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    Inhibition of Alzheimer’s type toxic aggregates of tau with fungal secondary metabolites

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    Paranjape_ku_0099D_14219_DATA_1.pdf (4.366Mb)
    Issue Date
    2015-08-31
    Author
    Paranjape, Smita Ramesh
    Publisher
    University of Kansas
    Format
    175 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Molecular Biosciences
    Rights
    Copyright held by the author.
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    Abstract
    Tau is a microtubule-associated protein that is typically found in the axons of neurons. The aggregation of the tau is a significant event in many neurodegenerative diseases including Alzheimer's disease. In these disease tau dissociates from microtubules and begins to form toxic insoluble intracellular tau aggregates. The process of conversion of soluble monomeric tau to insoluble aggregates in not well understood. Differential conformational changes in pathological forms of the protein may affect its propensity for aggregation and function. Post translational modifications such as hyperphosphorylation or truncation may induce these conformational changes and alter aggregation and function. The studies described here used in vitro assays to determine how truncation affects tau conformation and how they can alter aggregation and function. This information helps to describe how intrinsic differences due to modifications of tau can manifest themselves in the varying pathologies of tauopathies. Tau aggregation in a common mode of pathogenesis in tauopathies, including Alzheimer's disease. Tau aggregation correlates with dementia and neurodegeneration and is viewed as a potential therapeutic target for AD. Fungi have historically been a good source of medicinally important compounds. We identified secondary metabolites obtained from Aspergillus nidulans as tau aggregation inhibitors. We identified a novel class of tau aggregation inhibitors, azaphilones. Four of the azaphilones inhibited tau aggregation and disassembled pre-formed tau aggregates without inhibiting tau’s ability to polymerize microtubules. Preliminary NMR studies showed that our most potent azaphilone, aza-9 interacts with specific residues of tau protein in a dose dependent fashion. Aza-9 also disassembled tau aggregates formed by aggregation enhancing truncation mutant 1-391 in a dose dependent fashion. Azaphilones are therefore very promising lead compounds for tau aggregation inhibitors, provide a novel scaffold for the same and represent a new class of compounds with tau aggregation inhibitor activity.
    URI
    http://hdl.handle.net/1808/21597
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    • Dissertations [4475]
    • Molecular Biosciences Dissertations and Theses [270]

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    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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