Abstract
Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.
Highlights
Exposure to a history of repetitive mild traumatic brain injury has been recognized as a major risk factor for the development of age-related degenerative diseases, such as Alzheimer’s disease, and chronic traumatic encephalopathy (CTE) typified by immunoreactive tau aggregates in the depths of the sulci (Gedye et al, 1989; Mortimer et al, 1991; Schofield et al, 1997; Fleminger et al, 2003; McKee et al, 2013; Omalu et al, 2011; Smith et al, 2013)
Unlike changes observed in the cortex, we observed a significant increase in LPE and LPC in repetitive mild traumatic brain injury (mTBI) mice compared to sham counterparts
Arachidonic Acid (AA) and Docosahexaenoic Acid (DHA) Containing Phospholipid Species, and Their Ratio in the Cortex and Hippocampus of Repetitive mTBI Mice at Longitudinal Timepoints In the cortex, we observed a significant increase in arachidonic acid (AA) levels for PI and PC species at the 24 h post-injury time point in the repetitive mTBI vs. sham mice (Figures 5A,E), and a significant decrease in AA levels for LPC was observed at the 3 months post-injury time point in the repetitive mTBI vs. sham mice (Figure 5G)
Summary
Exposure to a history of repetitive mild traumatic brain injury (mTBI) has been recognized as a major risk factor for the development of age-related degenerative diseases, such as Alzheimer’s disease, and chronic traumatic encephalopathy (CTE) typified by immunoreactive tau aggregates in the depths of the sulci (Gedye et al, 1989; Mortimer et al, 1991; Schofield et al, 1997; Fleminger et al, 2003; McKee et al, 2013; Omalu et al, 2011; Smith et al, 2013). Lipidomic profiling is an extremely powerful tool that enables large-scale study of novel pathways and networks of lipids in biological systems (Sparvero et al, 2010; Wenk, 2010) It has been utilized very successfully in recognizing the roles of lipids in several metabolic diseases such as atherosclerosis, hypertension and diabetes, but to date has received little attention in the study of neurodegenerative disorders. Phospholipids are important molecules, forming the membrane lipid bilayers of neurons, glia and cerebrovascular cells They provide structural integrity for intracellular and cell surface membrane proteins (Adibhatla and Hatcher, 2007). There are, no current studies that have explored the role of phospholipids in repetitive mTBI, especially at chronic time points post-injury, and how this may confer risk for the development of age-related neurodegenerative diseases
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