• Login
    View Item 
    •   Home
    • Theses and Dissertations
    • Theses and Dissertations
    • View Item
    •   Home
    • Theses and Dissertations
    • Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of TUScholarShareCommunitiesDateAuthorsTitlesSubjectsGenresThis CollectionDateAuthorsTitlesSubjectsGenres

    My Account

    LoginRegister

    Help

    AboutPeoplePoliciesHelp for DepositorsData DepositFAQs

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    MODULATION OF THE 5-LIPOXYGENASE PROINFLAMMATORY PATHWAY AND ENDOSOMAL RETROMER SORTING COMPLEX AND THE DEVELOPMENT OF THE TAUOPATHY PHENOTYPE

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    TETDEDXVagnozzi-temple-0225E-1 ...
    Size:
    4.288Mb
    Format:
    PDF
    Download
    Genre
    Thesis/Dissertation
    Date
    2019
    Author
    Vagnozzi, Alana Noelle
    Advisor
    Praticò, Domenico
    Committee member
    Unterwald, Ellen M.
    Ramirez, Servio H.
    Abood, Mary Ellen, 1958-
    Bennett, Michael J., 1951-
    Department
    Biomedical Sciences
    Subject
    Neurosciences
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/3988
    
    Metadata
    Show full item record
    DOI
    http://dx.doi.org/10.34944/dspace/3970
    Abstract
    Neurodegenerative tauopathies represent a heterogeneous group of central nervous system (CNS) diseases characterized by accumulation of insoluble neurofibrillary tangles of tau protein, synaptic dysfunction, neuroinflammation, and progressive neuronal loss, culminating in debilitating cognitive decline. In recent years, studies have attempted to elucidate potential mechanisms underlying the pathogenicity of tauopathies, with particular focus on preventative strategies that may target key initiating factors or events which occur before the onset of memory loss and neurofibrillary tangle deposits in the brain. Two such potential initiating events are neuroinflammatory activation and improper protein sorting via the endosomal-lysosomal trafficking network. This work describes two novel players in each biological system, the 5-lipoxygenase proinflammatory pathway and its relevance to the neuroinflammatory response as well as the endosomal retromer complex in protein recycling. Importantly, we investigate the contribution of these pathways in the development of tau accumulation and pathology, with the ultimate goal to demonstrate the therapeutic potential of these novel players in neurodegeneration. In current literature, there is great debate whether neuroinflammation functions as a primary or secondary pathogenic event in tauopathies. Furthermore, investigating novel pathways which activate inflammation in the CNS is an integral part of understanding their relevance to neurodegeneration. Recent studies implicate the proinflammatory 5-lipoxygenase (5LO) enzymatic pathway as a potential effector of neuroinflammation in Alzheimer’s disease (AD); however, little is known about the role of 5LO on tau pathology in the absence of amyloid beta. Thus, our work focused on investigating the contribution of the 5LO pathway in tauoapthy by implementing a genetic approach to modulate this enzyme in a P301S mouse model of tauopathy and in neuronal cells. First, we provide evidence for an age-dependent and region-specific upregulation of the 5LO pathway (protein, message and activity) in a transgenic mouse model of tauopathy. Additionally, global genetic deletion of 5LO in this mouse model results in significant memory improvement, reduces neuroinflammation in association with reduced tau phosphorylation at specific epitopes, and improves synaptic pathology. Utilizing the opposite approach by overexpressing 5LO using AAV2/1, we demonstrate that tau mice given AAV-5LO perform significantly worse on several cognitive assessments, display elevated tau pathology and neuroinflammation, and have greater synaptic pathology. Mechanistically, the effect of 5LO modulation on tau phosphorylation is dependent on the activity of kinase, cdk5, as confirmed in a neuronal cell line. Simultaneously, an equally important aspect of tauopathies is the inefficient sorting and degradation of accumulated proteins in the brain. Improper degradation of toxic proteins is considered an early event in pathogenesis, and thus, targeting this aspect of neurodegeneration has received considerable attention in recent years. One such sorting mechanism, the endosomal retromer complex, has been implicated in abnormal processing of amyloid precursor protein (APP) and accumulation of amyloid beta (Aβ) within endosomes. Most notably, a small pharmacological chaperone mitigated this retromer-dependent effect on Aβ in primary hippocampal neurons. Current studies have only recently focused on the relationship between the retromer complex and tau accumulation, thus our aim was to investigate the effects of retromer dysfunction on the development of the tauopathy phenotype. First, we assessed that core components of the retromer complex are down-regulated in two distinct human primary tauopathies in cortical and hippocampal brain regions. Furthermore, retromer core protein levels are reduced in an age-dependent and region-specific manner in P301S mice. To manipulate the retromer complex, first, using a genetic approach, we demonstrate that knockdown of VPS35 using shRNA AAV resulted in exacerbation of cognitive and motor learning deficits in P301S mice. This coincided with greater accumulation of pathological and phosphorylated tau, increased neuroinflammation, and elevated synaptic pathology. Second, utilizing TPT-260, a pharmacological stabilizer of VPS35, we demonstrate ameliorated behavioral performance, reduced tau pathology and neuroinflammation, and rescued synaptic pathology in P301S mice. Finally, using a neuronal cell line, we confirm the direct role of VPS35 on tau phosphorylation and accumulation using genetic and pharmacological manipulation of VPS35, the effect of which, is mediated by lysosomal protease, cathepsin D. Taken together, our data reveal a direct role of the 5LO proinflammatory pathway on tau phosphorylation as well as a VPS35-dependent effect on tau solubility and pathological accumulation. Importantly, this work highlights the relevance of investigating the mechanisms that underscore neuroinflammatory activation and improper protein sorting in tauopathies and the potential of targeting these pathways for therapeutic intervention in neurodegenerative diseases.
    ADA compliance
    For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
    Collections
    Theses and Dissertations

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Temple University Libraries | 1900 N. 13th Street | Philadelphia, PA 19122
    (215) 204-8212 | scholarshare@temple.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.