Abstract
The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer’s disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features, respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-“onset” of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24 h, 3, 6, 9, and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini–Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wild-type littermates with aging. Six proteins were found to be significantly regulated in all three models, i.e., r-mTBI, hTau, and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Data are available via ProteomeXchange with identifier PXD010664.
Highlights
Traumatic brain injury (TBI) is one of the major causes of death and disability, and is one of the largest risk factors for neurodegenerative diseases such as Alzheimer’s disease (AD)
Mice as we have previously described, and it is worth mentioning that we have previously documented behavioral and histopathological findings in our wild type mouse model from 24 h to 24 months post-injury, indicating that behavioral deficits in this model are mediated by a non-tau/amyloid mechanism. In this same cohort we have conducted proteomics analyses of brain tissue at the same time points of analyses described in this current work, and we present distinct and overlapping proteomic response to injury in our TBI model compared with AD mouse models, indicating a distinct TBI mediated neurodegeneration, that shares features with AD pathogenesis (Ojo et al, pers comm)
We hypothesized that controlled preclinical studies in mouse models that demonstrate TBI sequelae and AD pathogenesis would identify areas of molecular overlap that may represent critical elements in the pathogenic interrelationship between TBI and AD
Summary
Traumatic brain injury (TBI) is one of the major causes of death and disability, and is one of the largest risk factors for neurodegenerative diseases such as Alzheimer’s disease (AD). Some studies have shown a significant role for AD-related tau protein species (total tau, caspase cleaved tau fragments, phosphorylated tau) in the blood following mTBI in athletes and military personnel (Di Battista et al, 2013; Neselius et al, 2013b; Shahim et al, 2014, 2016; Olivera et al, 2015; Rubenstein et al, 2015; Gill et al, 2018) Most of these human studies lack adequate controls, and chronic (or longitudinal) time points that are more relevant to the current at risk patients with a history of mTBI exposures, some have been based on acute studies and retrospective design reports, which have inherent limitations, such as selection bias, substantial heterogeneity in patient populations, variance in type/nature of injury and post-injury intervals. These studies have not been well-validated and reproducible by independent laboratories in different prospective cohorts of a variety of TBI patients
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