Author ORCID Identifier
Date of Award
Doctor of Philosophy (PhD)
Basic Biomedical Science
Alzheimer’s Disease (AD) is a devastating disorder with no disease-modifying agent that stops or reverses the progression of the disease. Exosomes, 50 – 150 nanometers in diameter extracellular vesicles, play a role in intracellular communication and are currently being explored as a therapeutic agent in various diseases. In addition, exosomes possess favorable characteristics as a therapy; however, their low yield following isolation hinders their ability as a therapeutic agent. We exposed neuroprogenitor cells to heat shock (HS) before exosomes were isolated to explore the possibility of increasing exosome secretion. HS-derived exosomes exhibit significantly increased concentration and diameter compared to non-heat shock (NHS)-derived exosomes. The therapeutic efficacy of exosomes was tested in vitro and in vivo. HS-derived exosomes protect against amyloid- induced toxicity and improve the learning and memory capabilities of AD mice. Next, the role of the ubiquitin-proteasome system in AD was explored using a genetic mouse model to ablate the expression of Psmc1, a subunit of the 19S proteasome, in neurons of the forebrain region. Psmc1 knockout (KO) animals exhibit an impairment in learning and memory, synaptic loss, protein aggregation, accumulation of the transcription factor Nuclear Factor Kappa B (NF- B), and neuroinflammation, all hallmarks of AD. To reverse the overt neuroinflammatory response in Psmc1 KO animals, we administered PDTC, an NF- B inhibitor, at five weeks of age. PDTC treatment reverses the learning and memory deficits caused by 26S proteasome disruption. Finally, the role of UBE2O, an E2/E3 hybrid enzyme, was explored in aging and AD. The expression of UBE2O increases with aging; proteasome activity is significantly decreased in the brains of UBE2O KO animals. These data provide support for HS-derived exosomes as a therapy for AD, the causative role of the proteasome in AD, and UBE2O as a therapeutic target in AD.
Alzheimer's Disease, Exosomes, Neuroinflammation, Proteostasis, Ubiquitin-Proteasome System
Number of Pages
University of South Dakota
Huber, Christa C., "Proteostasis & Neuroinflammation in Alzheimer's Disease" (2023). Dissertations and Theses. 132.