Author ORCID Identifier
Date Available
5-15-2023
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Physiology
First Advisor
Dr. Steve Estus
Abstract
Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny.
First, I conducted a study on APOE targeted replacement mice to investigate the impact of APOE alleles on the murine gut microbiome. The relative abundance of bacteria from the family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of the class Erysipelotrichia increased with APOE4 status, a finding that extended to humans. Since Ruminococacceae have been associated with increased SCFA production, these findings suggest that SCFA-producing bacteria are increased in the AD-protective APOE2 positive mice.
Next, I compared the effects of short-chain fatty acid (SCFA)- vs. saline-treated water on APPswe/PSEN1dE9 mice maintained under standard laboratory conditions. I found that SCFA treatment increased alpha-diversity and impacted the gut microbiome profile by increasing the relative abundance of the genera Bifidobacterium and Lactobacillus, which are known to produce SCFAs and SCFA precursors. Although gut microbiome changes in SCFA-treated mice were robust, SCFA treatment did not significantly affect behavior, cortical or hippocampal astrocyte activation, or soluble and insoluble amyloid levels.
In conclusion, there is robust evidence of an APOE allelic effect on the murine gut microbiome that implies an AD-relevant genetic impact on the gut microbiome. The gut microbiome can be modulated by SCFA supplementation, revealing a potential therapeutic for AD prevention. These pioneering studies represent the medical importance of gut health on disease prevention and treatment.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.243
Funding Information
The gut microbiome studies were funded by NIH (R56AG057589-01A1). The student was also funded by an in-house grant through Sander-Brown Center on Aging (T32 GM118292-03).
Recommended Citation
Zajac, Diana, "Alzheimer’s Disease genetics and short-chain fatty acid treatment in studies of the murine gut microbiome" (2023). Theses and Dissertations--Physiology. 62.
https://uknowledge.uky.edu/physiology_etds/62
Included in
Bacteria Commons, Genetics Commons, Molecular, Genetic, and Biochemical Nutrition Commons, Other Neuroscience and Neurobiology Commons, Translational Medical Research Commons
