Doctoral Dissertations

Date of Award

8-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

Rebecca A. Prosser

Committee Members

Jim Hall, Francisco Barrera, Jae Park, Chris Baker

Abstract

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease that is pathologically defined by the accumulation of amyloid plaques and neurofibrillary tangles. A few of the common symptoms of AD include memory loss, confusion of time and places, changes in mood or behavior, among other things. These symptoms are due to a breakdown of synaptic connections between damaged neurons beginning in brain regions like the entorhinal cortex (EC).

The suprachiasmatic nucleus (SCN) is also thought to be affected by AD pathology as disrupted sleep is another common symptom of AD. In this work, we investigated the response of these two brain regions after being exposed to AD associated peptides, amyloid-beta (Ab) and tau.

We have demonstrated that within the first 12 hours of exogenous peptide exposure, both the EC and SCN exhibits cell death and Ab, specifically, increases lactate dehydrogenase (LDH) release. To further expand on this research and answer more specific questions about changes in tissue due to peptide exposure we developed a novel microfluidic device. We demonstrated that Ab and tau can induce an increase in intracellular calcium similar to potassium chloride depolarization. Additionally, we have shown that Ab:tau stimulation leads to cell death, specifically microglial cells, within the EC. Upon targeting the ryanodine receptor with dantrolene to block the release of calcium from intracellular calcium stores, increases in fluorescence intensity due to intracellular calcium changes are still observed. However, we observed more healthy cells in the EC and SCN tissue stimulated with Ab and tau in the presence of dantrolene as well as a reduction in LDH released. For the first time, dynamic response to exogenous Ab and tau exposure via real-time changes in intracellular calcium concentrations has been shown. The results presented here elucidate changes in the brain that occur with the onset of AD before cognitive symptoms may occur.

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