Alzheimer’s is a highly heritable disease with about 60% of the risk coming from a person’s genes. The other 40% of the risk remains less well-studied and may, in part, come from environmental stressors.
The University of Texas at San Antonio was recently awarded a highly competitive Alzheimer’s Association research grant to investigate the gene-environment interaction and how it may contribute to an increased risk for Alzheimer’s disease. The grant will begin in April and provides $200,000 to fund the study over the next three years.
“We are trying to incorporate as many genetic variants and environmental stressors as we can to have a robust model that mimics late-onset Alzheimer’s disease, as opposed to other preclinical work that shows early onset, highly aggressive, non-physiological models,” said principal investigator Juan Pablo Palavicini, PhD, assistant professor in the Department of Cellular and Integrative Physiology in the Joe R. and Teresa Long School of Medicine. He is also a researcher with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Circadian disruption as an environmental stressor
Palavicini is teaming with Kevin B. Koronowski, PhD, assistant professor in the Department of Biochemistry and Structural Biology in the Long School of Medicine and researcher with the Barshop Institute, to primarily study the effects of circadian rhythm disruption as an environmental stressor and its effects on human phosphorylated-tau proteins.
The aggregation of tau proteins and amyloid plaques are well-known hallmarks of Alzheimer’s disease and other dementias.
“In modern society, it’s difficult to reduce environmental stressors like disrupted sleep schedules and diet. That is the whole point of our study. We don’t yet know all the potential consequences of this disruption,” Koronowski said.
Creating chronic jet lag
With Koronowski’s expertise in circadian rhythm, the team developed an earlier study funded by the William and Ella Owens Medical Foundation.
A chronic jet lag condition was created in an animal model by shifting the light-dark schedule forward by eight hours twice per week.
“It is as if you traveled from Texas to Europe, from Europe to Australia and then back to Texas,” Palavicini said.
During that study, some mice started misbehaving and developing metabolic abnormalities, but the effects were not strong. For the upcoming study, the research team will incorporate changes to create more dramatic consequences of circadian rhythm disruption.
“A key adjustment will be to start the process in middle-aged subjects instead of younger ones to account for age-related resiliency and recovery capacity,” Palavicini said.
For the upcoming study, researchers will also provide a Western diet with higher fat and sugar content. Many clinical studies show that people who work rotating or night shifts tend to have lower-quality diets. In replicating actual human scenarios of circadian disruption, Koronowski said it makes sense to include dietary stress.
“This type of food falls perfectly into the big picture of what we are doing,” he said. “This shows the additional stress of an unhealthy diet that many people eat, the typical Western-style diet.”
The research team is also proposing a second aim of the study in which they will determine if a time-restricted feeding schedule rescues circadian disruption-induced metabolic abnormality.
In their previous study, the team noticed the chronic jet lag caused eating at all times of the day and night. In the upcoming study, they will have an automated system that only allows for feeding 12 hours a day.
Cause or effect?
“We are especially testing whether restoring metabolic rhythms while light is disrupted can prevent the progression of Alzheimer’s disease. In the context of neurodegeneration, we still don’t know if circadian disruption is a cause or effect, so this study can help us determine that,” Koronowski said.
Rather than only focusing on the genetic component, Koronowski said this study is a more holistic view of health and how loss of homeostasis in the body and misalignment of natural rhythms can contribute to disease.
“Night is a critical time for our brains because these proteins that accumulate, like tau and amyloid beta, get flushed out as we are sleeping. The different stages of sleep, especially REM, are essential for memory consolidation. Disrupted sleep, even for one night, can alter the amount of tau and amyloid in the brain substantially,” Palavicini said.
Findings from this study could help clarify how environmental stressors such as disrupted sleep and diet interact with genetic risk, offering new insight into how Alzheimer’s disease develops later in life.
Other researchers on the team include Qing Zhang, MD, a research scientist in Koronowski’s lab, and Andrea Gonzalez, a student associate in Palavicini’s lab.