Georgetown University LogoGeorgetown University Library LogoDigitalGeorgetown Home
    • Login
    View Item 
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Pharmacology and Physiology
    • Graduate Theses and Dissertations - Pharmacology
    • View Item
    •   DigitalGeorgetown Home
    • Georgetown University Institutional Repository
    • Georgetown University Medical Center
    • Biomedical Graduate Education
    • Department of Pharmacology and Physiology
    • Graduate Theses and Dissertations - Pharmacology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    ACTIVITY-DEPENDENT REGULATION OF AMYLOID PRECURSOR PROTEIN (APP) BY POLO-LIKE KINASE 2 (PLK2): NOVEL ROLES IN SYNAPTIC PLASTICITY

    Cover for ACTIVITY-DEPENDENT REGULATION OF AMYLOID PRECURSOR PROTEIN (APP) BY POLO-LIKE KINASE 2 (PLK2): NOVEL ROLES IN SYNAPTIC PLASTICITY
    View/Open
    View/Open: Lee_georgetown_0076D_13430.pdf (3.0MB) Bookview

    Creator
    Lee, Ji Soo
    Advisor
    Pak, Daniel T.S.
    Abstract
    The brain uses a special feature, synaptic plasticity, for learning and memory. As forms of synaptic plasticity, associative plasticity, long-term potentiation (LTP) and long-term depression (LTD), is a positive feedback mechanism for memory encoding, whereas homeostatic plasticity (HSP) is a tuning process to stabilize neural networks. The synaptic plasticity is impaired in neurodegenerative disorders, including Alzheimer disease (AD). AD demonstrates pathological hallmarks, neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid β (Aβ) which is a proteolytic fragment of the amyloid precursor protein (APP). While APP expression facilitates synaptic formation and transmission, APP processing by synaptic activity and APP knock-out contribute to synaptic depression, suggesting APP involvement in synaptic plasticity. However, the physiological roles of APP and APP processing are not well understood.
     
    Herein, we identify novel functions of APP and APP processing in synaptic plasticity and suggest their contribution to memory and AD pathogenesis. In heightened synaptic activity, Polo-like kinase 2 (Plk2), a homeostatic repressor of overexcitation, phosphorylates T668 and S675 of APP and promotes APP β-processing. Plk2 levels in brains of AD mouse models and patients are elevated in both a spatial and temporal manner. Genetic blockade of Plk2 kinase function prevents plaque deposits and activity-dependent Aβ production, and pharmacological inhibition hinders Aβ formation, synapse loss, and memory decline in AD mouse models. Furthermore, APP phosphorylation at T668 and S675 by Plk2 promotes GluA2 endocytosis in HSP. On the other hand, blocking phosphorylation of S655 and T686 inhibits GluA2 internalization in NMDAR-LTD. The synaptic connection between APP and GluA2 appears to occur via N-ethylmaleimide-sensitive factor (NSF).
     
    Overall, Plk2-mediated Aβ production links synaptic overactivity to APP β-processing and synaptic depression; this process supports a physiological role for Plk2 as a homeostatic modulator. Pathological conditions in AD, however, disturb this homeostatic balance and increase Aβ production by Plk2. Moreover, regulation of GluA2-containing AMPAR trafficking by exclusive dual phosphosites of APP in HSP and LTD implicates a role for APP in the cellular mechanisms underlying learning and memory. Thus, alterations in APP phosphorylation or related kinases may have effects on cognitive processes in the brains.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1041853
    Date Published
    2016
    Subject
    Neurosciences; Molecular biology; Medicine; Neurosciences; Molecular biology; Medicine;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    110 leaves
    Collections
    • Graduate Theses and Dissertations - Pharmacology
    Metadata
    Show full item record

    Related items

    Showing items related by title, author, creator and subject.

    • Cover for Identification of NF-kappa B and DNA-dependent protein kinase (DNA-PK) as new players
      in the regulation and signaling of the oncogenic phosphatase Wip1

      Identification of NF-kappa B and DNA-dependent protein kinase (DNA-PK) as new players in the regulation and signaling of the oncogenic phosphatase Wip1 

      Lowe, Julie. (Georgetown University, 2010)
    Related Items in Google Scholar

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility
     

     

    Browse

    All of DigitalGeorgetownCommunities & CollectionsCreatorsTitlesBy Creation DateThis CollectionCreatorsTitlesBy Creation Date

    My Account

    Login

    Statistics

    View Usage Statistics

    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility