Targeting Toxic Oligomeric Protein Variants Generated After Traumatic Brain Injury to Decrease Risk of AD
Abstract
Background and Focus Area: Traumatic brain injury (TBI) affects around two million people each year, including around 10%-20% of Soldiers serving in Iraq and Afghanistan. Even mild traumatic brain injury (mTBI) frequently leads to significant brain damage and disorders including Alzheimer’s disease (AD) and related dementias (ADRDs), so potential long-term consequences of TBI can be quite devastating. TBI and the neuronal stress involved induce increased formation of two proteins implicated in AD, amyloid-beta (Abeta) and tau. While these proteins are normally produced in the brain after stress, the proteins may misfold and aggregate to toxic species. Various small toxic forms of both of these proteins are thought to be responsible for spread of pathology, and they correlate well with disease progression and outcomes. Generation of increased levels of toxic Abeta and tau variants following TBI provides a direct mechanistic link between TBI and the increased incidence and earlier onset of AD. Similarly small toxic aggregates of two other neuronal proteins, alpha-synuclein (a-syn) and variants of TarDNA Binding Protein-43 (TDP-43), play an important role in ADRDs, and toxic variants of both a-syn and TDP-43 are also generated following TBI providing a mechanism to account for the spectrum of neurological diseases that can result from brain injury. Our objective in this proposed work addresses the Overarching Challenge as stated in the program announcement: Foundational Research: Research to examine the interrelationship between TBI and subsequent AD/ADRD for the military, Veteran, and civilian communities, and to translate these findings. This challenge will be directly addressed in this proposal since one of the outcomes of this proposal is identify protein variants of key neuronal proteins that accumulate in brain after TBI. We will show that accumulation of specific protein variants in specific brain regions correlates with specific behavioral outcomes. Finally, we will translate these findings to potential therapeutic applications by showing that targeting and clearing key disease-related protein variants generated after TBI provides substantial therapeutic benefit to lessen neuronal damage and facilitate return of Soldiers to active duty. Hypothesis: Our long-range hypothesis is that protein variants of Abeta, tau, a-syn, and TDP-43 are generated in the brain following TBI and that the specific profile of the generated toxic protein variants determines the susceptibility of each individual for different neurodegenerative diseases. Our proposal objective is to use a mouse TBI model that replicates key elements of the biomarker profile observed in early AD patients and to demonstrate that selectively targeting toxic protein variants is an effective therapeutic to minimize neuronal damage and subsequent risk of AD following TBI. To achieve this objective, we have developed the following specific aims: Aim 1: In wild-type and ApoE4,4 mice, induce diffuse TBI at varying severity. Comorbidity stressors will then be administered at acute (7-day) and chronic (30-day) time points. Aim 2: Characterize TBI models to determine spatial and temporal profiles of 12 key AD-related protein variants as a function of injury severity and timing of administration of additional comorbidity stressors. Aim 3: Identify protein variants that correlate with functional deficits in the different models. Aim 4: Validate the therapeutic potential of targeting specific protein variants on reducing neuronal damage and risk of AD following TBI. Research Strategy: We will induce TBI in two different mouse models, a wild-type model and a mouse model that replicates the most dominant risk factor for AD, the ApoeE4,4 genotype. We will induce TBI in both models and observe how the 3-D profile of toxic variants of Abeta, tau, TDP-43 and a-syn are generated in the brain following injury. We will observe how addition of stress after TBI a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110837
Entities
People
- Michael R Sierks
Organizations
- Arizona State University
- United States Army