Traumatic brain injury (TBI) is a major health concern in the current population. Animal models are increasingly important for identifying early neurobehavioural changes associated with mild to severe as well as repetitive brain injuries. In this study, we analysed behavioural changes in a mouse model of repetitive mild TBI using unbiased quantification metrics. Our approach enabled automated markerless pose estimation of thigmotaxis together with spatial working memory and locomotor activity assessments specifically during the scarcely-studied subacute phase after brain injury. We found that animals exposed to repetitive mild head impacts developed anxiety-like behaviour, manifested by avoidance of the central zone and increased thigmotaxis in the open field test, while maintaining total distance travelled compared to the control group. However, analysis of exploratory behaviour and spatial working memory in the Y-maze, along with assessment of sensorimotor coordination and balance using rotarod tests, revealed no significant difference between the TBI and control groups. These findings suggest that repetitive mTBI is associated with selective anxiety-like behaviour during the subacute phase after brain injury, without detectable motor or cognitive deficits, reflecting the early affective symptomatology frequently reported in clinical populations with mTBI.

Importance:Repetitive head impacts (RHIs) are associated with later-life neurodegeneration. Because soccer is the most widely played sport among youth worldwide, identifying early changes associated with RHI is important. Objective:To determine whether participation in 1 season of youth soccer is associated with changes in cognition, behavior, balance, brain structure or function, or blood biomarkers compared with noncontact sports. Design, Setting, and Participants:Prospective longitudinal cohort study at European centers (Munich, Germany; Leuven, Belgium; and Oslo, Norway). Male adolescent soccer players and noncontact athletes were each studied across a single competitive season with assessments at preseason, postseason, and 2 months later. Data were analyzed from January 2023 to March 2025. Exposures:Soccer players were compared with noncontact athletes. In addition, self-reported heading of a soccer ball was assessed among soccer players as a measure of RHI. Main Outcomes and Measures:Cognition, behavior, balance, magnetic resonance imaging (brain structure, function, and biochemistry), and plasma biomarkers. Results:Male adolescent soccer players (n = 82; mean [SD] age, 14.8 [0.6] years) did not differ from noncontact sport athletes (n = 47; mean [SD] age, 14.7 [0.7] years) in cognition, behavior, balance, cortical thickness, brain volumes, white-matter microstructure, or functional connectivity. At preseason, soccer players had higher total N-acetylaspartate (tNAA; β, -0.379 [95% CI, -0.627 to -0.131]; P = .003), glial fibrillary acidic protein (GFAP; β, -0.055 [95% CI, -0.103 to -0.006]; P = .03), and neurofilament light chain (NfL; β, -0.071 [95% CI, -0.122 to -0.020]; P = .01) than noncontact sport controls. Across the season, tNAA (β, 0.047 [95% CI, 0.020-0.074]; P = .001) declined in soccer players and increased in controls, converging by postseason. Group trajectories of GFAP and NfL did not differ between groups. Within soccer players, heading exposure was not significantly associated with changes in any outcome. Conclusions and Relevance:In this cohort study of adolescent males, no statistically significant differences were detected over 1 season between soccer players and noncontact sport athletes in cognition, behavior, or brain structure and function. Group differences in GFAP and NfL may represent early signs of exposure, but lack of association with heading exposure warrants further investigation. These results highlight the need for large, multiyear studies to inform health policy.

Exposure to repetitive head impacts (RHI) has been shown to be associated with cognitive impairment and markers of neurodegeneration in professional male soccer players. However, data on the effects of RHI in female players are very limited. In this exploratory study, we investigated changes in blood biomarkers along with the cognitive status of elite female soccer players and compared the effect of RHI with outcomes in male players. In a cohort study, elite female soccer players (age 16–41 years) performed training without heading the ball (n = 36) and training including heading (n = 30). Athletes were evaluated for the parameters of physical activity (heart rate) and neuropsychological testing (focused attention and cognitive flexibility) before and 1 h after each training. The levels of plasma tau, pTau181, pTau217 and microRNAs were determined at four timepoints: before training, 1 h, 24 h, and 48 h after each training session. Parameters in females were compared with control male players (n = 32). The levels of tau, pTau181 and pTau217 are significantly increased in the plasma of female soccer players 1 hour after physical exercise (tau, 1.4-fold; pTau181, 1.3-fold; pTau217, 1.2-fold) and repetitive head impacts (tau, 1.2-fold; pTau181, 1.3-fold; pTau217, 1.3-fold) compared to pre-training levels. The ratio of pTau181 to tau fold change is significantly higher 1 hour after heading and remains elevated specifically in the heading group even after 48 h. The analysis of deregulated microRNAs in plasma reveals enrichment of neuroprotective pathways after heading training. Female soccer players show worse cognitive functions after heading compared to exercise and also compared to male soccer players. RHIs may lead to acute disbalance of tau and phosphorylated tau in plasma, and are associated with short-term decline in cognitive performance and neuroprotective pathways in elite female soccer players. The sexual dimorphism in response to RHI may reflect biological risk factors potentially relevant to the different degree of susceptibility to neurological disorders in females and males in later life. Majority of neuroscience research is conducted on male subjects, creating a gap in the knowledge. Here we investigated the effect of repetitive non-concussive head impacts (RHI) in elite female soccer players. The athletes were evaluated for the parameters of physical activity, cognition and levels of plasma tau protein which are known biomarkers of neurodegeneration. Our data demonstrate that repetitive heading of the ball is associated with biochemical alterations, reduction in focused attention, and cognitive flexibility. Here we also show that females are more sensitive to head impacts when compared to males and that the RHI exposure is associated with neuroprotective signaling. These findings link specific molecular pathways, potentially operating in the early stage of brain diseases. Deeper exploration of these pathways could be a promising approach to identify new biomarkers and therapeutic targets in the treatment of neurodegeneration. Cente et al. investigate the acute effects of mild repetitive head impacts in female soccer players. Findings reveal that female players are more sensitive to head impacts compared to males, as manifested by short-term decline in cognitive performance, altered plasma tau protein profile, and initiation of neuroprotective pathways.

Canine mammary tumors (CMTs) are common in female dogs and represent a key model for studying human breast cancer (BC). Among the various subtypes of CMT, adenocarcinoma of the mammary gland (AMG) is one of the most prevalent and aggressive. In this study, we analyzed the expression of 84 microRNAs (miRNAs) in AMG and healthy mammary tissues using qRT-PCR. MiRNA profiling in canine AMG tissue revealed upregulation of miR-101, miR-106b, miR-143, miR-15a, miR-205, and miR-93, and downregulation of let-7c, miR-10b, miR-191, and miR-26a. Pathway enrichment linked these deregulated miRNAs to key oncogenic networks, particularly PI3K/AKT/mTOR, Wnt/β-catenin, and EMT regulation, demonstrating conserved molecular mechanisms shared with human BC and highlighting their potential as biomarkers in CMTs. These findings provide insights into the molecular mechanisms of CMT adenocarcinoma and suggest the potential of miRNA-based biomarkers for the diagnosis and treatment of CMTs.

Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 µM; while at 100 µM the increase (129.74±3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.

Rickettsial infections of the central nervous system (CNS) are manifested by severe neurological symptoms and represent a serious life-threatening condition. Despite the considerable health danger, only a few studies have been conducted focusing on the pathogenesis induced by Rickettsia sp. in CNS. To investigate the signaling pathways associated with the neurotoxic effects of rickettsiae, we employed an experimental model of cerebrocortical neurons combined with molecular profiling and comprehensive bioinformatic analysis. The cytopathic effect induced by Rickettsia akari and Rickettsia slovaca was demonstrated by decreased neuronal viability, structural changes in cell morphology, and extensive fragmentation of neurites in vitro. Targeted profiling revealed the deregulation of genes involved in the neuroinflammatory and neurotoxic cell response pathways. Although quantitative analysis showed differences in gene expression response, functional annotation revealed that the biological processes are largely shared between both Rickettsia species. The identified enriched pathways are associated with cytokine signaling, chemotaxis of immune cells, responses to infectious agents, interactions between neurons, endothelial and glial cells, and regulation of neuronal apoptotic processes. The findings of our study provide new insight into the etiopathogenesis of CNS infection and further expand the understanding of molecular signaling associated with neuroinvasive Rickettsia species.

IMPORTANCE Head impacts resulting in traumatic brain injury (TBI) lead to the elevation of phosphorylated tau protein (p-tau(181)) in plasma. To our knowledge, this study is the first to investigate dynamics of p-tau(181) levels and the ratio of p-tau(181) to total tau in individuals after nonconcussive head impacts. OBJECTIVE To determine the association of repetitive low-intensity head impacts on p-tau(181) and total tau protein levels in the plasma of young adult elite soccer players and assess the possible association of head impacts with focused attention and cognitive flexibility. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, young elite soccer players performed intense physical activity with and without heading the ball. The studywas conducted at a university facility in Slovakia from October 1, 2021, to May 31, 2022. Eligible participantswere selected based on similarities in demographic variables, excluding those with a history of TBI. MAIN OUTCOMES AND MEASURES The primary study outcomes were the levels of total tau protein and p-tau(181) in plasma samples and the cognitive status of the study participants. RESULTS A total of 37 male athletes participated in the study (mean [SD] age: exercise group, 21.6 [1.6] years; heading group, 21.2 [1.5] years). We found significantly elevated levels of total tau and p-tau(181) in the plasma of soccer players 1 hour after physical exercise (tau, 1.4-fold; 95% CI, 1.2-1.5; P <.001; p-tau(181), 1.4-fold; 95% CI, 1.3-1.5, P <.001) and repetitive head impacts (tau, 1.3-fold; 95% CI, 1.2-1.4; P <.001; p-tau(181), 1.5-fold; 95% CI, 1.4-1.7 P <.001). The ratio of p-tau(181) to tau was significantly higher 1 hour after exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold; 95% CI, 1.1-1.3; P =.002). Performance in cognitive tests revealed a significant decline in focused attention and cognitive flexibility after physical exercise and heading training; physical exercise of higher intensity without heading training was associated with a greater negative cognitive performance than heading only. CONCLUSIONS AND RELEVANCE In this cohort study of young elite soccer players, the elevation of p-tau(181) and tau was observed after acute intense physical activity and nonconcussive repetitive head impacts. The increase of p-tau(181) levels relative to tau after 24 hours indicated an acute enrichment of phosphorylated tau fraction in the periphery when compared with preimpact levels; an imbalance of tau proteins may have long-lasting consequences in the brain of head-impacted individuals.

History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain's inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein-protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.

Background The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resis-tant against some of the therapeutic antibodies authorized for emergency use. Methods We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2. Findings AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addi-tion, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection. Interpretation The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy. Funding The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s. Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Superscript/Subscript Available

ABSTRACTIMPORTANCEHead impacts resulting in traumatic brain injury (TBI) lead to elevation of phosphorylated tau protein in plasma, the biomarkers for patients with acute and chronic TBI. Dynamics of phosphorylated tau protein level (pTau) and ratio of pTau and total tau in subjects after the non-concussive head impact was not yet investigated.OBJECTIVETo determine the acute effect of repetitive low-intensity head impacts on phosphorylated and total tau protein levels in plasma of young adults and to assess the effect of the head impacts on focused attention and cognitive flexibility.DESIGNThe study cohort consisted of young professional soccer players performing intense physical activity without heading the ball (n=32) and physical activity including the heading (n=28).SETTINGThe effect of repetitive non-concussive head impacts was monitored in all athletes evaluating the parameters of physical activity, impact force during heading the ball, together with neuropsychological testing of cognitive attention and cognitive flexibility at multiple time-points before and during a set of controlled training exercises. The total and phosphorylated tau protein levels were determined using an ultrasensitive single molecule assay at 3 time points: before training, 1 h, and 24 h after each training session in a non-fasting state. The psychological scores were collected before and 1 h after the training using Trail Making Test.PARTICIPANTSThe study included volunteer male college soccer players. The eligible participants were selected based on the similar demographic variables, such as age, years of performing organized sport, weekly sport activity and body mass index. The subjects with the history of previous TBI were excluded from the study.MAIN OUTCOMES AND MEASURESThe primary study outcomes are the levels of total tau protein and tau protein phosphorylated at the Threonine 181 in plasma samples, and cognitive status of the study participants. The study hypothesis was formulated before the data collection.RESULTSWe found significantly elevated levels of total tau and phospho-tau protein (pT181) in the plasma of soccer players one hour after physical exercise (Tau: 1.35-fold, 95% CI 1.2-1.5,P= .0001; pT181: 1.4-fold, 95% CI 1.3-1.5,P< .0001) and repetitive head impacts (Tau: 1.3-fold, 95% CI 1.2-1.4,P< .0001; pT181: 1.5-fold, 95% CI 1.4-1.7,P< .0001) in comparison to baseline. The pT181/Tau ratio was significantly higher 1 hour after the exercise and heading training, and remained elevated specifically in the heading group even after 24 hours (1.2-fold, 95% CI 1.1-1.3,P= .0024). Performance in cognitive tests revealed a significant decline in focused attention (TMT-A) and cognitive flexibility (TMT-B) after the physical exercise (TMT-A: 75.16 [95% CI, 68.3-82.01,P< .0001]; TMT-B: 80.26 [95% CI, 69.83-90.68,P< .0001]) and heading training (TMT-A: 33.76 [95% CI, 30.11-37.42,P= .0004]; TMT-B: 63.92 [95% CI, 56.99-70.84,P= .0434]). Nevertheless, the physical exercise of higher intensity without the heading had a more negative impact than heading training (TMT-A:P< .0001; TMT-B:P= .0207).CONCLUSIONS AND RELEVANCEOur study showed, that non-concussive repetitive head impacts elevate pT181-Tau and pT181/total-Tau in plasma of young adults. The increase of pT181-Tau was observed also after the intense physical activity alone, however the elevation of pT181/Tau ratio after 24 hours was highly significant and specific for non-concussive repetitive head impacts. The results support the idea that phosphorylated tau-enriched fraction of tau proteins may have long-lasting consequences in the brain of head-impacted individuals. The possible longitudinal disbalance of tau proteins induced by repetitive head impacts needs to be further investigated in larger and broader cohorts, and over longer period of time.

Neurodegeneration is associated with hypertension and disturbance in fat metabolism. The complex interaction of neurodegenerative processes with both metabolic changes and blood pressure is still not fully elucidated. Here we demonstrate that the experimentally induced tauopathy in hypertensive transgenic animals causes significant downregulation of plasma leptin (53% of control), reduction of body weight by 11%, a 1.2-fold drop of adiposity index, and decrease in HDL cholesterol level, while the fasting glucose and insulin concentration remain unchanged. Despite of these alterations we found the leptin projection circuit including the arcuate nucleus, paraventricular nucleus in hypothalamus, and nucleus tractus solitarius in the brainstem not affected by neurofibrillary pathology. Furthermore, hypertension does not alter disturbances in leptin signalling. The presented data provide further insight into neurodegeneration-induced metabolic alterations relevant for human tauopathies.

Alzheimer’s disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 μg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference −0.360 (95% CI −1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI −0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers. The authors present the results of a 24-month phase 2 study of AADvac1, a tau vaccine against Alzheimer’s disease. AADvac1 was safe and induced high levels of antibodies. In the whole study sample, there were no significant changes on clinical outcomes.

Repetitive concussive head impacts and their harmful consequences described in the brains of contact sports players represent a major risk factor for development of chronic traumatic encephalopathy. However, the molecular events together with peripheral markers of repetitive head impacts were not fully elucidated to date. As soccer is one of the contact sports with a high risk of head injuries, this study focused on the altered expression level of circulating microRNAs (miRNAs) in soccer players following accidental head impacts and repetitive heading the ball, accounting for the effects of physical activity alone. Furthermore, the study aimed to define the associations between detected miRNAs and signaling pathways. The current study was based on a subset of blood samples available from a prospective cohort study by Straume-Næsheim et al., 2008 and 2009 assessing the effects of head impacts in senior elite soccer on neuropsychological tests and serum protein biomarkers (PMID: 18824996, 19349829). Blood samples of professional soccer players were drawn at the rest and then repeatedly after three conditions: (1) accidental head impacts in a match, (2) repetitive heading during training, and (3) high-intensity exercise. Altered levels of circulating miRNAs were obtained by real-time PCR. Using bioinformatic approaches, we identified the predicted miRNA gene targets and their roles in biological pathways. We found six miRNAs implicated in the repetitive heading, unaffected by high-intensity exercise, and eight miRNAs in the accidental head impacts. MiRNA gene targets were subsequently linked to overlapping, as well as unique signaling pathways for each of the studied conditions. These findings suggest that concussive and sub-concussive head impacts in soccer cause specific alterations in circulating microRNAs that are unaffected by high-intensity exercise.

Recently emerged SARS-CoV-2 variants show resistance to some antibodies that were authorized for emergency use. We employed hybridoma technology combined with authentic virus assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize new variants of SARS-CoV-2. AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 and B.1.351. Finally, the combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. The neutralizing properties were fully reproduced in chimeric mouse-human versions, which may represent a promising tool for COVID-19 therapy.

Discovering novel diagnostic biomarkers and signatures for traumatic brain injury (TBI) represents a major challenge in the brain trauma research. Detailed analysis of post-concussive molecular pathways based on experimental data could provide a new insight into the pathophysiological sequelae and mapping of recovery mechanisms involved in TBI. MicroRNAs (miRNAs) detectable in peripheral body fluids after TBI are promising carriers of this missing knowledge. In order to define the signature of peripheral miRNAs signaling associated with mild TBI (mTBI), we performed a comprehensive meta-analysis of miRNA profiles in mTBI patients using multiple curated pathway databases. Using a bioinformatic pipeline with integrated data analysis we identified a set of genes that are connected to deregulated circulating miRNAs following the mTBI. Identified genes belong to specific pathways of MAPK, TGF-β, WNT, TLR2/4, PI3K/AKT, insulin, and growth factor signaling. Since the enriched pathways markedly overlap among the various biological fluids, signaling associated with mTBI that is concomitantly reflected in serum, plasma and saliva is robust and unique. Furthermore, we identified a network of 33 validated interacting proteins and their regulatory miRNAs that link the post-mTBI signaling in peripheral fluids with neurodegeneration-associated interaction pathways. Presented data provide a comprehensive insight into molecular events following mTBI, and the top predicted genes represent a group of novel candidate targets to be validated in connection with mTBI.

Spreading of tau pathology to anatomical distinct regions in Alzheimer's disease (AD) is associated with progression of the disease. Studies in recent decade have strived to understand the processes involved in this characteristic spread. We recently showed that AD-derived insoluble tau seeds are able to initiate neurofibrillary pathology in transgenic rodent model of tauopathy. In the present study, we pursued to identify the molecular changes that govern the induction and propagation of tau pathology on the transcriptomic level. We first show that microglia in vicinity to AD-Tau-induced pathology has phagocytic morphology when compared to PBS-injected group. On transcriptomic level, we observed deregulation of 15 genes 3-month post AD-Tau seeds inoculation. Integrated bioinformatic analysis identified 31 significantly enriched pathways. Amongst these, the inflammatory signalling pathway mediated by cytokine and chemokine networks, along with, toll-like receptor and JAK-STAT signalling were the most dominant. Furthermore, the enriched signalling also involved the regulation of autophagy, mitophagy and endoplasmic reticulum stress pathways. To our best of knowledge, the study is the first to investigate the transcriptomic profile of AD-Tau seed-induced pathology in hippocampus of transgenic model of tauopathy.

BackgroundThe link between head-impact exposure in football and neurological sequelae remains controversial. Blood-based biomarkers can provide valuable information in traumatic brain injuries, reflecting e.g. axonal damage.ObjectiveTo investigate if repetitive headers or accidental head impacts in football could cause structural damage to the brain, detected as an increase in serum concentrations of neurofilament light (NfL) or tau proteins.DesignProspective cohort study.SettingElite division football.ParticipantsMale football players in the Norwegian premier league, including a total of 621 player seasons.Independent VariablesShort- and long-term exposures in football, with and without head impacts.Main Outcome MeasurementsBaseline NfL and tau were measured in Norwegian professional football players in pre-season. Then, the effect of short-term exposures (independent variable) was assessed by measuring biomarker levels (dependent variable) after three conditions: (1) high-intensity exercise, (2) repetitive headers, and (3) head-impact incidents in a match. The effect of long-term head impact exposure was assessed by comparing two groups with relative differences in previous concussions and headers at baseline (low vs. high levels).ResultsWe analyzed 354 samples. Mean (±SD) NfL concentration was 6.8±2.6 pg/mL; mean tau concentration was 1.2±0.7 pg/mL. We observed no short-term effects on NfL after exposure from either of the three conditions. Tau levels rose in response to high-intensity exercise and repetitive headers, but not after accidental head-impact incidents; the highest absolute values were seen 1 h after high-intensity exercise. We did not detect any long-term effects on serum NfL or tau concentrations from previous concussions and headers.ConclusionsNfL and tau in serum were unaffected by head impacts in football, after both short-term and long-term exposure. Importantly, tau levels seem to rise in response to exercise, emphasizing the need for appropriate control groups in future studies. Our findings highlight important characteristics and limitations for using NfL and tau as biomarkers in sports.

The constant aging of the population worldwide leads to an increased prevalence of age‐related diseases like neurodegenerative disorders. Alzheimer´s disease (AD) as one of the most widespread form of neurodegeneration is defined by the gradual deterioration of memory and cognitive functions. The pathological changes emerge years before the onset of clinical symptoms. Small non‐coding RNAs, known as microRNAs (miRNAs), act like post‐transcriptional gene regulators that trigger translational inhibition or mRNA degradation. The biological role and stability of miRNAs in peripheral biofluids imply their candidate role as diagnostic and prognostic markers. Our study aimed to detect and validate candidate miRNA biomarkers related to AD neurodegeneration. Transcriptomic analysis was executed on AD patients compared to healthy age‐matched controls to determine expression levels of miRNAs in plasma samples. The examination of samples identified a panel of dysregulated miRNAs differentiating the AD individuals from healthy controls. Our data suggest the diagnostic potential of microRNAs in AD and other neurodegenerative diseases.