Low-Intensity Blast-Induced Brain Molecular and Ultrastructural Abnormalities in Human Tau Transgenic Mice
Abstract
Neurotrauma caused by explosive weaponry is the most prominent type of injury that occurs in military personnel. Over 82% of the subjects in the U.S. Armed Forces, most suffering blast-induced neurotraumas (BINTs), are classified as mild traumatic brain injury (mTBI) — the “signature wound” of recent wars. This type of injury is often un- or under-diagnosed because currently available diagnostic techniques, including imaging, are not sensitive enough to detect the early pathological or biochemical changes in the brain caused by low-intensity blast (LIB). The effects of this “invisible injury” on our Service members are devastating, often with a myriad of behavioral deficits ranging from short-term shifts in mood to decreases in cognitive performance or even self-harm. There is evidence that these invisible injuries are important underlying factors for increased risk of neurodegenerative diseases, including the Alzheimer’s disease-related dementia (ADRD). These lifelong disabilities impose striking socioeconomic burdens on patients, families, and society. However, the underlying mechanism(s) and pathogenesis for BINT and subsequent neurodegenerations are poorly understood. Thus, there is a pressing need for studies to better understand BINT and behavioral deficits by using reliable animal models, and open-field blast, which is the “real-world” scenario, and with injuries mimicking deployed combat personnel and those in active military training. This project utilizes the established “Missouri Blast” model in which mice are placed in a platform and subjected to LIB generated by C4 explosive with detonation of 46.6-kPa, which is a condition close to the “safety threshold.” In our preliminary studies, these blast-exposed mice showed abnormalities in ultrastructure of myelinated axons and synapses and mitochondria, and reduction in locomotion and exploratory activities, as well as increase in anxiety-like activity. In addition, changes were also observed in the molecular pathways and an increase in levels of tau and phospho-tau proteins, suggesting blast-induced tau-mediated neurodegeneration. These findings thus support the hypothesis that LIB exposure-induced molecular and ultrastructural abnormalities, including microtubule/axonal/synaptic damages and mitochondrial dysfunction, are important underlying factors for tau-mediated neurodegeneration and cognitive deficits in BINT. Since hyperphosphorylation of tau and accumulation of neurofibrillary tangles (NFTs) are known to play an important role in tauopathy, this study will use the transgenic rTg4510 mice, a well-characterized mouse model with large increases in human tau and NFT formation in the cortex linked with frontotemporal-dementia (FTD). Considering that combat Soldiers confronted with blasts are frequently in the standing position, and there is evidence that brain injuries in this position are more complex and may include damages of other body organs, studies here will use animals in the upright (i.e., vertical) position during blast detonation. Specifically, Aim 1 will examine whether LIB-induced tau hyperphosphorylation, ultrastructural abnormalities on microtubules/axons, and tau-mediated pathology in rTg4510 mice exacerbate cognitive deficits reflecting FTD. Aim 2 will determine if LIB-induced pTau-containing NFTs and synaptic degeneration in rTg4510 mice involves specific subtypes of excitatory neurons and whether Tau-mediated neurodegeneration may extend to other cell types, including astrocytes, microglia, and cells in the cerebral vasculatures. Aim 3 will use a systems biology approach by quantitative proteomic techniques to investigate altered proteomes and signaling pathways in LIB-induced mice and to determine whether these changes play a role in the pathogenesis of FTD in rTg4510 mice. In addition, since there are increasing females in the military combat, this study will include evaluating sex differences associated with blast injuries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910694
Entities
People
- Zezong Gu
Organizations
- Curators of the University of Missouri
- United States Army