Effects of Pterostilbene and OSI-027 on Hyperphosphorylated Tau and mTOR in Rat Hippocampal Astrocytes

Date of Award

6-2020

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Harold Komisky, PhD

Second Advisor

Dennis Peffley, JD, PhD

Third Advisor

Xinyu Wang, PhD

Fourth Advisor

Richard White, PhD

Abstract

The pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease share an involvement of Tau aggregation in neuronal cells and glial cells. Tau has shown to be a crucial component in functioning neurons, and its aggregation in glial cells such as astrocytes has become a target in uncovering a treatment for neurodegenerative diseases. When Tau becomes altered to a pathological state, it is unable to stabilize the microtubules of the cell. In the case of AD, neuronal stability cannot be maintained. Hyperphosphorylated Tau form aggregates often called Tau tangles. These tangles are insoluble, and have been associated with the pathological symptoms seen in neurodegenerative diseases. Astrocytes have a major neuroprotective role, including homeostasis and autophagy that allows for the clearance of dysfunctional proteins, such as hyperphosphorylated Tau in the central nervous system. Rapalogues, functional analogues to Rapamycin, offer an alternate solution as they may reduce the biological limitations of mTORC1 blockades that can be seen in long-term use of Rapamycin. In effect, this research aims to explore two potential therapeutic compounds, including the second generation mTOR inhibitor OSI-027 as well as the naturally produced pterostilbene (PT). OSI-027 is a potential alternative chemical that provides higher tolerability to chronic use of mTORC1/mTORC2 inhibitors and a means of mediating the progression of AD by inducing autophagy. Resveratrol enhances the activation of AMPK, an inhibitor of mTOR, has been shown to induce autophagy. As pterostilbene has a similar structure and is more potent than resveratrol, it may serve as an option for therapy in autophagyrelated diseases as well. The current study examines inhibitors of mTOR that have the potential to increase the levels of autophagy, and therefore increase levels of intracellular tau hyperphosphorylation. Expression of Tau protein was examined in E18 rat hippocampal astrocytes exposed for 48 hours to (1) glucose deprivation, recapitulating pathology of AD, and (2) PT or OSI-027 via pTau ELISA, Western blot, and immunofluorescence. Preliminary cell viability data from this research suggests PT and OSI-027 as an inducer of cytoprotective effects in metabolically stressed rat hippocampal astrocytes. Furthermore, preliminary data indicate that exposure to PT and OSI-027 is associated with increased intracellular phosphorylated Tau in rat hippocampal astrocytes. In the experimental condition of increased stress induced via glucose manipulation in growth media, PT and OSI-027 may have a cytoprotective role in these glial cells.

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