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To explore the short-term effects of accidental head impacts and repetitive headers on circulating microRNAs, accounting for the effects of high-intensity exercise alone. Blood samples were collected from professional soccer players at rest. Repeat samples were drawn 1 h and 12 h after three conditions: (1) accidental head impacts in a match, (2) repetitive headers during training, and (3) high-intensity exercise. 89 samples were screened to detect microRNAs expressed after each exposure. Identified microRNAs were then validated in 98 samples to determine consistently deregulated microRNAs. Deregulated microRNAs were further explored using bioinformatics to identify target genes and characterize their involvement in biological pathways. Accidental head impacts led to deregulation of eight microRNAs that were unaffected by high-intensity exercise; target genes were linked to 12 specific signaling pathways, primarily regulating chromatin organization, Hedgehog and Wnt signaling. Repetitive headers led to deregulation of six microRNAs that were unaffected by high-intensity exercise; target genes were linked to one specific signaling pathway (TGF-β). High-intensity exercise led to deregulation of seven microRNAs; target genes were linked to 31 specific signaling pathways. We identified microRNAs specific to accidental head impacts and repetitive headers in soccer, potentially being useful as brain injury biomarkers.

Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that usually do not result in acute symptoms and are therefore also referred to as "subconcussive" head impacts. RHI occur e.g., when heading the ball or during contact with another player. Evidence suggests that exposure to RHI may have cumulative effects on brain structure and function. However, little is known about brain alterations associated with RHI, or about the risk factors that may lead to clinical or behavioral sequelae. REPIMPACT is a prospective longitudinal study of competitive youth soccer players and non-contact sport controls aged 14 to 16 years. The study aims to characterize consequences of exposure to RHI with regard to behavior (i.e., cognition, and motor function), clinical sequelae (i.e., psychiatric and neurological symptoms), brain structure, function, diffusion and biochemistry, as well as blood- and saliva-derived measures of molecular processes associated with exposure to RHI (e.g., circulating microRNAs, neuroproteins and cytokines). Here we present the structure of the REPIMPACT Consortium which consists of six teams of clinicians and scientists in six countries. We further provide detailed information on the specific aims and the design of the REPIMPACT study. The manuscript also describes the progress made in the study thus far. Finally, we discuss important challenges and approaches taken to overcome these challenges. ispartof: Brain Imaging And Behavior vol:16 issue:1 ispartof: location:United States status: published

Introduction: Blood-based biomarkers can provide valuable information on the effects of repetitive head impacts in sports. This study investigated if repetitive headers or accidental head impacts in soccer could cause structural brain injury, detected as an increase in serum neurofilament light (NfL) or tau. Methods: NfL and tau were measured in professional soccer players in pre-season. Then, the effect of three short-term exposures on biomarker levels was assessed: (1) high-intensity exercise, (2) repetitive headers, and (3) head impacts in a match. Results: We analyzed 354 samples and observed no effects on NfL from any of the three short-term exposures. Tau levels rose significantly from baseline to 1 h after (1) high-intensity exercise (Δ0.50 pg/ mL, 95% CI 0.19–0.81, p < .01); the same was observed after (2) repetitive headers (Δ0.29 pg/mL, 95% CI 0.10–0.48, p < .01), but not after (3) accidental head-impact incidents (Δ0.36 pg/mL, 95% CI −0.02–0.74, p = .06). The highest absolute values were seen 1 h after high-intensity exercise (mean±SD, 1.92 ± 0.83 pg/mL). Conclusion: NfL and tau in serum were unaffected by head impacts in soccer. Importantly, tau levels seem to rise in response to exercise, emphasizing the need for control groups. Our findings highlight important characteristics and limitations when using these biomarkers in sports.

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies.The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.

Pathologically altered tau protein is a common denominator of neurodegenerative disorders including Alzheimer’s disease (AD) and other tauopathies. Therefore, promising immunotherapeutic approaches target and eliminate extracellular pathogenic tau species, which are thought to be responsible for seeding and propagation of tau pathology. Tau isoforms in misfolded states can propagate disease pathology in a template-dependent manner, proposed to be mediated by the release and internalization of extracellular tau. Monoclonal antibody DC8E8, binding four highly homologous and independent epitopes in microtubule-binding domain (MTBD) of diseased tau, inhibits tau-tau interaction, discriminates between healthy and pathologically truncated tau and reduces tau pathology in animal model in vivo. Here, we show that DC8E8 antibody acts via extracellular mechanism and does not influence viability and physiological functions of neurons. Importantly, in vitro functional assays showed that DC8E8 recognises pathogenic tau proteins of different size and origin, and potently blocks their entry into neurons. Next, we examined the mechanisms by which mouse antibody DC8E8 and its humanized version AX004 effectively block the neuronal internalization of extracellular AD tau species. We determined a novel mode of action of a therapeutic candidate antibody, which potently inhibits neuronal internalization of AD tau species by masking of epitopes present in MTBD important for interaction with neuron surface Heparan Sulfate Proteoglycans (HSPGs). We show that interference of tau-heparane sulfate interaction with DC8E8 antibody via steric hindrance represents an efficient and important therapeutic approach halting tau propagation. Electronic supplementary material The online version of this article (10.1186/s40478-019-0770-y) contains supplementary material, which is available to authorized users.

Neurofibrillary degeneration induced by misfolded protein tau is considered to be one of the key pathological hallmarks of Alzheimer's disease (AD). In the present study, we have introduced a novel transgenic rat model expressing a human truncated tau that encompasses 3 microtubule binding domains (3R) and a proline-rich region (3R tau151-391). The transgenic rats developed progressive age-dependent neurofibrillary degeneration in the cortical brain areas. Neurofibrillary tangles (NFTs) satisfied several key histological criteria used to identify neurofibrillary degeneration in human Alzheimer's disease including argyrophilia, Congo red birefringence, and Thioflavin S reactivity. Neurofibrillary tangles were also identified with antibodies used to detect pathologic tau in the human brain, including DC11, recognizing an abnormal tau conformation and antibodies that are specific for hyperphosphorylated forms of tau protein. Moreover, neurofibrillary degeneration was characterized by extensive formation of sarkosyl insoluble tau protein complexes consisting of rat endogenous and truncated tau species. Interestingly, the transgenic rats did not show neuronal loss either in the cortex or in the hippocampus. We suggest that novel transgenic rat model for human tauopathy represents a valuable tool in preclinical drug discovery targeting neurofibrillary degeneration of Alzheimer's type.

The effect of 3,5,3′- l -triiodothyronine (T 3 ) on survival and morphology of primary cultured neurons of the fetal rat brain was studied. In defined conditions of serum-free culture media we found the death preventing effect of T 3 in all tested neuronal populations cultivated at high initial densities of plating (10 5 cells/cm 2 ). While the survival of cerebrocortical neurons was improved very slightly, the number of surviving hippocampal and septal neurons reached 127.2 ± 2.0% or 134.8 ± 12.3% of their respective controls. The septal neurons responded at normal physiological concentration of T 3 (1nM) in high density as well as in low density cultures (5 × 10 3 cells/cm 2 ). Moreover the treatment with 10 nM of T 3 caused significant extension of the axon elongation of septal neurons (194.5 ± 15.7%). These findings suggest the direct positive effect of T 3 on pure cell population of septal neurons derived from embryonic rat brain and support the evidence for the role of this peripheral hormone during neuritogenesis.