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    Clusterin in the Brain

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    Available after: 2018-12-31 (10.63Mb)
    Issue Date
    2017-12-31
    Author
    Woody, Sarah Katharyn
    Publisher
    University of Kansas
    Format
    200 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmacology & Toxicology
    Rights
    Copyright held by the author.
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    Abstract
    Late-onset Alzheimer’s disease (LOAD) is an age-related chronic neurodegenerative disorder traditionally characterized by the presence of neurotoxic amyloid beta (Aβ) plaques, neurofibrillary tangles, and progressive, irreversible cognitive decline. Though extensively studied, the molecular mechanisms underlying the onset of AD-related neuropathologies are not understood. Moreover, over 200 clinical trials have failed to produce a viable therapeutic treatment strategy in the last 15 years. The inability to generate a treatment for clinical AD has led to a shift in focus from disease treatment to disease prevention and early intervention in the preclinical stage of AD development (pAD). As sex, genetics, and epigenetic influence have been identified as key contributors to early neurophysiological changes, it is imperative that research be conducted to elucidate intersecting risk mechanisms that would allow for the development of novel therapeutic entities that could be targeted in pAD. Clusterin (CLU), initially identified in 1983, is a multifaceted, nearly ubiquitously expressed homeostatic regulator that is postulated to exist as multiple protein isoforms including a glycosylated mature/secreted form (mCLU) and smaller non-modified nuclear and/or intracellular forms. CLU, also known as apolipoprotein J (APOJ) which belongs to the same protein family as APOE, is currently listed as the third most potent genetic risk factor for the development of LOAD. However, despite many clinical observations of CLU SNPs-conferred increased AD risk, an extensive gap exists pertaining to the basic molecular properties of CLU in the healthy brain. Therefore, this dissertation focuses on the neurophysiological characterization of brain CLU with specific emphasis on understanding the expression, distribution, and potential physiological function(s) of individual CLU protein isoforms. The data indicate that at least two CLU mRNAs are generated from the CLU gene which are translated to 3 different CLU pre-proteins. These pre-proteins, which are differentially modified by N-linked glycosylation, are targeted to distinct cellular compartments in both adult rodent brain and embryonic brain cell types. Moreover, we observe a distinct difference in the CLU protein expression profile between astrocytes and neurons with astrocytes generating and secreting extracellular mCLU and neurons primarily generating intracellular CLU protein isoforms. Of particular significance, we demonstrate for the first time that CLU protein isoforms are integrally associated with brain mitochondrial function. Specifically, we identify a previously unknown mitochondria-targeted CLU protein isoform that is localized to the mitochondrial matrix where it directly interacts with a key component of the MICOS complex. In addition, the data indicate that non-mitochondrial CLU regulates some aspect of brain mitochondrial respiration in young adult female mice. Furthermore, we show for the first time that the mCLU pre-protein is significantly and positively regulated by estrogen in the brain. Specifically, the data indicate direct ligand-mediated regulation via estrogen receptor beta (ERβ) signaling through one or more previously unidentified estrogen receptor response elements on the CLU promoter. Collectively, these data suggest a possible hypothesis whereby CLU SNPs, which are associated with reduced circulating CLU, may contribute increased AD risk via interaction with brain mitochondrial bioenergetics and female sex hormones.
    URI
    http://hdl.handle.net/1808/27337
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    • Pharmacy Dissertations and Theses [118]
    • Dissertations [4321]

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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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