Browsing Theses and Dissertations by Author "Duggan, Michael Ronan"
The Role of HIV Proteins in Mediating Neuronal Mechanisms Implicated in Age-Related Cognitive DysfunctionParikh, Vinay; Olson, Ingrid; Khalili, Kamel; Giovannetti, Tania; Wimmer, Mathieu; Drabick, Deborah A. (Temple University. Libraries, 2020)While the proportion of aged individuals is increasing across populations, therapeutic advances have resulted in a particular increase amongst aged persons living with HIV, who maintain an elevated risk for developing HIV-Associated Neurological Deficits (HANDs). To determine the neurobiological mechanisms of HAND, the current experiments assessed if mechanistic insights from Alzheimer’s Disease, such as oxidative stress and protein quality control (i.e. stress granules, BAG chaperones), may similarly contribute to neuronal dysfunction in response to HIV proteins Tat and Nef. Although data indicate limited effects on stress granules, Tat and Nef facilitated elevations in intraneuronal oxidative stress, decreased BAG1 transcription and suppressed BAG3 levels (i.e. protein and RNA), while these disrupted mechanisms coincided with impaired electrophysiological firing capacities in neurons. Oxidative stress, in the form of H2O2, exacerbated the reduction in BAG3, induced an upregulation of BAG1 and dysregulated key mitochondrial proteins. Such inverse BAG chaperone ratios were maintained in two animal models which express viral proteins in the CNS, the doxycycline-inducible Tat (iTat) and Tg26 mouse. Interestingly, the inhibition of oxidative stress in primary neurons was capable of partially preserving electrophysiological functioning and BAG3 levels otherwise altered by HIV viral proteins. Results suggest oxidative stress induced by HIV proteins or other factors (i.e. aging) may dysregulate neuronal PQC, particularly BAG chaperones, and contribute to the neurobiological mechanisms underlying HAND.