuroprotective sAPPα.  Growing evidence indicate that aberrant post-translational modifications of APP may play a pivotal role in AD pathogenesis by dysregulating APP processing. APP Ser675 phosphorylation occurs in AD brains and here we for the first time show that this phosphorylation decreases the release of sAPPα, while the level of an alternative APP-C83-CTF fragment is increased. Moreover, we found that while APP Ser675 phosphorylation increased the APP-Fe65 interaction, the level of APP at the plasma membrane were unaltered. Taken together these results suggest that APP Ser675 phosphorylation alters the α-secretase processing of APP at the plasma membrane. As α-secretase processing of APP is an essential step in decreasing the generation of Aβ these results suggest that Ser675 phosphorylation could contribute to AD pathology.

  • 10.
    Menon, Preeti
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Koistinen, Niina
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    APP Ser675 phosphorylation alters APP processing resulting in decreased secretion of neuroprotective ectodomain sAPPalphaManuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of amyloid-β (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP) and aberrant post-translational modifications of APP could alter APP processing and increased Aβ generation. In AD brain, seven different residues, including Ser675 (APP695 numbering), in the APP cytoplasmic domain has been found to be phosphorylated. Here we for the first time show that phosphorylation of APP at Ser675 alters APP processing, without affecting the plasma membrane level of APP. The altered processing results in increased expression of an alternative CTF, similar in size to β-secretase generated C99, but sensitive to metalloprotease inhibitors. Moreover, reduced secretion of sAPPα, as well as total sAPP, was observed. Taken together these findings suggest that Ser675 phosphorylation likely promote APP processing by the metalloprotease Meprin β, an alternative β-secretase localized at the plasma membrane and known to generate a C99 like CTF, but no sAPP fragments. As previous studies have shown that the Meprin β CTF can be furthered processed by γ-secretase yielding highly aggregate prone, truncated Aβ peptides, an increased Meprin β processing of APP upon Ser675 phosphorylation could contribute to AD pathology. It will hence be of importance to clarify how APP Ser675 phosphorylation could promote Meprin β cleavage at the plasma membrane in future studies.

  • 11.
    Revol, Rebecca
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Koistinen, Niina A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Menon, Preeti K.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Chicote-Gonzalez, Almudena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair2023In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 127, article id 103903Article in journal (Refereed)
    Abstract [en]

    Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-beta precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following beta and gamma-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different alpha-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon gamma-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) alpha-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of alpha-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that alpha-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.

1 - 11 of 11
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