Browsing by Subject "Alzheimer’s disease"
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Item N-Acylethanolamine Signaling in Neurons(2008-12-01) Duncan, Raymond Scott; Koulen, Peter; Simpkins, James; Forster, MichaelDuncan, Raymond S., N-acylethanolamine signaling in neurons. Doctor of Philosophy (Biomedical Sciences), December 2008, 356 pp., 1 table, 70 illustrations, bibliography, 576 titles. Neurodegenerative diseases including Alzheimer’s disease are and will continue to be significant health problems as the aging population increases. The maintenance of neuronal calcium homeostasis has been a focus in degenerative disease research for many years. Within the last several years, lipids that activate cannabinoid receptors, and thus called cannabinoids, have gained recognition as neuroprotectants in models of neurodegenerative diseases. A subset of these cannabinoids, the N-acylethanolamines (NAEs), includes the well characterized neuroprotective lipid, arachidonylethanolamine. Other NAEs, such as palmitoylethanolamine (PEA), are more abundant in neurons and do not activate cannabinoid receptors, suggesting other targets for these lipids exist. Since non-cannabinoid NAEs rapidly accumulate after neuronal injury, it is likely they play a role in cellular responses to injury. Interestingly, some NAEs can alter intracellular Ca2+ signaling, but the underlying mechanism of action remains unclear. I hypothesized that the non-cannabinoid NAEs, such as PEA, protect the hippocampal cell line, HT22, from oxidative stress in part by reducing intracellular calcium release. I determined that HT22 cells and cultured mouse cortical neurons express proteins involved in NAE signaling, thus warranting the use of pharmacological inhibitors of these proteins in subsequent neuroprotection studies. Using HT22 cells, I determined that PEA exhibitis antiproliferative effects and neuroprotects against oxidative stress. In addition, I determined that PEA facilitates the nuclear translocation of putative protective proteins that can be regulated by Ca2+ through a mechanism not involving cannabinoid receptor activation. These findings led me to hypothesize that PEA alters release of Ca2+ from intracellular stores. To test this hypothesis, I determined that our cell models express inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) both of which are intracellular Ca2+ channels elevated in response to oxidative stress. I determined that treatment of HT22 cells with PEA reduced intracellular Ca2+ release elicited by chemical depolarization with KCI. My results suggest that non-cannabinoid NAEs, such as PEA, protect the hippocampal cell line, HT22, from oxidative stress in part by activating putative neuroprotective signaling proteins and by reducing intracellular calcium release.Item Translational Control by Estrogen-Induced Signaling in Primary Rat Hippocampal Neurons(2008-07-01) Smith, Lonell T.; Simpkins, James; Das, Hriday K.; Machu, Tina K.Smith, Lonell T., Estrogen-Induced Signaling in Primary Rat Hippocampal Neurons. Masters (Biomedical Sciences). July 2008. 53 pages, 1 illustration, 7 figures. 37 titles. Abstract. The enhancing effects of 17-beta estradiol (E2) on performing cognitive tasks has been well demonstrated in laboratory mice, rats, and primates. Also there is ample clinical evidence indicating E2 enhances memory and reduces risk for Alzheimer’s disease. Furthermore, by increasing the capacity for long-term potentiation (LTP) in the hippocampus, E2 effectively increases the synaptic plasticity of this brain region in a manner that correlates with memory formation. The molecular mechanisms underlying LTP and synaptic plasticity have largely focused on the role of E2-induced signal transduction in the nucleus, and regulation of plasticity related gene expression at the transcriptional level. Conversely, the idea that E2-incuded signaling regulates at the level of translation and may play a role in these processes has yet to be explored. Recently, extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways have been shown to couple synaptic activation to protein synthesis machinery. Here we investigate translational control by E2-induced ERK and mTOR signaling in primary neuronal culture. E2-induced signaling resulted in enhanced phosphorylation of ribosomal protein (S6) and eIF4E binding protein 1 (4EBP1) in an ERK and mTOR-dependent manner. Neuronal activity-dependent ERK and mTOR signaling have been shown to induce translation of a diverse array of dendritic resident mRNAs, including α-CaMKII and GluR1 subunits. Using a green fluorescent protein (GFP) translational reporter, we demonstrated that E2 stimulates GFP protein synthesis. We have also demonstrated that E2 treatment of hippocampal neurons increases surface expression of GluR1. Taken together, our results provide a mechanism by which E2 modulates the components necessary for persistent forms of LTP and long-term depression (LTD).