Abstract
Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer’s disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing ‘pre’, ‘peri’ and ‘post’ onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.
Highlights
There has been little exploration of the trajectory of lipid changes following repetitive mild TBI (r-mTBI) in humans; to our knowledge no studies have been conducted on postmortem mTBI brains and most studies to date have been based on CSF samples collected from severe TBI patients, which show an increase in lipoprotein PL fractions and increased free fatty acids (FFA) within 48 days to 1 week after injury (Pilitsis et al, 2003; Pasvogel et al, 2010; Hankin et al, 2011)
We propose that longitudinal studies in relevant preclinical models can assist our understanding, and so we have applied lipidomic profiling to our preclinical model of r-mTBI and an established model of Alzheimer’s Disease (AD) (PSAPP)
Total phosphatidylethanolamine (PE), phosphatidylcholine (PC) and sphingomyelin (SM) were significantly increased in the hippocampi at 24 h, 6 and 12 months post-injury in r-mTBI mice compared to shams (Table 1 and Supplementary Figures S1A,C,F)
Summary
For many years it has been known that a history of repetitive mild TBI (r-mTBI) increases the risk for the development of neurodegenerative diseases such as Alzheimer’s Disease (AD) (Gedye et al, 1989; Mortimer et al, 1991; Schofield et al, 1997; Fleminger et al, 2003; Omalu et al, 2011; McKee et al, 2013; Smith et al, 2013). There has been little exploration of the trajectory of lipid changes following r-mTBI in humans; to our knowledge no studies have been conducted on postmortem mTBI brains and most studies to date have been based on CSF samples collected from severe TBI patients, which show an increase in lipoprotein PL fractions and increased free fatty acids (FFA) within 48 days to 1 week after injury (Pilitsis et al, 2003; Pasvogel et al, 2010; Hankin et al, 2011) Some of these human studies have been insightful in providing a common dysregulation of lipid involvement in TBI and AD, a prospective study examining longitudinal changes is non-existent. To explore the interrelationship between TBI and AD we analyzed timepoints post-TBI ranging from acute to chronic (24 h, 3, 6, 9, and 12 months) following injury at early adulthood (2–3 months) and in the PSAPP model we analyzed time points encompassing ‘pre,’ ‘peri’ and ‘post’ onset of amyloid pathology (3, 9, 15 months of age)
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