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. / Psychology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/4712 |
| Date | January 2020 |
| Creators | Duggan, Michael Ronan |
| Contributors | Parikh, Vinay, Olson, Ingrid, Khalili, Kamel, Giovannetti, Tania, Wimmer, Mathieu, Drabick, Deborah A. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 180 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/4694, Theses and Dissertations |
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