Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Pharmacology and Nutritional Sciences

First Advisor

Dr. Olivier Thibault


Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca2+ hypothesis of brain aging and dementia. Indeed, many Ca2+-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca2+ with age was due to increased Ca2+ channel density, elevated release from intracellular Ca2+ stores, and decreased Ca2+ buffering or clearance. Further, changes in intra- and intercellular Ca2+-dependent processes can lead to poor learning and spatial mapping in aged animals. As these are clear deficits in hippocampal function, many early studies assumed Ca2+ dysregulation phenotypes in animal models of aging were similar to the dysregulated cellular mechanisms seen in Alzheimer’s disease (AD) and other types of dementia. However, with the development of transgenic models to recapitulate hallmark AD phenotypes over the past 20 years, it has become apparent that the mishandling of Ca2+ is notably different across models. Importantly, many of these results were obtained while measuring Ca2+ indirectly and at limited ages. Thus, the once generalizable phenotypes associated with Ca2+ dysregulation, including increased intracellular Ca2+ and reduced synaptic communication, appear to diverge in normal brain aging and AD. The following dissertation investigates direct and indirect Ca2+ measures across the widely used 5xFAD familial AD mouse, as well as the less common Aldh2-/- sporadic AD mouse model. Based on previous evidence, it was hypothesized that a decrease in intracellular Ca2+ and associated processes would manifest in both models across age. Key results showed a reduction in resting Ca2+ in the 5xFAD mice, while in the Aldh2-/- model only minor Ca2+-dependent processes showed a genotype effect. These results highlight the non-generalizable nature of the Ca2+ hypothesis of brain aging to AD phenotypes and emphasize the importance of genetic background characterization, as well as underscore the complexity of cellular alterations in the divergence of aging and neurodegeneration.

Digital Object Identifier (DOI)

Funding Information

This study was supported by the National Institutes of Health Research Project Grant Program (R01AG058171) in 2016.

This study was also supported by the National Institutes of Health Predoctoral Training Program Grant (NIH T32 AG057461) in 2018.