Toxic Oligomeric Variants of TDP-43 May Contribute to Cognitive Deficits Secondary to Diffuse Experimental TBI

Traumatic Brain Injury (TBI) affects approximately two million people on an annual basis and increases the frequency and onset of Alzheimer’s disease (AD) and other related dementias (ADRDs). Mechanical damage and shearing of neuronal axons are thought to be responsible for producing toxic variants of proteins that contribute to disease pathology. Specifically, the tau, beta amyloid, alpha-synuclein, and TAR-binding DNA Protein-43 (TDP-43) variants contribute to the heterogenous pathology mechanisms of neurodegenerative diseases. The Sierks lab at Arizona State University has aimed to study how these protein variants collectively interact to contribute to pathologies characteristic of AD/ADRDs. This study focuses on the accumulation of toxic oligomeric variants of TDP-43 secondary to TBI. The first aim of this study was to identify the protein variant fingerprint as a function time following experimental diffuse TBI. The second aim was to investigate if toxic variants of TDP-43 were associated with cognitive and motor functional deficits. C57BL/6 mice were subjected to a single or repetitive diffuse TBI via midline fluid percussion injury or a control surgery (sham). Post-injury, mice were evaluated for cognitive performance, sensorimotor function, and depressive-like behavior at 7-, 14-, and 28-days post-injury. Tissue was collected for immunohistochemistry and stained for ADTDP-3, a single chain antibody variable fragment (ScFv) which binds to toxic variants of TDP-43 in amyotrophic lateral sclerosis (ALS) and AD tissue. A one-way analysis of variance (ANOVA) was performed to compare staining intensity across various brain regions. Subsequently, a Pearson correlation was performed to compare behavioral task performance to staining intensity by brain region for each injury group. There were significantly elevated levels of ADTDP3 binding in all regions except for the hippocampus, and there was a significant correlation between the cortex staining intensity vs the cognitive behavior test at 7 days post-injury. There was also a significant correlation between the thalamus staining intensity and sensorimotor test at 7 days post-injury. These findings support the hypothesis that the accumulation of toxic variants of TDP-43 can contribute to neurodegenerative pathology and loss of function. These variants also may contribute to behavioral deficits secondary to diffuse TBI.