Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: a Chronic Effects of Neurotrauma Consortium Study

Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI). Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury. Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. However, no noticeable difference was observed between the young and aged groups as initially hypothesized. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice. Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury. These findings suggest differential age-dependent effects in TBI pathobiology

Treatment With Nilvadipine Mitigates Inflammatory Pathology and Improves Spatial Memory in Aged hTau Mice After Repetitive Mild TBI

Mild traumatic brain injury (mTBI) is the most common form of brain trauma worldwide. The effects of mTBI are not well-studied within the elderly population, yet older adults constitute a significant portion of all mTBI patients. Few preclinical studies have focused on the effects of mTBI, or mTBI treatments, in the aged brain, and none have explored repetitive mTBI (r-mTBI). In this study, we have administered our well-characterized 5-injury model (5 r-mTBI) to hTau mice aged 24 months to explore the neurobehavioral and neuropathological outcomes, and the effects of treatment with the dihydropyridine, Nilvadipine. Our previous studies have shown that Nilvadipine inhibits spleen tyrosine kinase (Syk), is effective at reducing inflammation, tau hyperphosphorylation, and amyloid production, and it has recently been investigated in a European Phase III clinical trial for Alzheimer’s disease (AD). In our 24-month-old r-mTBI mice, we observed increased neuroinflammation and a trend toward impaired cognitive performance compared to sham controls. Treatment with Nilvadipine mitigated the TBI-induced inflammatory response in aged r-mTBI animals and significantly improved spatial memory. To our knowledge, this is the only preclinical study focusing on the treatment of r-mTBI in aged, and these results suggest a therapeutic potential of Nilvadipine for consequences of mTBI

Author Correction: Oleoylethanolamide treatment reduces neurobehavioral deficits and brain pathology in a mouse model of Gulf War Illness

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A permethrin metabolite is associated with adaptive immune responses in Gulf War Illness

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and  PER (PB+PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI

Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma

A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders. [Abstract copyright: Published by Elsevier Inc.

Documenting the Recovery of Vascular Services in European Centres Following the Initial COVID-19 Pandemic Peak: Results from a Multicentre Collaborative Study

Objective: To document the recovery of vascular services in Europe following the first COVID-19 pandemic peak. Methods: An online structured vascular service survey with repeated data entry between 23 March and 9 August 2020 was carried out. Unit level data were collected using repeated questionnaires addressing modifications to vascular services during the first peak (March – May 2020, “period 1”), and then again between May and June (“period 2”) and June and July 2020 (“period 3”). The duration of each period was similar. From 2 June, as reductions in cases began to be reported, centres were first asked if they were in a region still affected by rising cases, or if they had passed the peak of the first wave. These centres were asked additional questions about adaptations made to their standard pathways to permit elective surgery to resume. Results: The impact of the pandemic continued to be felt well after countries’ first peak was thought to have passed in 2020. Aneurysm screening had not returned to normal in 21.7% of centres. Carotid surgery was still offered on a case by case basis in 33.8% of centres, and only 52.9% of centres had returned to their normal aneurysm threshold for surgery. Half of centres (49.4%) believed their management of lower limb ischaemia continued to be negatively affected by the pandemic. Reduced operating theatre capacity continued in 45.5% of centres. Twenty per cent of responding centres documented a backlog of at least 20 aortic repairs. At least one negative swab and 14 days of isolation were the most common strategies used for permitting safe elective surgery to recommence. Conclusion: Centres reported a broad return of services approaching pre-pandemic “normal” by July 2020. Many introduced protocols to manage peri-operative COVID-19 risk. Backlogs in cases were reported for all major vascular surgeries

HORMONAL MECHANISMS UNDERLYING SEX DIFFERENCES IN PARKINSON’S DISEASE

(Statement of Responsibility) by Nicole Saltiel(Thesis) Thesis (B.A.) -- New College of Florida, 2016RESTRICTED TO NCF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE(Bibliography) Includes bibliographical references.This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.Faculty Sponsor: Beulig, Alfred

Impact of Repetitive Mild Traumatic Brain Injury on Behavioral and Hippocampal Deficits in a Mouse Model of Chronic Stress

Clinical studies examining the interaction between traumatic brain injury (TBI) and stress-related disorders (e.g., post-traumatic stress disorder) are often complicated by methodological constraints, such as heterogeneity in injury type and severity, time post-trauma, and predisposing risk factors. Developing relevant animal models whereby many variables can be efficiently controlled is thus essential to understanding this elusive relationship. Here, we use our repeated unpredictable stress (RUS) paradigm, in combination with our established mouse model of repetitive mild TBI (r-mTBI), to assess the impact of repeated exposures to these paradigms on behavioral and neurobiological measures. C57BL/6J male mice were exposed to RUS and r-mTBI at 3 and 6 months of age followed by batteries of behavioral testing. Mice were euthanized 10 days and 3 months post-exposure, with brain and plasma samples collected for molecular profiling. The RUS paradigm involved exposure to a predator odor (trimethylthiazoline; TMT) while under restraint, daily unstable social housing, five inescapable footshocks on separate days, and chronic social isolation. Animals receiving r-mTBI ( × 5) and stress were exposed to a single closed-head injury 1 h after each footshock. Stress-alone mice showed significant weight loss, recall of traumatic memories, and anxiety-like and passive stress-coping behavior when compared with control mice. However, in stress+r-mTBI animals, the changes in cued fear memory, anxiety, and stress-coping tests were diminished, possibly due to TBI-induced hyperactivity. We also report complex brain molecular and neuropathological findings. Stress and r-mTBI, either individually or comorbidly, were associated with a chronic reduction in dendritic spine GluN2A/GluN2B ratio in the hippocampus. While stress augmented the r-mTBI–dependent astrogliosis in the corpus callosum, it mitigated r-mTBI–induced increases in hippocampal pro–brain-derived neurotrophic factor. We anticipate that our model will be a good platform to untangle the complex comorbid pathophysiology in stress disorders and r-mTBI

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury

Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma