Date of Award
Doctor of Philosophy (PhD)
Brain energy metabolism is vital for many cellular processes including homeostasis and thus disturbances to metabolism can be the cause or consequence of neurodegeneration. Metabolic discrepancies have been hypothesized to be involved but less frequently demonstrated to be manipulated by acute and chronic neurodegenerative disorders such as stroke, traumatic brain injury, and epilepsy. I hypothesized that cerebral energy levels are decreased in my model systems for Alzheimer's disease, Autism, Down syndrome, and HIV-1 dementia and that dietary treatments could enhance energy reserves and protect against neurodegenerative disease. For rodent studies, I utlilized a high-energy head focused microwave irradiation system to kill animals but most importantly to snap-inactivate all cerebral enzymes, including those that contribute to the rapid degradation of high-energy phosphate compounds. I found that energy levels are diminished in a high-cholesterol diet model for Alzheimer's disease in rabbit, a trisomic mouse model for Down syndrome (Ts65Dn), and following administration of Tat to primary mouse cortical cultures as a model for HIV-1 dementia. My experiments also examined the extent to which protection is provided by creatine supplementation and the ketogenic diet in models of HIV-1 dementia and epilepsy, respectively. Creatine bioenergetically protected against Tat-induced decreases in cellular levels of ATP, Tat-induced mitochondrial hypopolarization, and Tat-induced mitochondrial permeability transition pore opening. My calorie restricted ketogenic diet studies demonstrated this diet's ability to protect against chemically induced seizures. As well, I observed a coordinated upregulation of all differentially regulated transcripts encoding energy metabolism enzymes, increased numbers of mitochondrial profiles, and ultimately augmented high-energy phosphate levels in seizure naïve rats. My studies demonstrate compromised brain energy levels in the aforementioned neurodegenerative disorders and that dietary treatments such as creatine supplementation for HIV-1 dementia and the ketogenic diet for epilepsy, may protect cerebral function by enhancing neuroenergetics.
Gawryluk, Jeremy W., "Alterations of High-Energy Brain Metabolites Across Multiple Neurodegenerative Disorders" (2009). Theses and Dissertations. 902.