Epidemiological studies have identified specific lifestyle factors that increase the risk of dementia, including lower levels of education, vision and hearing loss, physical inactivity, social isolation, and excessive alcohol consumption, among others. Current estimates suggest that addressing these factors could prevent or delay almost 50% of all dementia cases, including Alzheimer’s disease (AD). Despite the importance of this knowledge, there is still too little known about how these risk factors actually impact the brain and contribute to the onset or progression of AD pathologies. Understanding the signaling mechanisms at play in the body under different lifestyle factors will provide new, more specific molecular targets for drug development.
Stress is another potentially modifiable risk factor for AD. Dr. Swirski’s team believes that stress contributes to AD by various mechanisms, including damaging the blood-brain-barrier (BBB)—a protective boundary that controls what enters the brain—through immune cell activation, as well as by additional specific neuroimmune mechanisms.
In a recently completed project, Drs. Poller, Russo, and Swirski explored how stress impacts the brain in an amyloid mouse model (5xFAD). The researchers exposed mice to a stressful situation by placing them in a cage with a larger, more aggressive mouse for ten minutes a day over ten days.
The research team found that stressed mice showed a heightened immune response throughout their bodies and had more microglia (specialized immune cells) in the brain. The team also identified which brain regions became more active while stressed, offering important clues about how stress influences immune cell behavior and amyloid levels in the brain.
Dr. Swirski hypothesized that stress alters neuronal activity in specific brain regions, which, in turn, affects how immune cells function and where they migrate within the brain. He predicts that regulating activity in these stress centers could help protect against stress’s harmful effects.
This study has two experimental aims. In the first aim, they are increasing or decreasing neuronal activity in the PVH, a brain region that plays a central role in the body’s stress response. They will test this manipulation in 5xFAD mice at three different ages, comparing results between stressed mice and unstressed controls. They will measure several outcomes, including immune cell populations in the bloodstream and brain, the health of brain blood vessels, amyloid protein buildup, and cognitive function. In the second aim, they are determining how cells in the PVH communicate with immune cells outside of the brain (periphery). They think the stress hormone corticosterone is involved because immune cells express the corticosterone receptor. They are generating an amyloid mouse line to manipulate the neurons that produce corticosterone (CRH neurons) and test the impact of stress on AD pathologies and behavior. They are also mapping out the impact of stress on other peripheral immune cells.
In the first funding period, Dr. Swirski’s team made several important discoveries. In their initial experiments using the successfully generated proposed mouse models, they found that mice lacking CRH neurons exhibit a robust shift in their peripheral immune profile, with increased monocytes and decreased neutrophils. They will perform further experiments to assess how this shift changes over the course of amyloid buildup in these mice. Dr. Swirski’s team also identified brain regions beyond the PVH that change during stress exposure. In the second year, they intend to complete the study of stress-induced changes throughout the brain to develop a whole-brain picture of the impacts of stress on brain health and AD progression.
This project examines stress, a common factor in daily life, and teases apart its specific effects on the brain and immune system in the context of AD progression. Understanding how stress impacts the brain could lead to targeted interventions to protect against its harmful effects on brain health.
