Rapid Seeded Amyloid Amplification Assay to Assess TBI and Its Potential Linkage to CTE or AD
Abstract
Traumatic brain injury (TBI) is increasingly recognized not only as an acute injury but a risk factor for the development of neurological disease. Symptoms commonly recognized as post-traumatic stress disorder (PTSD) are being reclassified as a side effect of TBI or chronic traumatic encephalopathy (CTE). Moreover, TBI increases the chance of later developing neurological disorders, including Alzheimer s and Parkinson s diseases. How single or recurrent brain injury leads to CTE remains unknown. These brain disorders have in common the misfolding of a critical important brain protein called tau. This proposal focuses on early detection of abnormal changes that occur in tau before the onset of neurological symptoms. Tau functions to stabilize the long tail-like projections neurons called axons. Thus, tau functions like the screws that hold the two-by-four structure of the brain together. In brain diseases, proteins like tau become modified and non-functional, i.e., the screws rust and fall off. The tau protein, now dissociated from its typical role, becomes pathological. In a process that is yet not well understood, tau proteins zipper together into stacks termed amyloid. The initiation of tau amyloid formation is dangerous because the amyloid protein conformation can then convert normal forms of tau to an abnormal amyloid state, zombie-like. This process eventually leads to the brain cell death that is at the core of Alzheimer s, Parkinson s, CTE, and others brain disorders. However, some of these abnormal tau "seeds" also appear outside the brain, in the spinal fluid and even blood. To detect the origin and spread of tau amyloid seeds, we use the very process responsible for the disease to our advantage by emulating this process in the lab. We have successfully used this approach to study another amyloid seeding protein misfolding neurological disorder, prion disease. In this work, we have detected amyloid forming seeds in saliva, urine, blood, and cerebral spinal fluid of affected animals. Moreover, in preliminary experiments, we have detected amyloid-seeding tau in postmortem brain samples from human Alzheimer s disease and in a mouse model of tau disease. We hope to advance the diagnostic potential of this method to detect and monitor early signs of TBI (and AD) in this proposal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610577
Entities
People
- Edward A. Hoover
Organizations
- Colorado State University
- United States Army