Electronic Thesis and Dissertation Repository

Thesis Format



Master of Science




Cumming, Robert C.


Alzheimer’s Disease (AD) is the most common form of dementia with no effective therapies to currently prevent or slow its progression. Increasing research into cerebral energy metabolism has revealed the importance of lactate as an energy substrate and signaling molecule required during neuronal activation and memory formation, normal physiological glial function, and the regulation of gene transcription through a novel epigenetic process termed histone lactylation. In this study, I spatially and temporally mapped lactate levels and histone lactylation in brain tissues of wild type and an AD transgenic mouse model using MALDI-TOF imaging mass spectrometry and immunofluorescence microscopy, respectively. Lactate levels declined with age predominantly in male but not female mice. The spatial relationship between lactate levels and histone lactylation suggest that both processes may contribute to microglia activation and neuroinflammation, but the need for cell-type and region-specific investigation is required to further understand the relationship between lactate metabolism and epigenetic processes during aging and in AD.

Summary for Lay Audience

With no cure currently available for Alzheimer’s Disease, there is a desperate need for new therapeutic targets that can either prevent or slow the rate of dementia progression. Since glucose is considered to be the main source of energy in the brain, it is reasonable to further investigate the intermediary products that are produced along its pathway towards final energy production. Interestingly, it was once believed that lactate was a “waste product” created during the breakdown of glucose to energy since lactate was only generated if levels of oxygen were insufficient. However, a growing amount of evidence is revealing that lactate is actually a very important source of energy itself and also serves to trigger a whole cascade of events that support the activity of brain cells and memory development, the normal functioning of supporting cells, and the regulation of products to be assembled from our DNA.

This study aimed to make use of a powerful technique called MALDI-TOF imaging mass spectrometry that can detect hundreds of molecules and visually map out where in the brain these molecules accumulate. Much research has investigated lactate levels in critical whole brain structures, such as the hippocampus, but there are very few studies that utilize MALDI imaging to examine energy production within healthy brain tissue or in an Alzheimer’s Disease context. This study was successful in detecting lactate and by comparing lactate levels to levels of other important intermediary products, such as pyruvate, lactate production in the presence of oxygen was also directly assessed. Findings are presented highlighting the strong impact that sex and age have on brain activity and the importance to conduct further investigation based on the type of brain cell versus its location in the brain while keeping in mind whether excess lactate is being effectively removed.

This study provides a framework for a procedure that has the potential to produce invaluable information and insights into the brain’s energy changes with respect to Alzheimer’s Disease.

Available for download on Friday, August 29, 2025