Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases

Role of the basin boundary conditions in gravity wave turbulence

Gravity wave turbulence is studied experimentally in a large wave basin where irregular waves are generated unidirectionally. The role of the basin boundary conditions (absorbing or reflecting) and of the forcing properties are investigated. To that purpose, an absorbing sloping beach opposite to the wavemaker can be replaced by a reflecting vertical wall. We observe that the wave field properties depend strongly on these boundary conditions. Quasi-one dimensional field of nonlinear waves propagate before to be damped by the beach whereas a more multidirectional wave field is observed with the wall. In both cases, the wave spectrum scales as a frequency-power law with an exponent that increases continuously with the forcing amplitude up to a value close to -4, which is the value predicted by the weak turbulence theory. The physical mechanisms involved are probably different according to the boundary condition used, but cannot be easily discriminated with only temporal measurements. We have also studied freely decaying gravity wave turbulence in the closed basin. No self-similar decay of the spectrum is observed, whereas its Fourier modes decay first as a time power law due to nonlinear mechanisms, and then exponentially due to linear viscous damping. We estimate the linear, nonlinear and dissipative time scales to test the time scale separation that highlights the important role of a large scale Fourier mode. By estimation of the mean energy flux from the initial decay of wave energy, the Kolmogorov-Zakharov constant is evaluated and found to be compatible with a recent theoretical value.Comment: Journal of Fluid Mechanics, Cambridge University Press (CUP), 2015, in press in JF

Inter-brain synchronization occurs without physical co-presence during cooperative online gaming

Inter-brain synchronization during social interaction has been linked with several positive phenomena, including closeness, cooperation, prosociality, and team performance. However, the temporal dynamics of inter-brain synchronization during collaboration are not yet fully understood. Furthermore, with collaboration increasingly happening online, the dependence of inter-brain phase synchronization of oscillatory activity on physical presence is an important but understudied question. In this study, physically isolated participants performed a collaborative coordination task in the form of a cooperative multiplayer game. We measured EEG from 42 subjects working together as pairs in the task. During the measurement, the only interaction between the participants happened through on-screen movement of a racing car, controlled by button presses of both participants working with distinct roles, either controlling the speed or the direction of the car. Pairs working together in the task were found to have elevated neural coupling in the alpha, beta, and gamma frequency bands, compared to performance matched false pairs. Higher gamma synchrony was associated with better momentary performance within dyads and higher alpha synchrony was associated with better mean performance across dyads. These results are in line with previous findings of increased inter-brain synchrony during interaction, and show that phase synchronization of oscillatory activity occurs during online real-time joint coordination without any physical co-presence or video and audio connection. Synchrony decreased during a playing session, but was found to be higher during the second session compared to the first. The novel paradigm, developed for the measurement of real-time collaborative performance, demonstrates that changes in inter-brain EEG phase synchrony can be observed continuously during interaction.Peer reviewe

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies

Structures of filaments from Pick's disease reveal a novel tau protein fold

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers

Cryo-EM structures of tau filaments from Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases

Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.

The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level. We found that tau aggregates have an intrinsic ability to amplify by filament fragmentation, and determined the doubling times for this replication process by kinetic modeling. We then simulated the spreading time for aggregates through the brain and found this to be in good agreement with both the observed time frame for spreading of pathological tau deposits in Alzheimer's disease and in experimental models of tauopathies. With this work we begin to understand the physical parameters that govern the spreading rates of tau and other amyloids through the human brain

Inter-brain synchronization occurs without physical co-presence during cooperative online gaming

Inter-brain synchronization during social interaction has been linked with several positive phenomena, including closeness, cooperation, prosociality, and team performance. However, the temporal dynamics of inter-brain synchronization during collaboration are not yet fully understood. Furthermore, with collaboration increasingly happening online, the dependence of inter-brain phase synchronization of oscillatory activity on physical presence is an important but understudied question. In this study, physically isolated participants performed a collaborative coordination task in the form of a cooperative multiplayer game. We measured EEG from 42 subjects working together as pairs in the task. During the measurement, the only interaction between the participants happened through on-screen movement of a racing car, controlled by button presses of both participants working with distinct roles, either controlling the speed or the direction of the car. Pairs working together in the task were found to have elevated neural coupling in the alpha, beta, and gamma frequency bands, compared to performance matched false pairs. Higher gamma synchrony was associated with better momentary performance within dyads and higher alpha synchrony was associated with better mean performance across dyads. These results are in line with previous findings of increased inter-brain synchrony during interaction, and show that phase synchronization of oscillatory activity occurs during online real-time joint coordination without any physical co-presence or video and audio connection. Synchrony decreased during a playing session, but was found to be higher during the second session compared to the first. The novel paradigm, developed for the measurement of real-time collaborative performance, demonstrates that changes in inter-brain EEG phase synchrony can be observed continuously during interaction