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The Inflammasome for Understanding and Combating Neurodegenerative Diseases

Inflammasome Expression

(December, 2024) The Miami Project to Cure Paralysis’s rich history of conducting team science research on a variety of neurological conditions has resulted in an important federal award. The Co-Principal Investigators Drs. W. Dalton Dietrich, PhD, Professor and Scientific Director, and Juan Pablo de Rivero Vaccari, PhD, Associate Professor have received a   $1.6 million award, designated under the accelerated RF1 grant category by the National Institute of Neurological Disorders and Stroke (NINDS).  The project is investigating the cellular and molecular mechanisms underlying traumatic brain injury (TBI) as a clinically relevant risk factor for the development of Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (AD/ADRD). Proposed aims will determine the role that increased inflammasome activation plays in this increased vulnerability, including the measurements of diagnostic biomarkers to aid in the early detection of these potentially injurious mechanisms.  Secondary aims use novel cell-based methods to determine injury mechanisms and examine the therapeutic benefits of inflammasome inhibition in Alzheimer’s disease and TBI using transgenic models. In addition to Drs. Dietrich and de Rivero Vaccari, other important collaborations including Drs. Helen Bramlett, Nadine Kerr and Robert Keane provide additional expertise necessary to conduct this multi-disciplinary program.

Drs. Dietrich and de Rivero Vaccari combine their expertise to spearhead this cutting-edge team of science research. Dr. Dietrich’s significant contributions to neuroscience are supported by his recent 2023 Javits Neuroscience Investigator Award, a lifetime achievement award from the National Institute of Neurological Disorders and Stroke (NINDS). Dr. de Rivero Vaccari, who oversees the Miami Project blood biomarker core is leading the inflammasome field by clarifying the role that this  multiprotein complex plays in neurological conditions using fluid biomarker assessments. They now, once again, join forces to unravel the complexities of abnormal inflammasome activation—a process that plays a crucial role in the body’s innate immune response and is believed to be a critical link between TBI and neurodegenerative diseases like AD/ADRD.

This project now begs the question on the role of inflammasomes in the development and progression of AD/ADRD with and without preceding early life TBI. The team hypothesizes that inflammasome biomarkers, detectable through blood tests, could offer a minimally invasive and early indication of increased risk for AD/ADRD progression much earlier than the traditional diagnostic methods. Current approaches rely on structural brain changes or overt cognitive decline, while inflammasome activation seems to precede the onset of overt cognitive changes in ADRD. These important questions have led to exciting collaborations with Drs. David Loewenstein and Rosie Curiel Cid in the Department of Psychiatry. These investigators are working with Dr. de Rivero Vaccari to clarify   the importance of early increases in inflammasome biomarker signaling on disease progression and memory disorders in high-risk patients that show the earliest signs of  AD/ADRD.

To explore these hypotheses, the research team is employing a well-established pre-clinical model of AD/ADRD, which is genetically engineered to develop Alzheimer’s symptoms. In this model, the scientists induce TBI at a stage before AD/ADRD symptoms manifest. They predict that while TBI alone will cause a transient spike in inflammasome signaling, the combination of TBI with a predisposition to AD/ADRD will result in sustained inflammasome activation and accelerate AD onset when compared to mice that did not undergo TBI. Another novel aspect of this study is the use of a cellular stretch injury device to model in culture the mechanical injury experienced by brain cells after trauma. This mechanical stress, often referred to as primary injury, causes cells to release exosomes— lipid-bound spheres that carry a complex cargo from their cells of origin. The exosomes harvested from injured cells will serve a two-fold purpose, first being analyzed to understand the molecular mechanisms at play within the donor cell, and then infused into recipient cells to see the effect of their diseased cargo on healthy conditions. By comparing exosomes from TBI cells with those from TBI+AD/ADRD cells, the team hypothesizes that the latter will cause more severe damage when applied to healthy cells, thereby advancing our understanding of how TBI exacerbates AD/ADRD progression.

In addition to diagnostic exploration, the study will evaluate possible experimental therapeutic agents including IC100, a monoclonal antibody specifically directed at an adaptor protein critical for inflammasome signaling and MCC950, a small molecule that inhibits inflammasome activation. IC100 was discovered by the team at The Miami Project and is currently being manufactured for testing in clinical trials. By targeting the inflammasome, the researchers hope to mitigate the inflammatory cascade triggered by the neurological conditions under study, potentially delaying or even preventing the onset of AD/ADRD in high-risk individuals.

This project is part of a broader, collaborative team science AD/ADRD program at The Miami Project to Cure Paralysis to understand and combat neurodegenerative diseases. The research builds on work with University of Miami’s Brain Endowment Bank™ and the Departments of Neurology with Dr. Regina Vontell, and Psychiatry (Loewenstein and Curiel), funded by the State of Florida, demonstrating the potential of inflammasome biomarkers as early indicators of cognitive decline in AD patients.

The topic of early life TBI is, unfortunately, relevant given the high prevalence and insidious impact of head injury in children as documented by several Miami Project investigators. For example, Dr. Gilian Hotz, Professor and Director of UHealth Concussion Program and KiDZ Neuroscience Center is conducting outreach programs for our local South Florida communities to highlight bike safety approaches to limiting injuries. Dr. Jennifer Munoz Pareja, Associate Professor in the Division of Pediatric Critical Care Medicine is currently conducting a large clinical trial assessing various inflammatory blood biomarkers in pediatric TBI patients. Dr. Coleen Atkins, Associate Professor and pre-clinical TBI researcher is studying early life stress and how those events may lead to increased vulnerabilities to later-occurring TBI and behavioral abnormalities such as post-traumatic stress disorders and other quality of life issues.  Recent advances in the field suggest that abnormal inflammasome activation could be a key player in this process.

Finally, concurrent research led by The Miami Project’s Nadine Kerr, PhD, Assistant Professor, explores the role of the gut-brain axis in AD/ADRD progression, and further work with Suhrud Rajguru, PhD, Professor, looks at the impact of blast injuries leading to hearing loss on AD/ADRD outcomes. Indeed, the inflammasome protein complexes that mediate inflammatory responses, and their dysregulation have been implicated in many neurological conditions. Together, these efforts underscore The Miami Project’s commitment to advancing our understanding and management of neurodegenerative conditions, with the current project of Drs. Dietrich and de Rivero Vaccari highlighting the need for early detection to allow early intervention in AD/ADRD.