Gangliosides and Ceramides Change in a Mouse Model of Blast Induced Traumatic Brain Injury

Abstract

Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced "mild" traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5−5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology. E xplosive devices used in conflicts have increased the prevalence of blast-induced mild traumatic brain injuries (bTBI) in the U.S. military. It has been estimated that about 20% of deployed personnel have been exposed to at least one episode of bTBI. 1,2 Explosive detonations produce shock waves, blast wind and electromagnetic pulses. Primary injury is due to distortion of tissue by propagation of atmospheric pressure (AP) differential between blast overpressure and normal AP, thus compressing soft tissues (lung, GI, ear, brain), followed by reverse negative pressure leading to tearing and shearing of tissue, including veins. 3 These AP changes result in nonpenetrating mild bTBI, with physical and psychological consequences. However, behavioral manifestations of mild bTBI are often not associated with discernible structural changes in brain tissue or neurological signs, in either animal models or humans. 4−9 Diagnosis is problematic and indeed even the existence of a bTBI syndrome has been debated. 10 Ceramide and derived glycosphingolipids form 20% of total lipids of plasmalemma and intracellular organelle membranes. 11Gangliosides constitute 6% by weight of total brain lipids and include four major structural series of species, constructed on a ceramide scaffold with an oligosaccharide chain containing at least one sialic acid moiety. Their formation is catalyzed by membrane-bound glycosyltransfersases in the Golgi apparatus and endoplasmic reticulum. GM1, accounts for approximately 21% of total gangliosides, while GM2, a very minor ganglioside species, constitutes less than 0.5% of total gangliosides or 0.08% of all brain lipids. Concentration ratios of ganglioside species in intracellular membranes (e.g., Golgi apparatus and endoplasmic reticulum) and plasmalemma compartments (components of lipid rafts) appear to be tightly regulated i...

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…In addition, accumulation of GM2 has been observed in neurodegenerative diseases such as Alzheimer disease (31)(32)(33) and Angelmanlike syndrome ( 34 ), and in rodent acute brain injury models such as blast-induced mild traumatic brain injury ( 35 ) and a transient focal cerebral ischemia model ( 36 ). However, the mechanisms behind and the roles of accumulated GM2 have not been well elucidated.…”

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

“…10,11,14,21,22 However, even low-level blast pressure waves are transmitted to the brain and exert a variety of biochemical, pathological, and physiological effects in animals, including the induction of chronic behavioral effects. 3,10,14,[21][22][23][24][25][26][27][28][29] Modulation of gene expression mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, is one way the brain creates new homeostasis in response to experience, including response to injury. 30 Aberrant regulation of gene expression contributes to long-lasting behavioral abnormalities, where epigenetic modifications serve as a regulatory layer decoding environmental signals into sustained changes in gene expression.…”

Mass Spectrometry Imaging of Biomolecular Information

“…Lipidomics imaging by MALDI MSI has also been applied to study blast-induced mild traumatic brain injuries 124 , thyroid papillary cancer 125 , to glaucoma research by studying 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 optic nerve tissue 126 , to study myocardial infarction 127 , to investigate porcine eye sections 128 and to improve shrimp production 129 .…”