Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury

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

Impact of age-related neuroglial cell responses on hippocampal deterioration

Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS). These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signaling. These changes may occur without any overt concurrent pathology, however, they typically correlate with deteriorations in hippocamapal or cognitive function. In this review we examine two important phenomenons, firstly the relationship between age-related brain deterioration (focusing on hippocampal function) and underlying neuroglial response(s), and secondly how the latter affects molecular and cellular processes within the hippocampus that makes it vulnerable to age-related cognitive decline

Hemotoxicity Induced by Chronic Chlorpyrifos Exposure in Wistar Rats: Mitigating Effect of Vitamin C

The study evaluated the ameliorative effect of vitamin C on chronic chlorpyrifos-induced hematological alterations in Wistar rats. Twenty adult male rats divided into 4 groups of 5 animals each were exposed to the following regimens: group I (S/oil) was administered soya oil (2 mL/kg b.w.), while group II (VC) was given vitamin C (100 mg/kg b.w.); group III was dosed with CPF (10.6 mg/kg b.w.); group IV was pretreated with vitamin C (100 mg/kg) and then exposed to CPF (10.6 mg/kg b.w.), 30 minutes later. The regimens were administered by oral gavage once daily for a period of 17 weeks. Blood samples collected at the end of the study revealed reduction in the levels of pack cell volume, hemoglobin, red blood cells, leukocytes (attributed to neutropenia, lymphopenia, and monocytopenia), and platelets in the CPF group, which were ameliorated in the vitamin C- pretreated group. The elevated values of malonaldehyde, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and neutrophil/lymphocyte ratio in the CPF group were restored in those pretreated with vitamin C. The study has shown that chronic CPF-induced adversity on hematological parameters of Wistar rats was mitigated by pretreatment with vitamin C

Unbiased Proteomic Approach Identifies Unique and Coincidental Plasma Biomarkers in Repetitive mTBI and AD Pathogenesis

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

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

Objective: Exposure to repetitive concussion, or mild traumatic brain injury (mTBI), has been linked with increased risk of long-term neurodegenerative changes, specifically chronic traumatic encephalopathy (CTE). To date, preclinical studies largely have focused on the immediate aftermath of mTBI, with no literature on the lifelong consequences of mTBI in these models. This study provides the first account of lifelong neurobehavioral and histological consequences of repetitive mTBI providing unique insight into the constellation of evolving and ongoing pathologies with late survival. Methods: Male C57BL/6J mice (aged 2–3 months) were exposed to either single or repetitive mild TBI or sham procedure. Thereafter, animals were monitored and assessed at 24 months post last injury for measures of motor coordination, learning deficits, cognitive function, and anxiety-like behavior prior to euthanasia and preparation of the brains for detailed neuropathological and protein biochemical studies. Results: At 24 months survival animals exposed to r-mTBI showed clear evidence of learning and working memory impairment with a lack of spatial memory and vestibule-motor vestibulomotor deficits compared to sham animals. Associated with these late behavioral deficits there was evidence of ongoing axonal degeneration and neuroinflammation in subcortical white matter tracts. Notably, these changes were also observed after a single mTBI, albeit to a lesser degree than repetitive mTBI. Interpretation: In this context, our current data demonstrate, for the first time, that rather than an acute, time limited event, mild TBI can precipitate a lifelong degenerative process. These data therefore suggest that successful treatment strategies should consider both the acute and chronic nature of mTBI

Prospects and constraints on utilization of Jatropha curcas seeds in animal feedstuff

Combined physical, chemical and biochemical methods were used to process virgin seed meal of Jatropha curcas L. into treated Jatropha Seed Meal (JSM). Graded levels (0, 5, 10, 15, 20 and 25%) JSM treated by the various methods was included in the test diets which were fed ad libitum to 360 albino rats for a month in a single factor design trial. The results revealed that feed intake was numerically highest (p > 0.05) for the rats on the 5 % treated JSM diet, while feed efficiency was highest (p > 0.05) for those on the 10 % treated JSM diets. Weight gain was significantly highest (p< 0.05) for the rats on 10 and 15 % treated JSM diets. Lowest survival rate (17%) was observed on treated JSM diet processed by boiling, roasting followed by fermenting. Biochemical indices measured on treated JSM based diets were comparable with those obtained on the conventional diet (p > 0.05) except for blood cholesterol level (p < 0.05) which was elevated with increasing treated JSM in diets. There were also no significant differences recorded on AST and ALP activities (p > 0.05) between the treatments. Haematological indices investigated including PCV, RBC, Hb were insignificantly influenced by the 5% dietary treated JSM compared with the control diet (p > 0.05) and there was non-significant effect of the dietary treatment on the WBC differential counts of lymphocytes, eosinophils, monocytes and neutrophils. It was established in this study that inclusion of 5% treated JSM in diets had no detrimental effect on albino rats. Further researches are in progress to investigate inclusion of the treated JSM in diets at levels higher than the 5% used in this study.Keywords: JSM, Cockerels, Performance, Biochemical and haematological parameter

Makroskopska građa malog mozga afričkoga divovskog trstičnog štakora (Thryonomys swinderianus - Temminck, 1827) tijekom fetalnog i postnatalnog razvoja

In Nigeria, the African grasscutter (Thryonomys swinderianus) is bred as a mini-livestock, and research model. This study provides some information on the ontogeny of its cerebellum through gross observations of external cerebellar features from foetuses on foetal days 60 and 90, neonates on postnatal day 3, juveniles on postnatal day 72 and adults on postnatal day 450. On foetal day 60, the cerebellum was a smooth, semi-circular mass, devoid of folia or sulci; cerebellar lobes and vermal lobules were not present. On foetal day 90, the vermis was distinct, but vermal lobules were indistinct. On postnatal day 3, the cerebellar cortex was convoluted with the folia and fissures of grossly distinct lobes. The cerebellar vermis was divided into all the lobules typical of mammalian vermis; while the lingula, central lobule, culmen and declive were on the cerebellar dorsum, the folium, tuber, pyramis, uvula and nodulus were caudally located. The culmen was undivided and the crus rostralis was unpaired. On postnatal day 72, the pre-central fissure was deeper than that observed on postnatal day 3; the culmen was divided into the pars rostralis and pars caudalis; the crus rostralis was bifoliated by a fissural line. On postnatal day 450, the cerebellar fissures were deeper than before; the vermal and hemispheric lobules were better delineated. The bifoliation of the crus rostralis was more evident. The intra-crural fissure was very distinct and referred to as the great horizontal fissure. The results of the present study will add to the data base of rodent neuroanatomy, necessary for teaching and research.U Nigeriji se afrički divovski trstični štakor (Thryonomys swinderianus) uzgaja kao mini stoka i model za istraživanje. U radu su prikazani podaci o razvoju njegova malog mozga, prikupljeni makroskopskim promatranjem vanjskih obilježja mozga kod fetusa u dobi 60 i 90 dana, novorođenčadi u dobi 3 dana, mladih životinja u dobi od 72 dana i odraslih životinja u dobi od 450 dana. Mali mozak fetusa u dobi od 60 dana bio je glatka, polukružna masa bez vijuga i brazda, na kojoj nisu bili prisutni moždani režnjevi ni vermisni režnjići. U dobi fetusa i u dobi od 90 dana bio je izražen vermis, ali vermisni su režnjići bili nejasni. Treći dan nakon porođaja kora maloga mozga je na vrlo izraženim režnjevima bila isprepletena s vijugama i usjeklinama. Vermis maloga mozga bio je podijeljen na sve režnjeve tipične za vermis sisavaca. Lingula, središnji režanj, kulmen i declive bili su na dorzumu maloga mozga, dok su folium, tuber, pyramis, uvula i nodulus smješteni kaudalno. Kulmen je bio nepodijeljen, a crus rostralis nesparen. 72 dana nakon porođaja predsredišnja usjeklina bila je dublja u odnosu na opažanja 3. dana nakon porođaja. Kulmen je bio podijeljen na pars rostralis i pars caudalis. Crus rostralis je linijom usjekline bio dvovijugav. Mali mozak životinja u dobi od 450 dana imao je dublje usjekline, a vermisni i hemisferični režnjevi bili su bolje razgraničeni. Dvovijugavost crus rostralis bila je još naglašenija. Intrakruralna usjeklina bila je vrlo izražena i prikazana kao velika vodoravna usjeklina. Rezultati ove studije nadopunit će bazu podataka o neuroanatomiji glodavaca koja je potrebna za poučavanja i istraživanja

Unbiased Proteomic Approach Identifies Pathobiological Profiles in the Brains of Preclinical Models of Repetitive Mild Traumatic Brain Injury, Tauopathy, and Amyloidosis

No concerted investigation has been conducted to explore overlapping and distinct pathobiological mechanisms between repetitive mild traumatic brain injury (r-mTBI) and tau/amyloid proteinopathies considering the long history of association between TBI and Alzheimer’s disease. We address this problem by using unbiased proteomic approaches to generate detailed time-dependent brain molecular profiles of response to repetitive mTBI in C57BL/6 mice and in mouse models of amyloidosis (with amyloid precursor protein KM670/671NL (Swedish) and Presenilin 1 M146L mutations [PSAPP]) and tauopathy (hTau). Brain tissues from animals were collected at different timepoints after injuries (24 hr–12 months post-injury) and at different ages for tau or amyloid transgenic models (3, 9, and 15 months old), encompassing the pre-, peri-, and post-“onset” of cognitive and pathological phenotypes. We identified 30 hippocampal and 47 cortical proteins that were significantly modulated over time in the r-mTBI compared with sham mice. These proteins identified TBI-dependent modulation of phosphatidylinositol-3-kinase/AKT signaling, protein kinase A signaling, and PPARα/RXRα activation in the hippocampus and protein kinase A signaling, gonadotropin-releasing hormone signaling, and B cell receptor signaling in the cortex. Previously published neuropathological studies of our mTBI model showed a lack of amyloid and tau pathology. In PSAPP mice, we identified 19 proteins significantly changing in the cortex and only 7 proteins in hTau mice versus wild-type littermates. When we explored the overlap between our r-mTBI model and the PSAPP/hTau models, a fairly small coincidental change was observed involving only eight significantly regulated proteins. This work suggests a very distinct TBI neurodegeneration and also that other factors are needed to drive pathologies such as amyloidosis and tauopathy postinjury

Chronic repetitive mild traumatic brain injury results in reduced cerebral blood flow, axonal injury, gliosis, and increased T-Tau and Tau oligomers

Exposure to repetitive mild traumatic brain injury (mTBI) is a risk factor for chronic traumatic encephalopathy, which is characterized by patchy deposition of hyperphosphorylated tau aggregates in neurons and astrocytes at the depths of cortical sulci. We developed an mTBI paradigm to explore effects of repetitive concussive-type injury over several months in mice with a human tau genetic background (hTau). Two injuries were induced in the hTau mice weekly over a period of 3 or 4 months and the effects were compared with those in noninjured sham animals. Behavioral and in vivo measures and detailed neuropathological assessments were conducted 6 months after the first injury. Our data confirm impairment in cerebral blood flow and white matter damage. This was accompanied by a 2-fold increase in total tau levels and mild increases in tau oligomers/conformers and pTau (Thr231) species in brain gray matter. There was no evidence of neurofibrillary/astroglial tangles, neuropil threads, or perivascular foci of tau immunoreactivity. There were neurobehavioral deficits (ie, disinhibition and impaired cognitive performance) in the mTBI animals. These data support the relevance of this new mTBI injury model for studying the consequences of chronic repetitive mTBI in humans, and the role of tau in TBI