UC Irvine

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is growing inprevalence and is impactful on individuals and society as a whole. Treatment options are limited, and there is no known cure; a better understanding of this disease, particularly at its early stages, is essential for the betterment of human health. This dissertation investigates how neuronal communication is disrupted throughout disease progression in AD, how these changes may be explained molecularly, and how disease-associated changes appear to occur in a brain-region specific manner.

Chapter 1 of this work reviews prior AD research, and how methods we utilize such asneuronal tracing and transcriptomic analysis have previously been applied to the research of this disease. Following this summary of previous work, we explore a rabies-based viral tracing method, the results of which can reflect cellular excitability (Chapter 2). While this component of the dissertation did not focus on AD, the methodology and insights into cellular communication, communication between brain regions, and how gene expression can influence these factors informs the rest of this work, particularly Chapter 4.

In Chapter 3, we delve into the molecular changes present in the entorhinal cortex (ENT).We utilize a mouse model of AD, and noted cellular and neuronal communication pathways that were disrupted in disease. We saw some overlap of these changes with those observed in previously published human AD data, particularly in glutamatergic signaling.

Chapter 4 synthesizes and extends the work done in earlier chapters: we first utilize therabies-based viral tracing method characterized in Chapter 2, the results of which identified the retrospenial cortex (RSC) as an important input region to the ENT in AD mice. We followed up with multi-omic analysis of the RSC and the ENT over time in the AD mouse brain, as well as sequencing of tissue from patients with or without cognitive deficits. Glutamatergic neurons were once again seen to have gene expression changes implicating cellular excitability in disease.

Combined, these projects implicate cellular excitability in both the ENT and the RSC, butsuggest that changes in the RSC may precede those in the ENT. While further research is needed and questions remain (Chapter 5), this work has yielded insights into brain-region specific molecular changes in AD, and highlights the RSC as a promising target for future study.