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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Early molecular events preceding hallmark structural pathology in animal models of neurodegenerative disease

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    Date
    2015
    Author
    Gertner, Michael J.
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    Abstract
    Neurodegenerative diseases that affect the hippocampus include Alzheimer's disease, frontotemporal dementia, ischemic stroke, and others that are characterized by extensive neuronal loss and learning and memory deficits. Transient global or forebrain ischemia elicits delayed neurodegeneration that is restricted mainly to hippocampal CA1 (but not CA3) pyramidal neurons. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, development and homeostasis, mediating the balance between protein synthesis and protein degradation via its impact on the autophagy pathway. However, a causal role for mTOR function in the neuronal death associated with global ischemia remains unknown. In my first project, I demonstrated that mTOR is regulated at the level of protein stability following global ischemia in vivo. The decrease in mTOR protein abundance is accompanied by an increase in biochemical markers of autophagy, suggesting that global ischemia induces autophagy induction and clearance of autophagy cargo. I further showed that inhibitors of lysosomal (but not proteasomal) degradation rescue the ischemia-induced decrease in mTOR protein, suggesting that mTOR is degraded by the lysosome following global ischemia. Both siRNA targeting mTOR and pharmacological inhibition of mTOR, when administered before induction of ischemia, upregulate autophagy and partially attenuate ischemia-induced neuronal death. In a second project, I investigated a role for the Alzheimer's risk gene presenilin/gamma-secretase in synaptic function. An emerging view is that loss-of-function of the presenilin/y-secretase complex contributes to synaptic deficits and cognitive decline in familial Alzheimer's disease before the appearance of structural pathology and neurodegeneration. I found that two structurally distinct gamma-secretase inhibitors increased the amplitude and frequency of spontaneous glutamatergic transmission but did not alter forms of long-lasting plasticity such as long-term depression. gamma-secretase inhibitors enhanced basal synaptic transmission at high stimulus intensities but did not alter paired-pulse facilitation, a measure of presynaptic release probability. I also demonstrated that gamma-secretase inhibitors block the reduction in synaptic AMPAR expression and stabilizes the ephrinB2-GRIP-GIuA2 complex. In both Alzheimer's disease and ischemic stroke, molecular signaling pathways gone awry are critical elements to the pathophysiology of the disease even before the onset of structural abnormalities and neurodegeneration.
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    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3663230
    https://hdl.handle.net/20.500.12202/1531
    Citation
    Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.;Advisors: R. Suzanne Zukin.
    *This is constructed from limited available data and may be imprecise.
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    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

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