Onset of hippocampal network aberration and memory deficits in P301S tau mice are associated with an early gene signature.

Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer's disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of individual, pathology-harbouring neurons, thereby contributing to memory deficits.

NBS-SNI, an extension of the network-based statistic: Abnormal functional connections between important structural actors.

Elucidating the coupling between the structure and the function of the brain and its development across maturation has attracted a lot of interest in the field of network neuroscience in the last 15 years. Mounting evidence supports the hypothesis that the onset of certain brain disorders is linked with the interplay between the structural architecture of the brain and its functional processes, often accompanied with unusual connectivity features. This paper introduces a method called the network-based statistic-simultaneous node investigation (NBS-SNI) that integrates both representations into a single framework, and identifies connectivity abnormalities in case-control studies. With this method, significance is given to the properties of the nodes, as well as to their connections. This approach builds on the well-established network-based statistic (NBS) proposed in 2010. We uncover and identify the regimes in which NBS-SNI offers a gain in statistical resolution to identify a contrast of interest using synthetic data. We also apply our method on two real case-control studies, one consisting of individuals diagnosed with autism and the other consisting of individuals diagnosed with early psychosis. Using NBS-SNI and node properties such as the closeness centrality and local information dimension, we found hypo- and hyperconnected subnetworks and show that our method can offer a 9 percentage points gain in prediction power over the standard NBS.

Can hubs of the human connectome be identified consistently with diffusion MRI?

Recent years have seen a surge in the use of diffusion MRI to map connectomes in humans, paralleled by a similar increase in processing and analysis choices. Yet these different steps and their effects are rarely compared systematically. Here, in a healthy young adult population (n = 294), we characterized the impact of a range of analysis pipelines on one widely studied property of the human connectome: its degree distribution. We evaluated the effects of 40 pipelines (comparing common choices of parcellation, streamline seeding, tractography algorithm, and streamline propagation constraint) and 44 group-representative connectome reconstruction schemes on highly connected hub regions. We found that hub location is highly variable between pipelines. The choice of parcellation has a major influence on hub architecture, and hub connectivity is highly correlated with regional surface area in most of the assessed pipelines (ρ > 0.70 in 69% of the pipelines), particularly when using weighted networks. Overall, our results demonstrate the need for prudent decision-making when processing diffusion MRI data, and for carefully considering how different processing choices can influence connectome organization.

The effect of using group-averaged or individualized brain parcellations when investigating connectome dysfunction in psychosis.

Functional magnetic resonance imaging (fMRI) is widely used to investigate functional coupling (FC) disturbances in a range of clinical disorders. Most analyses performed to date have used group-based parcellations for defining regions of interest (ROIs), in which a single parcellation is applied to each brain. This approach neglects individual differences in brain functional organization and may inaccurately delineate the true borders of functional regions. These inaccuracies could inflate or underestimate group differences in case-control analyses. We investigated how individual differences in brain organization influence group comparisons of FC using psychosis as a case study, drawing on fMRI data in 121 early psychosis patients and 57 controls. We defined FC networks using either a group-based parcellation or an individually tailored variant of the same parcellation. Individualized parcellations yielded more functionally homogeneous ROIs than did group-based parcellations. At the level of individual connections, case-control FC differences were widespread, but the group-based parcellation identified approximately 7.7% more connections as dysfunctional than the individualized parcellation. When considering differences at the level of functional networks, the results from both parcellations converged. Our results suggest that a substantial fraction of dysconnectivity previously observed in psychosis may be driven by the parcellation method, rather than by a pathophysiological process related to psychosis.

Alzheimer's disease: Ablating single master site abolishes tau hyperphosphorylation.

Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer's disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. Here, we show that tau phosphorylation is governed by interdependence- a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer's mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.

Contribution of endogenous antibodies to learning deficits and astrocytosis in human P301S mutant tau transgenic mice.

Antibodies have been explored extensively as a potential therapeutic for Alzheimer's disease, where amyloid-ß (Aß) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aß, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT-/-) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT-/- mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.

Effect of surface chemistry on tropomyosin binding to actin filaments on surfaces.

Reconstitution of actin filaments on surfaces for observation of filament-associated protein dynamics by fluorescence microscopy is currently an exciting field in biophysics. Here we examine the effects of attaching actin filaments to surfaces on the binding and dissociation kinetics of a fluorescence-labeled tropomyosin, a rod-shaped protein that forms continuous strands wrapping around the actin filament. Two attachment modalities of the actin to the surface are explored: where the actin filament is attached to the surface at multiple points along its length; and where the actin filament is attached at one end and aligned parallel to the surface by buffer flow. To facilitate analysis of actin-binding protein dynamics, we have developed a software tool for the viewing, tracing and analysis of filaments and co-localized species in noisy fluorescence timelapse images. Our analysis shows that the interaction of tropomyosin with actin filaments is similar for both attachment modalities. © 2016 Wiley Periodicals, Inc.