Bioengineered 3D Human Brain Systems to Investigate Risk Factors, Mechanisms, and Treatments for Traumatic Brain Injury-Induced Alzheimer s Disease
Abstract
Fiscal Year 2021 Traumatic Brain Injury and Psychological Health Research Program Investigator-Initiated Research Program Focus Areas: Our research proposal addresses the following Focus Areas: (1) Understand – Understanding of pre-exposure risk, injury, and biological factors contributing to an individual’s response, recovery, and long-term outcomes following a brain injury or traumatic event and (2) Treat – Treatments that promote recovery and improve long-term outcomes. This project will make important contributions to understanding how specific genetic- and disease-based risk factors may predispose an individual to neurodegeneration following traumatic brain injury (TBI). It will likewise uncover treatment options to address these risk factors and reduce the prevalence of Alzheimer’s disease (AD), a progressive neurodegenerative disorder that is the leading cause of dementia affecting over 5 million Soldiers and civilians in the United States alone, following TBI. Objectives and Rationale: Recent data from the United States Department of Veterans Affairs has shown that active-duty Service Members and Veterans who have experienced TBI are approximately twice as likely to have dementia. Due to the prevalence of improvised explosive devices (IEDs) in recent conflicts in Iraq and Afghanistan, the frequency of TBI in Soldiers has greatly increased, with estimates of mild TBI (mTBI) among returning Service Members ranging up to nearly 25%. Paradoxically, because of improvements in medical treatments, Service Members are now increasingly surviving classical battlefield wounds, but are at greater risk for the invisible injuries suffered because of mTBI including AD and other forms of dementia and neurodegenerative disease. Patients with AD develop many clumps of proteins (called beta amyloid plaques and tau tangles) in their brain, leading to death of brain cells including neurons, progressive memory loss, and impaired language and other aspects of brain function needed for everyday life. Because of their exposure to TBI, Veterans may be diagnosed with AD as early as their 4th or 5th decade of life, are more likely to be hospitalized, and have longer hospital stays than Veterans without dementia. This results in health care costs being four times higher for Veterans with TBI than those without TBI. Despite several decades of research effort, we still do not understand the factors that initiate and propagate AD, and how to interrupt these processes to stop the disease, due to limitations imposed by current tools to address neurodegeneration. Clearly, understanding links between risk factors for TBI and development of AD is critically important for the health and well-being of the U.S. military population and the American public, in general. Current studies using animal models do not replicate all aspects of human disease and examining human pathological samples obtained at autopsy do not yield clues to the initiating events and factors that lead to neurodegeneration following TBI. This limitation is highlighted by the recent failures of clinical trials of anti-beta amyloid therapies (anti-clumping therapies) that were highly effective in mouse models. Thus, establishing a human cell-based model system that provides greater insight into the mechanistic links between TBI and AD progression is a critical step toward the development of potential solutions. We propose to develop the first human research model for TBI-induced AD: Bioengineered three-dimensional (3D) mini-brains made from human brain cells from normal patients and patients with specific AD risk factors that we can expose to TBI and examine disease progression over time (from days to years) and potential treatment options. Applicability: Our approach is ultimately applicable in that, by creating an unprecedented laboratory human cell-based model of TBI-induced AD, there is enormous potential to unlock the basic mechanisms that cause the disease and use th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211065
Entities
People
- David L. Kaplan
Organizations
- Tufts University
- United States Army