Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau

Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations

“…However, by examining the nominally significant genetic locus associated with the metabolite on chromosome 10 (BP 60,794,328-61,050,339), nearby genes and phenotypes associated with those genes were identified (genes included PHYHIPL, TRAF6P1, LINC00844, and FAM13C; phenotypes included DNA methylation, sleep duration, and QT-interval duration in Trypanosoma cruzi seropositivity). Together, these findings support and potentially shed light on the biological mechanism for metabolite X-24295's association with PTSD, as PTSD has been shown to be related to traumatic brain injury 68 (which has been associated with PHYHIPL in mice 69 ), altered DNA methylation 70 , and sleep disturbances 71 . These genetic annotations may also aid in the identification of the metabolite itself, as has been demonstrated by other metabolome-wide GWAS analyses 17 .…”

Advance of sporadic Alzheimer's disease animal models

“…According to the severity of the injury, mild, moderate, and severe TBI can be selected. In general, the elevated level of phosphorylated Tau, the expression of Aβ, degradation of white matter, BBB dysfunction as well as neurogenic inflammation in hippocampus were observed in TBI models …”

“…TBI-induced AD models have been developed to mimic the sAD pathological changes in the brain. Controlled cortical impact (CCI) model,[102][103][104] fluid percussion injury (FPI) model,[105][106][107][108] weight drop model,103,[109][110][111] and blast injury (BI) model[112][113][114][115] can be used to induce TBI in animals. According to the severity of the injury, mild, moderate, and severe TBI can be selected.…”

“…According to the severity of the injury, mild, moderate, and severe TBI can be selected. In general, the elevated level of phosphorylated Tau, the expression of Aβ, degradation of white matter, BBB dysfunction as well as neurogenic inflammation in hippocampus were observed in TBI models [101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118]. Wang et al discovered that TBI induced the activation of the calpain-2-PTPN13-c-Abl pathway contributed to promoted abnormal Tau aggregation and NFTs formation.…”

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

“…Moreover, progressive spreading of tau proteinopathy has been triggered in wild-type mice by impact or blast TBI [26][27][28][29]. Quantitation of tau and phosphorylated tau (p-tau) in mice show that tau and p-tau levels are significantly changed within 1 day after blast, then return to the pre-blast stage when mouse brains were examined at 15 weeks post-blast [30], consistent with previous findings in mini-pigs [31] and mice [32]. Other studies conducted in mice have shown long-term persistence and even progression of blast-and impact-induced p-tauopathy [26-28, 33, 34].…”