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    EFFECTS OF ALZHEIMER’S DISEASE GENETIC RISK FACTOR APOE4 ON THE NORMAL BRAIN

    Cover for EFFECTS OF ALZHEIMER’S DISEASE GENETIC RISK FACTOR APOE4 ON THE NORMAL BRAIN
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    View/Open: DiBattista_georgetown_0076D_13168.pdf (17.MB) Bookview

    Creator
    DiBattista, Amanda Marie
    Advisor
    Rebeck, G. William
    ORCID
    0000-0001-6047-7490
    Abstract
    Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer’s disease (AD), the E4 allele for apolipoprotein E (APOE4), but have few strategies to reduce their risk. To identify markers associated with APOE genotype, we have examined APOE4 knock-in mice, which display deficits in spatial learning and dendritic spine density in the medial entorhinal cortex, an area of the brain affected early in AD. Here, we report new APOE4-associated phenotypes in mice: increased levels of post-translational modifications (PTMs) of APOE via O-linked glycosylation and sialylation, increased ATP-Binding Cassette Transporter A1 (ABCA1) levels, increased Glucose Transporter 1 (GLUT1) levels, and decreased medial temporal lobe volume.
     
    We examined these phenotypes after putative AD preventive drug treatments to investigate whether APOE4-associated phenotypes are modifiable. Epidemiology studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce AD risk, particularly in APOE4-carriers. Thus, we treated APOE4 mice with NSAID ibuprofen, which acts as both a COX-2 inhibitor and PPAR-γ agonist. We also treated independent cohorts of animals with a selective COX-2 inhibitor (celecoxib) and a PPAR-γ agonist (pioglitazone). We found that ibuprofen fully mitigated, while celecoxib and pioglitazone partially mitigated, the APOE4-associated phenotypes, suggesting that both targets of ibuprofen are important for its effects.
     
    To identify the mechanism by which APOE affects dendritic spine density and cognition, we also studied the APOE receptor Very Low Density Lipoprotein Receptor, VLDLR. We discovered that VLDLR is found at the synapse, and dendritic spine number was dependent on VLDLR expression. Additionally, VLDLR knockdown differentially regulated levels of glutamate receptor subunits. We further found that VLDLR interacts with the Ras signaling pathway, which is involved in spinogenesis and neurodegeneration, to exert its effects at the synapse.
     
    Importantly, these findings have relevance in human APOE4-carriers. As seen in mice, alterations in PTMs of APOE and medial entorhinal cortex volume were observed in human APOE4 carriers. Functionally, APOE4 risk also contributed to performance on a memory task. These findings demonstrate that APOE4 mice are a powerful model to identify measures of APOE-associated AD risk, and demonstrate a mechanism by which ibuprofen may reduce risk of AD in APOE4 carriers.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/1040759
    Date Published
    2016
    Subject
    APOE; entorhinal cortex; ibuprofen; NSAID; spatial learning and memory; VLDLR; Neurosciences; Neurosciences;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    195 leaves
    Collections
    • Graduate Theses and Dissertations - Neuroscience
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      Alzheimer's disease (AD), unlike the other leading causes of death, does not have a cure or an effective intervention strategy. The largest genetic risk factor for AD is APOE, with the ε4 allele increasing and the ε2 allele ...
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    Georgetown University Seal
    ©2009 - 2022 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility