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In Alzheimer’s disease (AD), Tau and Aβ aggregates involve sequentially connected regions, sometimes distantly separated. These alterations were studied in the pillar of the fornix (PoF), an axonal tract, to analyse the role of axons in their propagation. The PoF axons mainly originate from the subicular neurons and project to the mamillary body. Forty-seven post-mortem cases at various Braak stages (Tau) and Thal phases (Aβ) were analysed by immunohistochemistry. The distribution of the lesions showed that the subiculum was affected before the mamillary body, but neither Tau aggregation nor Aβ deposition was consistently first. The subiculum and the mamillary body contained Gallyas positive neurofibrillary tangles, immunolabelled by AT8, TG3, PHF1, Alz50 and C3 Tau antibodies. In the PoF, only thin and fragmented threads were observed, exclusively in the cases with neurofibrillary tangles in the subiculum. The threads were made of Gallyas negative, AT8 and TG3 positive Tau. They were intra-axonal and devoid of paired helical filaments at electron microscopy. We tested PoF homogenates containing Tau AT8 positive axons in a Tau P301S biosensor HEK cell line and found a seeding activity. There was no Aβ immunoreactivity detected in the PoF. We could follow microcryodissected AT8 positive axons entering the mamillary body; contacts between Tau positive endings and Aβ positive diffuse or focal deposits were observed in CLARITY-cleared mamillary body. In conclusion, we show that non-fibrillary, hyperphosphorylated Tau is transported by the axons of the PoF from the subiculum to the mamillary body and has a seeding activity. Either Tau aggregation or Aβ accumulation may occur first in this system: this inconstant order is incompatible with a cause-and-effects relationship. However, both pathologies were correlated and intimately associated, indicating an interaction of the two processes, once initiated.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

Alzheimer’s disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short (“stubby”) spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines and the width of spine necks are inversely correlated with synapse density in frontal cortical biopsies from non-AD and AD patients. In mice, the reduction in the density of synapses in the stratum radiatum was preceded by an alteration of spine morphology, with a reduction of their length and an enlargement of their neck. Serial sectioning examined with electron microscopy allowed us to precisely measure spine parameters. Mathematical modeling indicated that the shortening and widening of the necks should alter the electrical compartmentalization of the spines, leading to reduced postsynaptic potentials in spine heads, but not in soma. Accordingly, there was no alteration in basal synaptic transmission, but long-term potentiation and spatial memory were impaired. These results indicate that an alteration of spine morphology could be involved in the early cognitive deficits associated with AD.

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.

Extracellular accumulation of Aβ peptides and intracellular aggregation of hyperphosphorylated tau proteins are the two hallmark lesions of Alzheimer disease (AD). The senile plaque is made of a core of extracellular Aβ surrounded by phospho-tau positive neurites. It includes multiple components such as axons, synapses, glial fibers and microglia. To visualize the relationships of those elements, an original technique was developed, based on the dilation of interstitial water during freezing. Samples of neocortex, hippocampus and striatum were taken from formalin-fixed brains (one control case; three cases with severe Alzheimer disease). The samples were subjected to various numbers of freezing/thawing cycles (from 0 to 320) with an automated system we devised. The samples were embedded in paraffin, cut and stained with haematoxylin-eosin or immunostained against Aβ, phospho-tau, and antigens enriched in axons, synapses, macrophages or astrocytes. Microcryodissection induced the dissociation of tissue components, especially in the grey matter where the neuropil formed an oriented “mesh”. The size of the empty spaces separating the fiber bundles and cells increased with the number of cycles. The amyloid core of the senile plaque separated from its neuritic crown at around 300 freezing/thawing cycles. The dissected core remained associated with macrophages containing Aβ in their cytoplasm. Phospho-tau positive axons were distinctly seen projecting from the neuritic crown to the isolated amyloid core, where they ended in large synapses. The microcryodissection showed astrocytic processes stuck directly to the core. The original method we developed—microcryodissection—helped understanding how histological components were assembled in the tissue.

Most vesicles in the interior of synaptic terminals are clustered in clouds close to active zone regions of the plasma membrane where exocytosis occurs. Electron-dense structures, termed bridges, have been reported between a small minority of pairs of neighboring vesicles within the clouds. Synapsin proteins have been implicated previously, but the existence of the bridges as stable structures in vivo has been questioned. Here we use electron tomography to show that the bridges are present but less frequent in synapsin knockouts compared to wildtype. An analysis of distances between neighbors in wildtype tomograms indicated that the bridges are strong enough to resist centrifugal forces likely induced by fixation with aldehydes. The results confirm that the bridges are stable structures and that synapsin proteins are involved in formation or stabilization.

Microglia exhibit diverse morphologies reflecting environmental conditions, maturity or functional states. Thus, morphological characterization provides important information to understand microglial roles and functions. Most recent morphological analysis relies on classifying cells based on morphological parameters. However, this classification is not always biologically relevant, as microglial morphologies constitute a continuum rather than segregated groups. Instead, we propose a new open-source tool, MorphoCellSorter, which assesses microglial morphology by automatically computing morphological criteria, using principal component analysis and Andrews plots to rank cells. MorphoCellSorter accurately ranked cells from various microglia datasets in mice and rats of different age, from in vivo , in vitro and ex vivo models, that were acquired using diverse imaging techniques. This approach allowed for the discrimination of cell populations in various pathophysiological conditions. Finally, MorphoCellSorter offers a versatile, easy and ready-to-use method to evaluate microglial morphological diversity that could easily be generalized to standardize practices across laboratories.

Microglia exhibit diverse morphologies reflecting environmental conditions, maturity or functional states. Thus, morphological characterization provides important information to understand microglial roles and functions. Most recent morphological analysis relies on classifying cells based on morphological parameters. However, this classification may lack biological relevance, as microglial morphologies represent a continuum rather than distinct, separate groups, and do not correspond to mathematically defined, clusters irrelevant of microglial cells function. Instead, we propose a new open-source tool, MorphoCellSorter, which assesses microglial morphology by automatically computing morphological criteria, using principal component analysis and Andrews plots to rank cells. MorphoCellSorter properly ranked cells from various microglia datasets in mice and rats of different age, from in vivo, in vitro and ex vivo models, that were acquired using diverse imaging techniques. This approach allowed for the discrimination of cell populations in various pathophysiological conditions. Finally, MorphoCellSorter offers a versatile, easy and ready-to-use method to evaluate microglial morphological diversity that could easily be generalized to standardize practices across laboratories.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Figure 1 has been revised Many semantical changes in the text

The Hall effect can be extended by inducing a temperature gradient in lieu of electric field that is known as the Nernst (-Ettingshausen) effect. The recently discovered spin Nernst effect in heavy metals continues to enrich the picture of Nernst effect-related phenomena. However, the collection would not be complete without mentioning the valley degree of freedom benchmarked by the valley Hall effect. Here we show the experimental evidence of its missing counterpart, the valley Nernst effect. Using millimeter-sized WSe 2 mono-multi-layers and the ferromagnetic resonance-spin pumping technique, we are able to apply a temperature gradient by off-centering the sample in the radio frequency cavity and address a single valley through spin-valley coupling. The combination of a temperature gradient and the valley polarization leads to the valley Nernst effect in WSe 2 that we detect electrically at room temperature. The valley Nernst coefficient is in good agreement with the predicted value. Atomically thin transition metal dichalcogenides possess a valley degree of freedom, which could enrich the physics underpinning the conventional Nernst effect observed in traditional solids. Here, the authors report experimental evidence of the valley Nernst effect in WSe 2  at room temperature.

The human brain is functionally organized into large-scale neural networks that are dynamically interconnected. Multiple short-lived states of resting-state functional connectivity (rsFC) identified transiently synchronized networks and cross-network integration. However, little is known about the way brain couplings covary as rsFC states wax and wane. In this magnetoencephalography study, we explore the synchronization structure among the spontaneous interactions of well-known resting-state networks (RSNs). To do so, we extracted modes of dynamic coupling that reflect rsFC synchrony and analyzed their spatio-temporal features. These modes identified transient, sporadic rsFC changes characterized by the widespread integration of RSNs across the brain, most prominently in the β band. This is in line with the metastable rsFC state model of resting-state dynamics, wherein our modes fit as state transition processes. Furthermore, the default-mode network (DMN) stood out as being structured into competitive cross-network couplings with widespread DMN-RSN interactions, especially among the β-band modes. These results substantiate the theory that the DMN is a core network enabling dynamic global brain integration in the β band. •We study synchronization among dynamic functional connectivity at rest.•We identify transient modes of dynamic coupling using an ICA of connectivity.•Some α-band modes are longer lived and β-band modes are more widespread.•Modes of the DMN are structured into competitive cross-network couplings.•Results concur with a metastable dynamics and the core network model of the DMN.