Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

Importance: Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. // Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. // Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. // Main Outcomes and Measures: Amyloid-β plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer–tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Šídák tests. // Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer–containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. // Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P \u3c .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

Role of extracellular vesicles in the propagation of Tau protein

L’agrégation de tau intra-neuronale est une caractéristique commune d’un groupe hétérogène de maladies neurodégénératives appelées tauopathies. Dans certaines d’entre elles, la pathologie affecte une région cérébrale avant de se propager à d’autres régions.Cette évolution stéréotypée dans le temps et dans l’espace est probablement liée à une propagation de type prion d’espèces de tau ayant des propriétés de recrutement. Ces espèces pathologiques de tau identifiées dans le liquide interstitiel cérébral (ISF) de souris transgéniques et dans le liquide céphalorachidien humain (LCR) peuvent être internalisées par des cellules et induire une agrégation intracellulaire de tau (Takeda et al., 2016). Ces espèces pathologiques sont encore mal caractérisées mais plusieurs mécanismes potentiellement impliqués dans leur propagation ont été démontrés. Parmi eux nous avons démontré que tau est sécrétée dans les vésicules extracellulaires (EV) (Dujardin et al., 2014).Dans ce contexte nous avons voulu : 1/ vérifier l’hypothèse selon laquelle la protéine Tau pathologique est présente dans les VE extraites de tissus de patients atteints de différentes Tauopathies et que ces dernières peuvent induire de la pathologie chez l’animal. 2/ détecter des espèces pathologiques de Tau dans les VE contenues dans le plasma et le LCR, potentiels biomarqueurs de Tauopathies. 3/déterminer si de la protéine Tau peut être transférée d’un neurone à un astrocyte et dans le cas échéant, de déterminer la/les voies de transfert.Afin de tester la présence de tau avec potentiel de recrutement dans les EV extraites d’ISF de patients atteints de tauopathie set de souris transgéniques nous avons utilisé un biosenseur biologique sensible et spécifique. Nos résultats démontrent que des EV extraites d’ISF de patients atteints de maladie d’Alzheimer, de paralysie supranucléaire progressive (PSP) et de souris Tau30 contiennent de la tau pro-nucléantes. Ces capacités de recrutement sont corrélées à la sévérité de la pathologie pour la MA (préfrontal>occipital>cervelet) et induisent de la pathologie chez la souris transgénique. La présence de tau dans ces VE supporte l’idée que les EV pourraient avoir un rôle dans la propagation de tau.Nous avons également démontré par différentes approches in-vitro que la protéine Tau peut être transférée de neurone à astrocyte. Ce transfert se fait principalement par les vésicules extracellulaires.Intra-neuronal accumulation of tau protein aggregates is one of the common feature of a group of heterogeneous neurodegenerative diseases called tauopathies. In some of them, the pathology will first affect a region before spreading to other regions.This staging could be linked to the prion-like propagation of pathological seed-competent tau species. These seeds, identified in transgenic mice interstitial fluid (ISF) and in human cerebrospinal fluid (CSF) are uptaken by cells and induce subsequent intracellular tau aggregation (Takeda et al., 2016). The pathological species of tau which are spreading are not yet well characterized but several mechanisms mediating their transfer (secretion and capture) have been highlighted. Among them, we demonstrated that tau is secreted in extracellular vesicles (EV´s) (Dujardin et al., 2014). We also know that neurons are implicated in this transfer but the role of glial cells is unknown.In this context, we wanted to: 1 / demonstrate that pathological Tau protein is present in EVs extracted from brain of patients suffering from different Tauopathy and that those EVS induce pathology in animals. 2 / detect pathological Tau species in EVs extracted from plasma and CSF, potential biomarkers of Tauopathies. 3 / demonstrate that Tau protein can be transferred from neuron to astrocyte and, if so, to determine the transfer pathway.To test the seeding potential of EV’s containing in ISF derived from human brain of patient presenting tauopathies, and Tau 30 mouse brain we have used a sensitive and specific tau biosensor assay. Our results demonstrate that EVs isolated from ISF of AD patient, PSP patient and Tau 30 mouse contain seed prion-like properties. The ability of these seeds to recruit tau seems to be correlated to the severity of tau pathology (prefrontal>occipital>cerebellum) for AD. This might reflect the slight presence of neurofibrillary degeneration as well as extracellular tau in this pathology in comparison to AD. Finally, the presence of seeds-containing EV’s in the extracellular space supports the idea that these shuttles might be implied in the prion-like propagation of tau pathology in Humans. Additionally, tau pathology spreading is driven by EV’s rather than by free-floating tau species.We also demonstrated that tau can be transferred from neuron to astrocyte; this transfer is more efficient with EV’s than with free floating tau.These data open new avenues for therapeutic interventions that might targets the toxic and propagative species

Rôle des vésicules extracellulaires dans la propagation de la protéine Tau

Intra-neuronal accumulation of tau protein aggregates is one of the common feature of a group of heterogeneous neurodegenerative diseases called tauopathies. In some of them, the pathology will first affect a region before spreading to other regions.This staging could be linked to the prion-like propagation of pathological seed-competent tau species. These seeds, identified in transgenic mice interstitial fluid (ISF) and in human cerebrospinal fluid (CSF) are uptaken by cells and induce subsequent intracellular tau aggregation (Takeda et al., 2016). The pathological species of tau which are spreading are not yet well characterized but several mechanisms mediating their transfer (secretion and capture) have been highlighted. Among them, we demonstrated that tau is secreted in extracellular vesicles (EV´s) (Dujardin et al., 2014). We also know that neurons are implicated in this transfer but the role of glial cells is unknown.In this context, we wanted to: 1 / demonstrate that pathological Tau protein is present in EVs extracted from brain of patients suffering from different Tauopathy and that those EVS induce pathology in animals. 2 / detect pathological Tau species in EVs extracted from plasma and CSF, potential biomarkers of Tauopathies. 3 / demonstrate that Tau protein can be transferred from neuron to astrocyte and, if so, to determine the transfer pathway.To test the seeding potential of EV’s containing in ISF derived from human brain of patient presenting tauopathies, and Tau 30 mouse brain we have used a sensitive and specific tau biosensor assay. Our results demonstrate that EVs isolated from ISF of AD patient, PSP patient and Tau 30 mouse contain seed prion-like properties. The ability of these seeds to recruit tau seems to be correlated to the severity of tau pathology (prefrontal>occipital>cerebellum) for AD. This might reflect the slight presence of neurofibrillary degeneration as well as extracellular tau in this pathology in comparison to AD. Finally, the presence of seeds-containing EV’s in the extracellular space supports the idea that these shuttles might be implied in the prion-like propagation of tau pathology in Humans. Additionally, tau pathology spreading is driven by EV’s rather than by free-floating tau species.We also demonstrated that tau can be transferred from neuron to astrocyte; this transfer is more efficient with EV’s than with free floating tau.These data open new avenues for therapeutic interventions that might targets the toxic and propagative species.L’agrégation de tau intra-neuronale est une caractéristique commune d’un groupe hétérogène de maladies neurodégénératives appelées tauopathies. Dans certaines d’entre elles, la pathologie affecte une région cérébrale avant de se propager à d’autres régions.Cette évolution stéréotypée dans le temps et dans l’espace est probablement liée à une propagation de type prion d’espèces de tau ayant des propriétés de recrutement. Ces espèces pathologiques de tau identifiées dans le liquide interstitiel cérébral (ISF) de souris transgéniques et dans le liquide céphalorachidien humain (LCR) peuvent être internalisées par des cellules et induire une agrégation intracellulaire de tau (Takeda et al., 2016). Ces espèces pathologiques sont encore mal caractérisées mais plusieurs mécanismes potentiellement impliqués dans leur propagation ont été démontrés. Parmi eux nous avons démontré que tau est sécrétée dans les vésicules extracellulaires (EV) (Dujardin et al., 2014).Dans ce contexte nous avons voulu : 1/ vérifier l’hypothèse selon laquelle la protéine Tau pathologique est présente dans les VE extraites de tissus de patients atteints de différentes Tauopathies et que ces dernières peuvent induire de la pathologie chez l’animal. 2/ détecter des espèces pathologiques de Tau dans les VE contenues dans le plasma et le LCR, potentiels biomarqueurs de Tauopathies. 3/déterminer si de la protéine Tau peut être transférée d’un neurone à un astrocyte et dans le cas échéant, de déterminer la/les voies de transfert.Afin de tester la présence de tau avec potentiel de recrutement dans les EV extraites d’ISF de patients atteints de tauopathie set de souris transgéniques nous avons utilisé un biosenseur biologique sensible et spécifique. Nos résultats démontrent que des EV extraites d’ISF de patients atteints de maladie d’Alzheimer, de paralysie supranucléaire progressive (PSP) et de souris Tau30 contiennent de la tau pro-nucléantes. Ces capacités de recrutement sont corrélées à la sévérité de la pathologie pour la MA (préfrontal>occipital>cervelet) et induisent de la pathologie chez la souris transgénique. La présence de tau dans ces VE supporte l’idée que les EV pourraient avoir un rôle dans la propagation de tau.Nous avons également démontré par différentes approches in-vitro que la protéine Tau peut être transférée de neurone à astrocyte. Ce transfert se fait principalement par les vésicules extracellulaires

Rôle des vésicules extracellulaires dans la propagation de la protéine Tau

Intra-neuronal accumulation of tau protein aggregates is one of the common feature of a group of heterogeneous neurodegenerative diseases called tauopathies. In some of them, the pathology will first affect a region before spreading to other regions.This staging could be linked to the prion-like propagation of pathological seed-competent tau species. These seeds, identified in transgenic mice interstitial fluid (ISF) and in human cerebrospinal fluid (CSF) are uptaken by cells and induce subsequent intracellular tau aggregation (Takeda et al., 2016). The pathological species of tau which are spreading are not yet well characterized but several mechanisms mediating their transfer (secretion and capture) have been highlighted. Among them, we demonstrated that tau is secreted in extracellular vesicles (EV´s) (Dujardin et al., 2014). We also know that neurons are implicated in this transfer but the role of glial cells is unknown.In this context, we wanted to: 1 / demonstrate that pathological Tau protein is present in EVs extracted from brain of patients suffering from different Tauopathy and that those EVS induce pathology in animals. 2 / detect pathological Tau species in EVs extracted from plasma and CSF, potential biomarkers of Tauopathies. 3 / demonstrate that Tau protein can be transferred from neuron to astrocyte and, if so, to determine the transfer pathway.To test the seeding potential of EV’s containing in ISF derived from human brain of patient presenting tauopathies, and Tau 30 mouse brain we have used a sensitive and specific tau biosensor assay. Our results demonstrate that EVs isolated from ISF of AD patient, PSP patient and Tau 30 mouse contain seed prion-like properties. The ability of these seeds to recruit tau seems to be correlated to the severity of tau pathology (prefrontal>occipital>cerebellum) for AD. This might reflect the slight presence of neurofibrillary degeneration as well as extracellular tau in this pathology in comparison to AD. Finally, the presence of seeds-containing EV’s in the extracellular space supports the idea that these shuttles might be implied in the prion-like propagation of tau pathology in Humans. Additionally, tau pathology spreading is driven by EV’s rather than by free-floating tau species.We also demonstrated that tau can be transferred from neuron to astrocyte; this transfer is more efficient with EV’s than with free floating tau.These data open new avenues for therapeutic interventions that might targets the toxic and propagative species.L’agrégation de tau intra-neuronale est une caractéristique commune d’un groupe hétérogène de maladies neurodégénératives appelées tauopathies. Dans certaines d’entre elles, la pathologie affecte une région cérébrale avant de se propager à d’autres régions.Cette évolution stéréotypée dans le temps et dans l’espace est probablement liée à une propagation de type prion d’espèces de tau ayant des propriétés de recrutement. Ces espèces pathologiques de tau identifiées dans le liquide interstitiel cérébral (ISF) de souris transgéniques et dans le liquide céphalorachidien humain (LCR) peuvent être internalisées par des cellules et induire une agrégation intracellulaire de tau (Takeda et al., 2016). Ces espèces pathologiques sont encore mal caractérisées mais plusieurs mécanismes potentiellement impliqués dans leur propagation ont été démontrés. Parmi eux nous avons démontré que tau est sécrétée dans les vésicules extracellulaires (EV) (Dujardin et al., 2014).Dans ce contexte nous avons voulu : 1/ vérifier l’hypothèse selon laquelle la protéine Tau pathologique est présente dans les VE extraites de tissus de patients atteints de différentes Tauopathies et que ces dernières peuvent induire de la pathologie chez l’animal. 2/ détecter des espèces pathologiques de Tau dans les VE contenues dans le plasma et le LCR, potentiels biomarqueurs de Tauopathies. 3/déterminer si de la protéine Tau peut être transférée d’un neurone à un astrocyte et dans le cas échéant, de déterminer la/les voies de transfert.Afin de tester la présence de tau avec potentiel de recrutement dans les EV extraites d’ISF de patients atteints de tauopathie set de souris transgéniques nous avons utilisé un biosenseur biologique sensible et spécifique. Nos résultats démontrent que des EV extraites d’ISF de patients atteints de maladie d’Alzheimer, de paralysie supranucléaire progressive (PSP) et de souris Tau30 contiennent de la tau pro-nucléantes. Ces capacités de recrutement sont corrélées à la sévérité de la pathologie pour la MA (préfrontal>occipital>cervelet) et induisent de la pathologie chez la souris transgénique. La présence de tau dans ces VE supporte l’idée que les EV pourraient avoir un rôle dans la propagation de tau.Nous avons également démontré par différentes approches in-vitro que la protéine Tau peut être transférée de neurone à astrocyte. Ce transfert se fait principalement par les vésicules extracellulaires

Les vésicules extracellulaires

Les vésicules extracellulaires (VE) sont libérées par une grande variété de cellules et contiennent des protéines, des ARN et des lipides, qui sont ainsi échangés entre ces cellules. Elles représentent donc un mode de communication intercellulaire majeur aussi bien en conditions physiologiques que pathologiques. C’est notamment le cas dans le système nerveux (SN) où les neurones et les cellules gliales forment un réseau très dense et où des milliards de connexions s’établissent. Cette revue fournit un aperçu des différents rôles joués par les VE dans un cerveau sain lors du renforcement des réseaux par exemple, mais également dans un cerveau malade où les VE participent, entre autres, à la progression des maladies neurodégénératives et tumorales

Découverte fortuite d’une atteinte hépatique d’amylose à leukocyte chemotactic factor 2

International audienceLeukocyte cell-derived chemotaxin 2-associated amyloidosis (ALECT2) is a recently described of amyloidosis described in the United States in 2007. It is a systemic disease that is predominantly associated with some ethnics groups. ALECT2 is usually diagnosed on a kidney biopsy performed in the context of slowly progressive chronic renal disease but can also be found incidentally on a liver sample. We report the case of a Syrian patient who benefited from a partial hepatectomy for the treatment of multiple metastasis of a colorectal adenocarcinoma. Microscopic analysis of the surgical specimen revealed numerous amyloid deposits that did not match any of the usual forms of liver amyloidosis after immunohistochemistry typing. Some morphologic features of the deposits were highly suggestive of ALECT2. Complementary immunohistochemical study and mass spectrometry confirmed the diagnosis

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

International audiencePediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity

Specific detection of tau seeding activity in Alzheimer's disease using rationally designed biosensor cells

Background: The prion-like propagation of tau in neurodegenerative disorders implies that misfolded pathological tau can recruit the normal protein and template its aggregation. Here, we report the methods for the development of sensitive biosensor cell lines for the detection of tau seeding activity. Results: We performed the rational design of novel tau probes based on the current structural knowledge of pathological tau aggregates in Alzheimer's disease. We generated Förster resonance energy transfer (FRET)-based biosensor stable cell lines and characterized their sensitivity, specificity, and overall ability to detect bioactive tau in human samples. As compared to the reference biosensor line, the optimized probe design resulted in an increased efficiency in the detection of tau seeding. The increased sensitivity allowed for the detection of lower amount of tau seeding competency in human brain samples, while preserving specificity for tau seeds found in Alzheimer's disease. Conclusions: This next generation of FRET-based biosensor cells is a novel tool to study tau seeding activity in Alzheimer's disease human samples, especially in samples with low levels of seeding activity, which may help studying early tau-related pathological events.</p