PROJECT SUMMARY/ABSTRACT
Alzheimer’s Disease (AD) is the most common cause of dementia in the elderly, and it is the sixth leading cause
of death in the United States. AD currently cannot be prevented, cured, or even slowed, and it has a significant
public health impact in terms of health care dollars and quality of life for those affected and their family members.
Experimental models of ADRD have implicated the gut microbiome-bile acid-brain axis in the development and
progression of ADRD. Neurotoxic environmental toxicants, such as polychlorinated biphenyls (PCBs), alter the
function of the microbiome, resulting in an altered bile acid homeostasis; however, it is unknown if PCB-mediated
changes in the gut microbiome-bile acid-brain axis play a role in the etiology of ADRD. Furthermore,
epidemiological studies have major limitations assessing the complex effects of PCB exposure on the gut
microbiome-bile acid-brain axis across the lifespan. Thus, there is a critical need to assess how human-relevant
PCB mixtures alter the development and progression of ADRD-like phenotypes in experimental models of
ADRD via the gut microbiome-bile acid-brain axis. The long-term goal of the transdisciplinary team assembled
for this project is to characterize how environmental exposures contribute to ADRD and ultimately prevent ADRD
through a precision environmental health paradigm. The translational objective is to demonstrate with a systems
biology approach that exposure to a human-relevant PCBs mixture contributes to and accelerates the etiology
of ADRD-type outcomes in vivo. The central hypothesis is that exposure to PCBs adversely affects the ADRD
phenotype in rTg4510 and APP/PS1 mice, two experimental models of ADRD, by causing microbiome-mediated
alterations in the bile acid homeostasis and affecting vascular function in a dose and exposure time-dependent
manner. This hypothesis integrates strong preliminary data from the research team showing that PCBs are
present in the human brain, affect the microbiome, alter bile acid homeostasis, and cause vascular dysfunction.
The hypothesis will be tested using a systems biology approach by assessing how exposure to a human-relevant
PCB mixture affects ADRD-related outcomes in experimental models of ADRD. The Specific Aims are to a)
characterize effects of PCB exposure on gut microbiome composition and circulating bile acids; b) study the
effects of PCB exposure on vascular function, and c) identify ADRD-type pathological changes and memory loss
in the brain of PCB exposed rTg4510 or APP/PS1 mice. To ensure integration across all Aims, mediation analysis
will be used to demonstrate that the microbiome and/or vascular dysfunction mediates the effects of PCBs on
ADRD-type outcomes. These studies will demonstrate that PCB exposure leads to accelerated progression and
more severe disease pathology in experimental ADRD models. Identifying PCBs as environmental risk factors
that alter ADRD-related outcomes will lay the groundwork for mechanistic studies and inform translational studies
for preventing ADRD mediated by environmental toxicants using a precision environmental health paradigm.
