Neuronal Microtubule-associated Protein Tau Research Articles

Phase separation of the microtubule-associated protein tau.

The aggregation and misfolding of the neuronal microtubule-associated protein tau is closely linked to the pathology of Alzheimer's disease and several other neurodegenerative diseases. Recent evidence suggest that tau undergoes liquid-liquid phase separation in vitro and forms or associates with membrane-less organelles in cells. Biomolecular condensation driven by phase separation can influence the biological activities of tau including its ability to polymerize tubulin into microtubules. In addition, the high concentrations that tau can reach in biomolecular condensates provide a mechanism to promote its aggregation and the formation of amyloid fibrils potentially contributing to the pathology of different tauopathies. Here, the authors discuss the role of tau phase separation in physiology and disease.

Fascia iliaca compartment block can reduce the incidence of early post-operative cognitive impairment in elderly patients with high-risk hip replacement.

In this study, we aimed to observe the effects of ultrasound-guided fascia iliaca compartment block (FICB) combined with hypobaric spinal anesthesia on post-operative pain and cognitive function in elderly patients with high-risk hip replacement. A total of 84 elderly patients-aged 65-85 years, with American Society of Anesthesiologists physical status III-IV, and scheduled for hip arthroplasty between September 2021 and May 2022-were selected. One or more organs with moderate to severe impairment were included in all patients. The patients were randomly divided into a hypobaric spinal anesthesia group (group C, control group) and an ultrasound-guided FICB combined with hypobaric spinal anesthesia group (group E, experimental group). Group C was given 3.5 mL of 0.32% ropivacaine hypobaric spinal anesthesia, and group E received ultrasound-guided FICB combined with 3.5 mL of 0.32% ropivacaine hypobaric spinal anesthesia. The patients were compared using the visual analog scale (VAS) for pain, Harris hip function score, and simple Mini-Mental State Examination (MMSE) scale. Blood β-amyloid (Aβ) and neuronal microtubule-associated protein (tau) levels were measured. We compared intraoperative conditions and post-operative complications between the two groups to assess the effects of FICB combined with hypobaric spinal anesthesia on post-operative pain and cognitive function in elderly patients with high-risk hip replacement. At 1 and 3 days after the operation, patients in group C had significantly higher VAS and lower MMES scores than those in group E. The differences were statistically significant at 1 (P < 0.01) and 3 (P < 0.05) days after the operation. At 1 day after operation, the Harris score of patients in group C was significantly lower than that of patients in group E (P < 0.05). The Aβ and tau levels of patients in group C were significantly higher than those of patients in group E at 1 day after the operation (P < 0.01). The Aβ levels of patients in group C were significantly higher than those of patients in group E at 3 days after the operation (P < 0.05). The intraoperative conditions and post-operative complication rates did not differ significantly between the two groups. At 1 day before and 5 days after the operation, there was no difference in any of the indicators. By lowering pain and managing Aβ and tau protein concentrations, FICB can successfully lower the incidence of early post-operative cognitive impairment in elderly patients with high-risk hip replacement. www.chictr.org.cn, identifier: ChiCTR2100051162.

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model

BackgroundMicrotubules (MTs) are critical for cell structure, function, and survival. MT instability may contribute to Alzheimer’s disease (AD) pathogenesis as evidenced by persistent negative regulation (phosphorylation) of the neuronal microtubule-associated protein tau. Hyperphosphorylated tau, not bound to MTs, forms intraneuronal pathology that correlates with dementia and can be tracked using positron emission tomography (PET) imaging. The contribution of MT instability in AD remains unknown, though it may be more proximal to neuronal dysfunction than tau accumulation. Our lab reported the first brain-penetrant MT-based PET ligand, [11C]MPC-6827, and its PET imaging with this ligand in normal rodents and non-human primates demonstrated high brain uptake and excellent pharmacokinetics. Target engagement and mechanism of action using in vitro, in vivo, and ex vivo methods were evaluated here.MethodsIn vitro cell uptake assay was performed in SH-SY5Y neuronal cells with [11C]MPC-6827, with various MT stabilizing and destabilizing agents. To validate the in vitro results, wild type (WT) mice (n = 4) treated with a brain-penetrant MT stabilizing drug (EpoD) underwent microPET/CT brain imaging with [11C]MPC-6827. To determine the influence of tau protein on radiotracer binding in the absence of protein accumulation, we utilized tau knockout (KO) mice. In vivo microPET imaging, ex vivo biodistribution, and autoradiography studies were performed in tau KO and WT mice (n = 6/group) with [11C]MPC-6827. Additionally, α, β, and acetylated tubulin levels in both brain samples were determined using commercially available cytoskeleton-based MT kit and capillary electrophoresis immunoblotting assays.ResultsCell uptake demonstrated higher radioactive uptake with MT destabilizing agents and lower uptake with stabilizing agents compared to untreated cells. Similarly, acute treatment with EpoD in WT mice decreased [11C]MPC-6827 brain uptake, assessed with microPET/CT imaging. Compared to WT mice, tau KO mice expressed significantly lower β tubulin, which contains the MPC-6827 binding domain, and modestly lower levels of acetylated α tubulin, indicative of unstable MTs. In vivo imaging revealed significantly higher [11C]MPC-6827 uptake in tau KOs than WT, particularly in AD-relevant brain regions known to express high levels of tau. Ex vivo post-PET biodistribution and autoradiography confirmed the in vivo results.ConclusionsCollectively, our data indicate that [11C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [11C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies.

Molecular crowding and RNA synergize to promote phase separation, microtubule interaction, and seeding of Tau condensates.

Biomolecular condensation of the neuronal microtubule‐associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, two conditions likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and to produce condensates with a strong affinity to charged surfaces. During condensate‐mediated microtubule polymerization, their synergy enhances bundling and spatial arrangement of microtubules. We further show that different Tau condensates efficiently induce pathological Tau aggregates in cells, including accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations and a condensate‐like density for nuclear‐envelope Tau. These findings suggest that a complex interplay between interaction partners, post‐translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding‐competent Tau and lead to distinct cellular Tau accumulations.

Methylation at a conserved lysine residue modulates tau assembly and cellular functions

The neuronal microtubule-associated protein tau undergoes multiple post-translational modifications, which dynamically modulate its molecular functions and biochemical features in space and time. Among them, we have recently reported that a conserved lysine residue mapping to the microtubule-binding domain of the protein (K306 in mouse and K317 in human) is differentially methylated in a model of chronic autoimmune demyelination. In contrast with other well-studied tau post-translational modifications such as phosphorylation, lysine methylation is far less investigated and its specific impact on tau biology is not fully understood. Here we performed a comprehensive analysis of the effects of K317 methylation on key tau features. By combining in silico simulations with in vitro biochemical assays and live-cell imaging, we show that methylated tau is more prone to self-assembly into insoluble structures. Moreover, we demonstrate that K317 methylation affects the stabilization activity of tau on microtubule dynamics. Lastly, we highlight a role for K317 methylation in regulating both neuronal differentiation and cell proliferation. Altogether, these findings shed light on the biology of an overlooked tau post-translational modification as well as on the fine tuning of tau functionality in health and disease.

A current view on Tau protein phosphorylation in Alzheimer's disease.

The functions of the neuronal microtubule-associated protein Tau in the central nervous system are regulated by manifold posttranslational modifications at more than 50 sites. Tau in healthy neurons carries multiple phosphate groups, mostly in its microtubule assembly domain. Elevated phosphorylation and aggregation of Tau are widely considered pathological hallmarks in Alzheimer's disease (AD) and other tauopathies, triggering the quest for Tau posttranslational modifications in the disease context. However, the phosphorylation patterns of physiological and pathological Tau are surprisingly similar and heterogenous, making it difficult to identify specific modifications as therapeutic targets and biomarkers for AD. We present a concise summary of - and view on - important previous and recent advances in Tau phosphorylation analysis in the context of AD.

Tau Avoids the GTP Cap at Growing Microtubule Plus-Ends.

SummaryPlus-end tracking proteins (+TIPs) associate with the growing end of microtubules and mediate important cellular functions. The majority of +TIPs are directed to the plus-end through a family of end-binding proteins (EBs), which preferentially bind the stabilizing cap of GTP-tubulin present during microtubule growth. One outstanding question is whether there may exist other microtubule-associated proteins (MAPs) that preferentially bind specific nucleotide states of tubulin. Here, we report that the neuronal MAP tau preferentially binds GDP-tubulin (KD = 0.26 μM) over GMPCPP-tubulin (KD = 1.1 μM) in vitro, as well as GTP-tubulin at the tips of growing microtubules, causing tau binding to lag behind the plus-end both in vitro and in live cells. Thus, tau is a microtubule tip avoiding protein, establishing the framework for a possible new class of tip avoiding MAPs. We speculate that disease-relevant tau mutations may exert their phenotype by their failure to properly recognize GDP-tubulin.

Characterisation of serum total tau following paediatric traumatic brain injury: a case-control study

Traumatic brain injury (TBI) is a major health problem in children. Blood-based biomarkers interpreted by use of normative values might improve the accuracy of diagnosis. Ultrasensitive assays can quantify serum concentrations of the neuronal microtubule-associated protein tau, which is increased in adult brains following TBI. We aimed to determine if serum total tau correlates with TBI diagnosis, severity, and radiological findings on CT scans in children younger than 18 years. In this case-control study, we included venous blood samples from healthy control children in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) biobank. For TBI cases, we recruited children (aged 0-17 years) who presented to the emergency department within 24 h of a TBI in three tertiary-care paediatric hospitals (Toronto, Vancouver, and Melbourne). Children were eligible if they required hospital observation for a minimum of 4 h or admission to the intensive care unit, and were excluded if they had had hospital treatment for a previous TBI, had birth trauma, or their parents could not speak English or French and therefore could not readily give consent. All available control samples were used and a case-control match was therefore not done. Venous and arterial blood samples were collected from patients with TBI within 28 h of injury (day 1). We used an ultrasensitive single-molecule immunoassay to measure serum total tau in blood samples. We first generated reference intervals of serum total tau from the control group, and used these normative data to interpret injury-associated changes in serum total tau in children with TBI. Concentrations of serum tau were measured in all CALIPER participants and patients with TBI, and no participants were excluded before analysis. We included samples from 416 control participants from the CALIPER cohort. Median total tau concentrations did not differ between sexes (p=0·12), but three significant reference intervals based on age groups were identified (1-3 years [0·88-19·2 pg/mL], 4-15 years [0·93-5·31 pg/mL], and 16-19 years [0·79-4·20 pg/mL]). Blood samples were obtained from 158 patients with TBI recruited between April 30, 2011, and June 28, 2013. Serum total tau on day 1 of TBI was negatively associated with Glasgow Coma Scale (GCS) score (rs=-0·42, 95% CI -0·55 to -0·28, p<0·0001). Median total tau was 2·86 pg/mL (IQR 1·52-4·83) in patients with GCS score 13-15 points (n=114), 7·08 pg/mL (3·75-41·1) in those with GCS score 9-12 points (n=13), and 8·48 pg/mL (2·53-70·6) in those with GCS score 3-8 points (n=31). Notably, participants who had GCS scores of 15 points had median total tau concentrations (2·57 pg/mL [1·50-4·61]) indistinguishable from those of control participants (2·46 pg/mL [1·77-3·42]), whereas those with GCS score 13-14 points had elevated total tau (6·41 pg/mL [2·97-42·5]). Serum total tau was not strongly associated with CT findings in patients with mild TBI. Serum total tau might help to differentiate between patients with mild TBI (GCS 13-14 vs GCS 15), but larger studies are needed to validate these results before this biomarker can be used for diagnosis and prognosis. Canadian Institutes of Health Research, Ontario Neurotrauma Foundation, and Victoria Neurotrauma Foundation.

Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia

SummaryThe neuronal microtubule-associated protein tau, MAPT, is central to the pathogenesis of many dementias. Autosomal-dominant mutations in MAPT cause inherited frontotemporal dementia (FTD), but the underlying pathogenic mechanisms are unclear. Using human stem cell models of FTD due to MAPT mutations, we find that tau becomes hyperphosphorylated and mislocalizes to cell bodies and dendrites in cortical neurons, recapitulating a key early event in FTD. Mislocalized tau in the cell body leads to abnormal microtubule movements in FTD-MAPT neurons that grossly deform the nuclear membrane. This results in defective nucleocytoplasmic transport, which is corrected by microtubule depolymerization. Neurons in the post-mortem human FTD-MAPT cortex have a high incidence of nuclear invaginations, indicating that tau-mediated nuclear membrane dysfunction is an important pathogenic process in FTD. Defects in nucleocytoplasmic transport in FTD point to important commonalities in the pathogenic mechanisms of tau-mediated dementias and ALS-FTD due to TDP-43 and C9orf72 mutations.

Serious damage by soluble tau

Neuroscience Alterations in the metabolism of the neuronal microtubule-associated protein tau are central to several neurodegenerative diseases. In these diseases, tau usually loses solubility and forms aggregates that impair cell function to trigger neuronal cell death and neurodegeneration. However, the in vivo neurotoxic potential of soluble tau is not yet fully understood. Bolos et al. stereotactically injected human soluble tau into the dentate gyrus of mice. Hippocampal granule neurons showed markedly reduced synapse numbers in the molecular layer. In addition, newborn granule cells showed reduced numbers of dendritic spines. Behaviorally, these animals exhibited an impaired capacity to perform pattern separation. Soluble tau thus causes long-term damage to the morphology and connectivity of newborn granule cells. Transl. Psych. 10.1038/s41398-017-0013-6 (2017).

Protein phosphatase 2A and tau: an orchestrated 'Pas de Deux'.

The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contributes to glutamatergic regulation and synaptic plasticity. Emerging evidence also suggests that tau serves as a signaling scaffold. Tau function and subcellular localization are tightly regulated, in part, by the orchestrated interplay between phosphorylation and dephosphorylation events. Significantly, protein phosphatase type 2A (PP2A), encompassing the regulatory PPP2R2A (or Bα) subunit, is a major brain heterotrimeric enzyme and the primary tau Ser/Thr phosphatase in vivo. Herein, we closely examine how the intimate and compartmentalized interactions between PP2A and tau regulate tau phosphorylation and function, and play an essential role in neuronal homeostasis. We also review evidence supporting a strong link between deregulation of tau-PP2A functional interactions and the molecular underpinnings of various neurodegenerative diseases collectively called tauopathies. Lastly, we discuss the opportunities and associated challenges in more specifically targeting PP2A-tau interactions for drug development for tauopathies.

The axonal transport motor kinesin-2 navigates microtubule obstacles via protofilament switching.

Axonal transport involves kinesin motors trafficking cargo along microtubules that are rich in microtubule-associated proteins (MAPs). Much attention has focused on the behavior of kinesin-1 in the presence of MAPs, which has overshadowed understanding the contribution of other kinesins such as kinesin-2 in axonal transport. We have previously shown that, unlike kinesin-1, kinesin-2 in vitro motility is insensitive to the neuronal MAP Tau. However, the mechanism by which kinesin-2 efficiently navigates Tau on the microtubule surface is unknown. We hypothesized that mammalian kinesin-2 side-steps to adjacent protofilaments to maneuver around MAPs. To test this, we used single-molecule imaging to track the characteristic run length and protofilament switching behavior of kinesin-1 and kinesin-2 motors in the absence and presence of 2 different microtubule obstacles. Under all conditions tested, kinesin-2 switched protofilaments more frequently than kinesin-1. Using computational modeling that recapitulates run length and switching frequencies in the presence of varying roadblock densities, we conclude that kinesin-2 switches protofilaments to navigate around microtubule obstacles. Elucidating the kinesin-2 mechanism of navigation on the crowded microtubule surface provides a refined view of its contribution in facilitating axonal transport.

Effects of Dexmedetomidine on Postoperative Cognitive Dysfunction and Serum Levels of b-Amyloid and Neuronal Microtubule-Associated Protein in Orthotopic Liver Transplantation Patients.

BACKGROUND Because of the restricted data available on patients with postoperative cognitive dysfunction (POCD) in orthotopic liver transplantation (OLT), the goal of our study was to determine the outcome of dexmedetomidine (DEX) on POCD and the mechanism operating in OLT patients. MATERIAL AND METHODS Our study included 80 patients randomly divided into 2 equal groups: the DEX group and the control group. In the DEX group, our patients received an initial dose of DEX at 1 µg/kg for 10 min followed by a continuous infusion at 0.3 µg/kg/h until the end of surgery. The control group received a saline treatment, and neurological tests were performed to assess the status of POCD. Serum level of b-amyloid protein (Aβ) and neuronal microtubule-associated protein (Tau) were measured at designated time points: at pre-operation (T1), 0.5 h after the anhepatic phase (T2), 2 h after the reperfusion of the new liver (T3), at the completion of operation (T4), at day 1 (T5), and at day 7 (T6) after the operation. RESULTS The incidence of POCD was significantly reduced in the DEX group (P=0.017). The score from the neurological tests was significantly decreased in the control group after the operation, but no statistical difference was observed in the DEX group. The DEX groups demonstrated a lower level of β-amyloid and Tau protein than those at the corresponding time points (T4~T6) in the control group (P<0.01). CONCLUSIONS Dexmedetomidine reduced the incidence of postoperative cognitive dysfunction in orthotopic liver transplantation patients. The decreased levels of b-amyloid and Tau protein may have contributed to this favorable outcome.

NMR Meets Tau: Insights into Its Function and Pathology.

In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same samples. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function.

Progressive supranuclear palsy: what do we know about it?

Progressive supranuclear palsy (PSP) is a progressive tauopathy characterized by supranuclear ophthalmoplegia, pseudobulbar palsy, dysarthria, axial rigidity, frontal lobe dysfunction, and dementia. The typical pathology includes neuronal loss, gliosis and microtubule-associated protein tau (MAPT)-positive inclusions in neurons and glial cells, primarily in basal ganglia, brainstem and cerebellum. The pathogenesis of PSP is not yet completely understood; however, there are several hypotheses. This article reviews the present knowledge about PSP, and the concepts underlying mitochondrial dysfunction, lipoperoxidation, and gene mutations. The clinical features of PSP are also discussed; these include vertical gaze palsy, pseudobulbar palsy, aphasia, dysarthria, axial rigidity, and neuropsychiatric symptoms, such as amnesia, irritability, loss of interest, and dementia. In terms of diagnosis, there is considerable interest in neuroimaging for detecting PSP; therefore, neuroimaging techniques such as magnetic resonance imaging (MRI) and [18F]- fluorodeoxyglucose positron-emission tomography (FDG-PET) are reviewed. A definitive diagnosis of PSP depends on pathology, and the introduction of new clinical subtypes challenges presents the widely adopted diagnosis criteria. PSP treatments such as serotonin antagonists, α2 receptor antagonists, and coenzyme Q10 are also discussed. There is no curative therapy for PSP; all of the available treatments are palliative.

Katanin Activity is Regulated by Common Cellular Components

Proper organization of the microtubule cytoskeletal network is required to perform necessary cellular functions. Network organization is achieved through remodeling by microtubule associated proteins (MAPs) that control microtubule dynamics by selectively stabilizing and destabilizing microtubules. Stabilizing MAPs are relatively well understood, while less is known about destabilizing MAPs, such as severing enzymes. Katanin, the first-discovered microtubule severing enzyme, is a AAA+ enzyme that oligomerizes into hexamers and uses ATP hydrolysis to sever microtubules. Using single molecule biophysics techniques in vitro we investigate how katanin and its severing activity can be regulated by the type of microtubule, free tubulin, ATP concentration, and the neuronal MAP tau isoform 4RL. This work provides evidence that katanin activity is regulated by common cellular contents that will ultimately affect microtubule organization in cells.

RNA Protein Granules Modulate tau Isoform Expression and Induce Neuronal Sprouting

The neuronal microtubule-associated protein Tau is expressed in different variants, and changes in Tau isoform composition occur during development and disease. Here, we investigate a potential role of the multivalent tau mRNA-binding proteins G3BP1 and IMP1 in regulating neuronal tau expression. We demonstrate that G3BP1 and IMP1 expression induces the formation of structures, which qualify as neuronal ribonucleoprotein (RNP) granules and concentrate multivalent proteins and mRNA. We show that RNP granule formation leads to a >30-fold increase in the ratio of high molecular weight to low molecular weight tau mRNA and an ∼12-fold increase in high molecular weight to low molecular weight Tau protein. We report that RNP granule formation is associated with increased neurite formation and enhanced process growth. G3BP1 deletion constructs that do not induce granule formation are also deficient in inducing neuronal sprouting or changing the expression pattern of tau. The data indicate that granule formation driven by multivalent proteins modulates tau isoform expression and suggest a morphoregulatory function of RNP granules during health and disease.

Regulation of alternative splicing of tau exon 10

The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer's disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.

Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis.

BackgroundChronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name “dementia pugilistica” (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e.g., [18 F] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE.MethodsMajor academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland.ResultsThe major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [18 F] T807 tauopathy imaging, are also introduced and their significance has been explained.ConclusionRecent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults.

Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice

BackgroundThe neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.FindingsWe tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry) reduced the number of phospho-tau (AT8 epitope) positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line). CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a−/− mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity.ConclusionsOur data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.