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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., (© 2021. The Author(s).)

Alzheimer's disease (AD) is a multifactorial disorder; neurofibrillary pathology composed of tau protein is found side by side with amyloid-β deposits and extensive neuroinflammation. The immune system of the brain is considered as one of the factors that could influence the speed of the progression of AD neuropathology as a potential mediator of the damage induced by AD protein deposits. Alzheimer's disease pathology can be impacted by psychological stress; however, signalling pathways in background are not well known. We have explored possible avenues of how stress could influence the brain's immune system in a rat model of AD. Animals were subjected either to a single or multiple instances of immobilization stress. The analysis of a panel of immunity-related genes was used to evaluate the impact of stress on the immune response in the brain. We have identified 19 stress-responsive genes that are involved in neuroinflammation accompanying tau pathology: Nos2, Ptgs2, IL-8rb, C5, Mmp9, Cx3cr1, CD40lg, Adrb2, IL-6, IL-6r, IL-1r2, Ccl2, Ccl3, Ccl4, Ccl12, TNF-α, IL-1α, IL-1β, IL-10. Most of them are deregulated under the stress conditions also in control animals; however, the magnitude of the response to either acute or chronic stress differs. This can lead to serious influence, most probably to acceleration of neurodegenerative phenotype in diseased animals. Several of the genes (IL-1β, Casp1, Cx3cr1 and C5) are deregulated solely in tauopathic animals. The stress-induced changes in the inflammatory picture of the brain highlight the fact that the brain's immune response is highly responsive to environmental stimuli. The pattern of changes is indicative of an attempt to protect the brain in the short term, while being potentially detrimental to the response against a long-term pathological process such as neurofibrillary degeneration.

Tau protein misfolding is a pathological mechanism, which plays a critical role in the etiopathogenesis of neurodegeneration. However, it is not entirely known what kind of stimuli can induce the misfolding. It is believed that physical and emotional stresses belong to such risk factors. Although the influence of stress on the onset and progression of Alzheimer's disease (AD) has already been proposed, the molecular links between stresses and AD are still unknown. We have therefore focused our attention on determination of the influence of acute immobilization stress (IMO) in normal mice and mice deficient in corticotropin-releasing hormone (CRH). Specifically, we have analyzed levels of hyperphosphorylated tau proteins, bearing the AD-specific phospho-epitopes (AT-8, pT181, and PHF-1), which are implicated in the pathogenesis of AD. We found that IMO induces transient hyperphosphorylation of tau proteins regardless of continuation of the stimulus. Concerning tau modifications, detailed analysis of the mouse brain revealed that neurons in different brain regions including frontal cortex, temporal cortex, hippocampal C1 and CA3 regions, dentate gyrus as well as nucleus basalis Meynert, and several brainstem nuclei such as locus coeruleus but also raphe nucleus and substantia nigra respond similarly to IMO. The strongest tau protein phosphorylation was observed after 30 min of IMO stress. Stress lasting for 120 min led either to the disappearance of tau hyperphosphorylation or to the induction of a second wave of hyperphosphorylation. Noteworthy is the magnitude of pathological phosphorylation of tau protein in CRH and glucocorticoids deficient mice, being much lower in comparison to that observed in wild-type animals, which suggests a critical role of CRH in the pathogenesis of AD. Thus, our results indicate that hyperphosphorylation of tau protein induced by stress may represent the pathogenic event upstream of tau protein misfolding, which leads to progression or eventually initiation of neurodegeneration. The data show that CRH plays an important role in stress induced hyperphosphorylation of tau protein, which might be either a direct effect of CRH innervations in the brain or an effect mediated via the hypothalamo-pituitary-adrenal axis.

We have previously shown that human misfolded tau proteins strongly perturb mitochondrial transport and induce accumulation of free radicals in neurons. This interference is underlying cause of increased susceptibility to oxidative stress and could be linked to excitotoxic pathways. In order to understand integral mechanisms of misfolded tau driven neurodegeneration, we have investigated the role of human truncated tau protein, derived from Alzheimer's disease, in rat cortical neurons under the conditions of excitotoxic stress induced by glutamate. We found that primary neurons expressing truncated tau protein are highly susceptible to glutamate-induced cell death. Pre-treatment with memantine (N-methyl-D-aspartate receptor antagonist) significantly improved survival of rat neurons exposed to glutamate and its effect was associated with overall decrease of reactive oxygen species (ROS) in both transgenic and nontransgenic neurons. Interestingly, despite of this overall effect, memantine was not able to decrease misfolded tau-induced ROS level specifically in transgenic cells. Our data suggest that memantine does not interfere with specific pathological pathways induced by misfolded tau protein nevertheless is able to attenuate oxidative stress in neurons.

Transition of protein tau from physiologically unfolded to misfolded state represent enigmatic step in the pathogenesis of tauopathies including Alzheimer's disease (AD). Major molecular events playing role in this process involve truncation and hyperphosphorylation of tau protein, which are accompanied by redox imbalance followed by functional deterioration of neuronal network. Recently we have developed transgenic rat model showing that expression of truncated tau causes neurofibrillary degeneration similar to that observed in brain of AD sufferers. Consequently we tested cortical and hippocampal neuronal cultures extracted from this model as a convenient tool for development of molecules able to target the mechanisms leading to and/or enhancing the process of neurodegeneration. Here we document three major pathological features typical for tauopathies and AD in cortical and hippocampal neurons from transgenic rat in vitro. First, an increased accumulation of human truncated tau in neurons; second, the hyperphosphorylation of truncated tau on the epitopes characteristic of AD (Ser202/Thr205 and Thr231); and third, increased vulnerability of the neurons to nitrative and oxidative stress. Our results show that primary neurons expressing human truncated tau could represent a cellular model for targeting tau related pathological events, namely, aberrant tau protein accumulation, tau hyperphosphorylation, and oxidative/nitrative damage. These characteristics make the model particularly suitable for detailed study of molecular mechanisms of tau induced neurodegeneration and easily applicable for drug screening.