Interrogating the Inflammasome, Traumatic Brain Injury and Alzheimer’s Risk
Article Summary
- Researchers Dr. W. Dalton Dietrich and Dr. Juan Pablo de Rivero Vaccari are using an NIH grant to investigate how inflammasome signaling following a traumatic brain injury affects the risk of Alzheimer’s disease.
- The inflammasome is a multiprotein complex that activates inflammation that accompanies many diseases.
- The research team is using a stretch injury device to mimic the initial trauma cells undergo during traumatic brain injury.
Inflammation plays a major role in many diseases, making it a prominent research topic.
Recently, W. Dalton Dietrich, Ph.D., scientific director of The Miami Project to Cure Paralysis and professor of neurological surgery, neurology, biomedical engineering and cell biology at the University of Miami Miller School of Medicine, and Juan Pablo de Rivero Vaccari, Ph.D., a research associate professor of neurological surgery at The Miami Project and the Miller School, received a $1.6 million NIH grant to investigate how inflammasome signaling following a traumatic brain injury (TBI) affects the risk of developing Alzheimer’s disease. The researchers hope these efforts will lead to new therapeutic targets and possibly treatments.
We spoke with Dr. Dietrich and Dr. de Rivero Vaccari about their work.
What is the inflammasome and why is it important?
Dr. de Rivero Vaccari: The inflammasome is a multiprotein complex that activates inflammatory molecules, called cytokines, that are implicated in many diseases.
As a result, the inflammasome has become a major focus in both academic and biotech industries. A number of pharma companies are developing inflammasome inhibitors.
This makes a lot of sense because the inflammasome is part of the innate immune response, which is the body’s first line of defense against invaders and damage. This makes the inflammasome part of the early inflammatory events taking place in injury and disease. Hence, targeting the inflammasome could allow us to target diseases earlier, and that’s often an easier battle.
In general, we see that diseases result in an exacerbated inflammatory response. Our studies in Alzheimer’s disease are starting to shine light that early in the disease, before there are cognitive changes, there is already an inflammatory response that is in part mediated by the inflammasome. We hope that, by studying the inflammasome, we get to the root of the problem.
How might TBI influence Alzheimer’s risk?
Dr. Dietrich: Traumatic brain injury is a clinical risk factor for neurodegenerative diseases, as well as cardiovascular disease, stroke and other conditions.
We know there’s a relationship between brain injury and these neurodegenerative diseases. We just don’t understand the mechanisms underlying this important risk factor. This current NIH team science program is therefore investigating injury mechanisms that may represent novel therapeutic targets that represent opportunities to reduce vulnerability to the progression and severity of neurodegenerative disorders.
We hypothesize that, following a brain injury, both systemic and organ-specific inflammation may increase the risk of developing neurodegenerative diseases later in life. The inflammasome is designed to protect us against bacteria and viruses. But after neural injury, it can get out of control and start killing neurons and other critical cells.
That’s why it’s so important to understand this process and ultimately develop drugs that target the inflammasome and other secondary injury and disease mechanisms. In the proposed studies we are using established models of TBI and genetic mouse models of Alzheimer’s disease combined with behavioral and neuropathological outcomes to address these important questions.
What kinds of methods are you using?
Dr. de Rivero Vaccari: We are using a new technology called a stretch injury device that mimics the mechanical injuries that happen after trauma. With this instrument, we can grow cells in culture and stretch them to mimic the initial trauma that cells undergo.
We’re in the process of getting cells from Alzheimer’s patients and then we’re going to see what happens when we stretch those cells. We will test whether there are inflammatory responses and Alzheimer’s-related markers expressed.
We want to understand the mechanisms that govern how TBI and other types of brain injury may influence Alzheimer’s disease, but we’re also focused on developing biomarker tests to diagnose issues early.
—Dr. W. Dalton Dietrich
We can precisely measure cytokines to analyze the inflammatory response to see how stretch or mechanical injury affects the inflammatory response in the cells from Alzheimer’s patients.
We are also isolating extracellular vesicles, which are these cargo-carrying particles that cells release to communicate with other cells. There’s evidence that inflammasome proteins are traveling all over the body in these vesicles, spreading the inflammatory response after trauma.
We are also using the IncuCyte for live cell imaging to measure processes like cell death, mitochondrial health and other cellular functions. These approaches allow us to measure the impact of stretch injuries and inflammasome activation, as well as whether we preserve function if we inhibit them.
What are the studies goals?
Dr. Dietrich: We want to understand the mechanisms that govern how TBI and other types of brain injury may influence Alzheimer’s disease, but we’re also focused on developing biomarker tests to diagnose issues early and a new therapy. Dr. de Rivero Vaccari has developed an exciting strategy to use blood or fluid samples from patients and accurately measure inflammasome levels to measure the severity of the injury. With that information, clinicians could determine whether a drug that attenuates inflammasome signaling would be beneficial for that patient.
Dr. de Rivero Vaccari: We’re identifying therapeutic targets we can develop drugs against. One thearpy we are trying to move forward is IC100, an antibody that targets the inflammasome we have developed, with Dr. Robert W. Keane and Dr. Helen Bramlett.
A number of pharmaceutical companies are developing drugs that target the inflammasome, but they all focus on one specific inflammasome complex. Our approach goes beyond targeting one inflammasome by targeting a component of the inflammasome that is present in multiple inflammasomes. In our own studies and in collaborative studies with other laboratories at the University of Miami, when this antibody was tested in TBI, spinal cord injury, stroke, Alzheimer’s disease, multiple sclerosis, acute lung injury and retinitis of prematurity models, we’ve been able to inhibit inflammasome activation. That was associated also with improved outcomes.
So now we’re hoping, in the next couple of years, this drug will be tested in clinical trials for the treatment of a variety of indications associated with inflammation.
Tags: Alzheimer's disease, Dr. Pablo de Rivero Vaccari, Dr. W. Dalton Dietrich III, inflammation, Miami Project to Cure Paralysis, neurology, neurosurgery