Molecular mechanisms involved in the destabilization of two types of R3-R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin.

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3-R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3-R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher ß-sheet structure probability. FS can destabilize both types of fibrils by decreasing the ß-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and ß7-ß8 angle of the fibrils. H-bonding, π-π stacking and cation-π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.

Disease-specific tau filaments assemble via polymorphic intermediates.

Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention1,2. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297-391) into paired helical filaments of Alzheimer's disease or into filaments of chronic traumatic encephalopathy3. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302-316. Nuclear magnetic resonance indicates that the same residues adopt rigid, ß-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies.

[Challenges of Diagnostic Imaging of Chronic Traumatic Encephalopathy].

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury (rmTBI). Clinically, CTE experienced by athletes with rmTBI can lead to long-term neurological impairment, including memory disturbances, Parkinsonism, behavioral changes, speech irregularities, and gait abnormalities, formerly described as punch-drunk syndrome and dementia pugilistica. CTE has gained significant public interest owing to dramatic cases involving retired professional athletes wherein severe behavioral problems and tragic incidents were reported. However, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can only be made via postmortem neuropathological examination. CTE is characterized by abnormal accumulation of hyperphosphorylated tau proteins. Neuropathological studies have revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes and accumulation of other misfolded proteins such as TDP-43. Furthermore, gross pathological findings were revealed, especially in severe CTE. Thus, we hypothesized that objective neuroimaging patterns linking the history of rmTBI or CTE might be established using tau positron emission tomography (PET) and magnetic resonance imaging (MRI). In this review, we present the clinical and neuropathological features of CTE and our efforts to develop a prenatal diagnostic method using MRI and tau PET. The unique findings of tau PET images and various signal and morphological abnormalities on conventional MRI in retired athletes with rmTBI may be useful in diagnosing CTE.

Destabilization mechanism of R3-R4 tau protofilament by purpurin: a molecular dynamics study.

The accumulation of tau protein aggregates is a common feature observed in many neurodegenerative diseases. However, the structural characteristics of tau aggregates can vary among different tauopathies. It has been established that the structure of the tau protofilament in Chronic traumatic encephalopathy (CTE) is similar to that of Alzheimer's disease (AD). In addition, a previous study found that purpurin, an anthraquinone, could inhibit and disassemble the pre-formed 306VQIVYK311 isoform of AD-tau protofilament. Herein, we used all-atom molecular dynamic (MD) simulation to investigate the distinctive features between CTE-tau and AD-tau protofilament and the influence of purpurin on CTE-tau protofilament. Our findings revealed notable differences at the atomic level between CTE-tau and AD-tau protofilaments, particularly in the ß6-ß7 angle and the solvent-accessible surface area (SASA) of the ß4-ß6 region. These structural disparities contributed to the distinct characteristics observed in the two types of tau protofilaments. Our simulations substantiated that purpurin could destabilize the CTE-tau protofilament and decrease ß-sheet content. Purpurin molecules could insert the ß4-ß6 region and weaken the hydrophobic packing between ß1 and ß8 through π-π stacking. Interestingly, each of the three rings in purpurin exhibited unique binding preferences with the CTE-tau protofilament. Overall, our study sheds light on the structural distinctions between CTE-tau and AD-tau protofilaments, as well as the destabilizing mechanism of purpurin on CTE-tau protofilament, which may be helpful to the development of drugs to prevent CTE.

Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.

Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.

Inflammation and neuronal gene expression changes differ in early versus late chronic traumatic encephalopathy brain.

BACKGROUND: Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. METHODS: To address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. RESULTS: Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. CONCLUSIONS: Together, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.

Understanding the Molecular Progression of Chronic Traumatic Encephalopathy in Traumatic Brain Injury, Aging and Neurodegenerative Disease.

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and adults in America. In addition, the acute morbidity caused by TBI is implicated in the development of devastating neuropsychiatric and neurodegenerative sequela. TBI is associated with the development of a neurodegenerative condition termed 'Punch Drunk syndrome' or 'dementia pugilistica', and the more recently renamed 'chronic traumatic encephalopathy'. Chronic traumatic encephalopathy (CTE) is a slowly progressive neurodegenerative condition caused by a single or repetitive blow to the head. CTE was first described in boxers and was later found to be associated with other contact sports and military combat. It is defined by a constellation of symptoms consisting of mood disorders, cognitive impairment, and memory loss with or without sensorimotor changes. It is also a Tauopathy characterized by the deposition of hyperphosphorylated Tau protein in the form of neurofibrillary tangles, astrocytoma tangles, and abnormal neurites found in clusters around small vessels, typically at the sulcal depths. Oxidative stress, neuroinflammation, and glutaminergic toxicity caused due to the insult play a role in developing this pathology. Additionally, the changes in the brain due to aging also plays an important role in the development of this condition. In this review, we discuss the molecular mechanisms behind the development of CTE, as well as genetic and environmental influences on its pathophysiology.

Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players.

PURPOSE: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. METHODS: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). RESULTS: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. CONCLUSIONS: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.

Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy.

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

Many neurodegenerative diseases, including Alzheimer's disease, the most common form of dementia, are characterised by knotted clumps of a protein called tau. In these diseases, tau misfolds, stacks together and forms abnormal filaments, which have a structured core and fuzzy coat. These sticky, misfolded proteins are thought to be toxic to brain cells, the loss of which ultimately causes problems with how people move, think, feel or behave. Reconstructing the shape of tau filaments using an atomic-level imaging technique called electron cryo-microscopy, or cryo-EM, researchers have found distinct types of tau filaments present in certain diseases. In Alzheimer's disease, for example, a mixture of paired helical and straight filaments is found. Different tau filaments are seen again in chronic traumatic encephalopathy (CTE), a condition associated with repetitive brain trauma. It remains unclear, however, how tau folds into these distinct shapes and under what conditions it forms certain types of filaments. The role that distinct tau folds play in different diseases is also poorly understood. This is largely because researchers making tau proteins in the lab have yet to replicate the exact structure of tau filaments found in diseased brain tissue. Lövestam et al. describe the conditions for making tau filaments in the lab identical to those isolated from the brains of people who died from Alzheimer's disease and CTE. Lövestam et al. instructed bacteria to make tau protein, optimised filament assembly conditions, including shaking time and speed, and found that bona fide filaments formed from shortened versions of tau. On cryo-EM imaging, the lab-produced filaments had the same left-handed twist and helical symmetry as filaments characteristic of Alzheimer's disease. Adding salts, however, changed the shape of tau filaments. In the presence of sodium chloride, otherwise known as kitchen salt, tau formed filaments with a filled cavity at the core, identical to tau filaments observed in CTE. Again, this structure was confirmed on cryo-EM imaging. Being able to make tau filaments identical to those found in human tauopathies will allow scientists to study how these filaments form and elucidate what role they play in disease. Ultimately, a better understanding of tau filament formation could lead to improved diagnostics and treatments for neurodegenerative diseases involving tau.

A proteomic network approach resolves stage-specific molecular phenotypes in chronic traumatic encephalopathy.

BACKGROUND: There is an association between repetitive head injury (RHI) and a pathologic diagnosis of chronic traumatic encephalopathy (CTE) characterized by the aggregation of proteins including tau. The underlying molecular events that cause these abnormal protein accumulations remain unclear. Here, we hypothesized that identifying the human brain proteome from serial CTE stages (CTE I-IV) would provide critical new insights into CTE pathogenesis. Brain samples from frontotemporal lobar degeneration due to microtubule associated protein tau (FTLD-MAPT) mutations were also included as a distinct tauopathy phenotype for comparison. METHODS: Isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) followed by integrated differential and co-expression analysis (i.e., weighted gene co-expression network analysis (WGCNA)) was used to define modules of highly correlated proteins associated with clinical and pathological phenotypes in control (n = 23), CTE (n = 43), and FTLD-MAPT (n = 12) post-mortem cortical tissues. We also compared these findings to network analysis of AD brain. RESULTS: We identified over 6000 unique proteins across all four CTE stages which sorted into 28 WGCNA modules. Consistent with Alzheimer's disease, specific modules demonstrated reduced neuronal protein levels, suggesting a neurodegeneration phenotype, while other modules were increased, including proteins associated with inflammation and glial cell proliferation. Notably, unique CTE-specific modules demonstrated prominent enrichment of immunoglobulins, including IGHM and IGLL5, and extracellular matrix (ECM) proteins as well as progressive protein changes with increasing CTE pathologic stage. Finally, aggregate cell subtype (i.e., neurons, microglia, astrocytes) protein abundance levels in CTE cases were similar in expression to AD, but at intermediate levels between controls and the more exaggerated phenotype of FTLD-MAPT, especially in astrocytes. CONCLUSIONS: Overall, we identified thousands of protein changes in CTE postmortem brain and demonstrated that CTE has a pattern of neurodegeneration in neuronal-synaptic and inflammation modules similar to AD. We also identified unique CTE progressive changes, including the enrichment of immunoglobulins and ECM proteins even in early CTE stages. Early and sustained changes in astrocyte modules were also observed. Overall, the prominent overlap with FTLD-MAPT cases confirmed that CTE is on the tauopathy continuum and identified CTE stage specific molecular phenotypes that provide novel insights into disease pathogenesis.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer's disease.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer's disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

Identifying degenerative effects of repetitive head trauma with neuroimaging: a clinically-oriented review.

BACKGROUND AND SCOPE OF REVIEW: Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aß-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aß-PET, and tau-PET in addition to comprehensive clinical examinations before death. REVIEW CONCLUSIONS: Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual's head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer's disease).

NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury.

Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.

Neuroimaging Biomarkers of Chronic Traumatic Encephalopathy: Targets for the Academic Memory Disorders Clinic.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts, such as those from contact sports. The pathognomonic lesion for CTE is the perivascular accumulation of hyper-phosphorylated tau in neurons and other cell process at the depths of sulci. CTE cannot be diagnosed during life at this time, limiting research on risk factors, mechanisms, epidemiology, and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders. Neuroimaging is an integral component of the clinical evaluation of neurodegenerative diseases and will likely aid in diagnosing CTE during life. In this qualitative review, we present the current evidence on neuroimaging biomarkers for CTE with a focus on molecular, structural, and functional modalities routinely used as part of a dementia evaluation. Supporting imaging-pathological correlation studies are also presented. We targeted neuroimaging studies of living participants at high risk for CTE (e.g., aging former elite American football players, fighters). We conclude that an optimal tau PET radiotracer with high affinity for the 3R/4R neurofibrillary tangles in CTE has not yet been identified. Amyloid PET scans have tended to be negative. Converging structural and functional imaging evidence together with neuropathological evidence show frontotemporal and medial temporal lobe neurodegeneration, and increased likelihood for a cavum septum pellucidum. The literature offers promising neuroimaging biomarker targets of CTE, but it is limited by cross-sectional studies of small samples where the presence of underlying CTE is unknown. Imaging-pathological correlation studies will be important for the development and validation of neuroimaging biomarkers of CTE.

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review.

Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age-affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (> 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects' left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma.

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.

BACKGROUND: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. METHODS: Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer's disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aß42 were compared to CCL2 levels to examine possible mechanistic pathways. RESULTS: An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aß42 in AD and CTE. Although levels of Aß42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aß42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. CONCLUSION: Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.

Mechanical injuries of neurons induce tau mislocalization to dendritic spines and tau-dependent synaptic dysfunction.

Chronic traumatic encephalopathy (CTE) is associated with repeated traumatic brain injuries (TBI) and is characterized by cognitive decline and the presence of neurofibrillary tangles (NFTs) of the protein tau in patients' brains. Here we provide direct evidence that cell-scale mechanical deformation can elicit tau abnormalities and synaptic deficits in neurons. Using computational modeling, we find that the early pathological loci of NFTs in CTE brains are regions of high deformation during injury. The mechanical energy associated with high-strain rate deformation alone can induce tau mislocalization to dendritic spines and synaptic deficits in cultured rat hippocampal neurons. These cellular changes are mediated by tau hyperphosphorylation and can be reversed through inhibition of GSK3ß and CDK5 or genetic deletion of tau. Together, these findings identify a mechanistic pathway that directly relates mechanical deformation of neurons to tau-mediated synaptic impairments and provide a possibly exploitable therapeutic pathway to combat CTE.

Chronic Traumatic Encephalopathy: A Comparison with Alzheimer's Disease and Frontotemporal Dementia.

The clinical diagnosis of chronic traumatic encephalopathy (CTE) is challenging due to heterogeneous clinical presentations and overlap with other neurodegenerative dementias. Depending on the clinical presentation, the differential diagnosis of CTE includes Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), Parkinson's disease, amyotrophic lateral sclerosis, primary mood disorders, posttraumatic stress disorder, and psychotic disorders. The aim of this article is to compare the clinical aspects, genetics, fluid biomarkers, imaging, treatment, and pathology of CTE to those of AD and bvFTD. A detailed clinical evaluation, neurocognitive assessment, and structural brain imaging can inform the differential diagnosis, while molecular biomarkers can help exclude underlying AD pathology. Prospective studies that include clinicopathological correlations are needed to establish tools that can more accurately determine the cause of neuropsychiatric decline in patients at risk for CTE.

Fluid Biomarkers for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.

Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms.

Exposure to repetitive neurotrauma increases lifetime risk for developing progressive cognitive deficits, neurobehavioral abnormalities, and chronic traumatic encephalopathy (CTE). CTE is a tau protein neurodegenerative disease first identified in boxers and recently described in athletes participating in other contact sports (notably American football, ice hockey, rugby, and wrestling) and in military veterans with blast exposure. Currently, CTE can only be diagnosed by neuropathological examination of the brain after death. The defining diagnostic lesion of CTE consists of patchy perivascular accumulations of hyperphosphorylated tau protein that localize in the sulcal depths of the cerebral cortex. Neuronal abnormalities, axonopathy, neurovascular dysfunction, and neuroinflammation are triggered by repetitive head impacts (RHIs) and likely act as catalysts for CTE pathogenesis and progression. However, the specific mechanisms that link RHI to CTE are unknown. This review will explore two important areas of CTE pathobiology. First, we will review what is known about the biomechanical properties of RHI that initiate CTE-related pathologies. Second, we will provide an overview of key features of CTE neuropathology and how these contribute to abnormal tau hyperphosphorylation, accumulation, and spread.