Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease (original) (raw)
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Extracellular vesicles: Major actors of heterogeneity in tau spreading among human tauopathies
Molecular Therapy, 2021
Tauopathies are neurodegenerative diseases characterized by tau inclusions in brain cells. Seed-competent tau species have been suggested to spread from cell to cell in a stereotypical manner, indicating that this may involve a prion-like mechanism. Although the intercellular mechanisms of transfer are unclear, extracellular vesicles (EVs) could be potential shuttles. We assessed this in humans by preparing vesicles from fluids (Brain-derived enriched extracellular vesicles; BD-EVs). These latter were isolated from different brain regions in various tauopathies and their seeding potential was assessed in vitro and in vivo. We observed considerable heterogeneity among tauopathies and brain regions. The most striking evidence was coming mainly from Alzheimer's disease where the BD-EVs clearly contain pathological species that can induce tau lesions in vivo. The results support the hypothesis that BD-EVs, participate in the prion-like propagation of tau pathology among tauopathies, and there may be implications for diagnostic and therapeutic strategies.
Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles
International journal of molecular sciences, 2018
Progressive cerebral accumulation of tau aggregates is a defining feature of Alzheimer's disease (AD). A popular theory that seeks to explain the apparent spread of neurofibrillary tangle pathology proposes that aggregated tau is passed from neuron to neuron. Such a templated seeding process requires that the transferred tau contains the microtubule binding repeat domains that are necessary for aggregation. While it is not clear how a protein such as tau can move from cell to cell, previous reports have suggested that this may involve extracellular vesicles (EVs). Thus, measurement of tau in EVs may both provide insights on the molecular pathology of AD and facilitate biomarker development. Here, we report the use of sensitive immunoassays specific for full-length (FL) tau and mid-region tau, which we applied to analyze EVs from human induced pluripotent stem cell (iPSC)-derived neuron (iN) conditioned media, cerebrospinal fluid (CSF), and plasma. In each case, most tau was free...
Extracellular Vesicle Biology in Alzheimer’s Disease and Related Tauopathy
Journal of Neuroimmune Pharmacology, 2017
Extracellular vesicles (EVs) are physiological vesicles secreted from most of eukaryotes and contain cargos of their cell of origin. EVs, and particularly a subset of EV known as exosomes, are emerging as key mediators of cell to cell communication and waste management for cells both during normal organismal function and in disease. In this review, we investigate the rapidly growing field of exosome biology, their biogenesis, cargo loading, and uptake by other cells. We particularly consider the role of exosomes in Alzheimer's disease, both as a pathogenic agent and as a disease biomarker. We also explore the emerging role of exosomes in chronic traumatic encephalopathy. Finally, we highlight open questions in these fields and the possible use of exosomes as therapeutic targets and agents.
Journal of Alzheimer's disease : JAD, 2014
Tau misprocessing to form aggregates and other toxic species has emerged as a major feature in our developing understanding of the etiology and pathogenesis of Alzheimer's disease (AD). The significance of tau misprocessing in AD has been further emphasized by recent studies showing that tau can be secreted from neurons via exosomes and may itself be an important agent in the spreading of neurofibrillary lesions within the brain. Tau secretion occurs most readily under disease-associated conditions in cellular models, suggesting that cellular changes responsible for secretion, possibly including tau oligomerization, could play a key role in the propagation of neurofibrillary lesions in neurodegenerative disease. Here we show that overexpression of 4R0N human tau in neuroblastoma cells recruits mitochondrial and axonogenesis-associated proteins relevant to neurodegeneration into the exosomal secretion pathway via distinct mechanisms. The recruitment of mitochondrial proteins appe...
Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission
European Journal of Neuroscience, 2013
It is well documented that neurofibrillary tangles composed of aggregated tau protein propagate in a predictable pattern in Alzheimer's disease (AD). The mechanisms underlying the propagation of tau pathology are still poorly understood. Recent studies have provided solid data demonstrating that in several neurodegenerative diseases including AD, the spreading of misfolded protein aggregates in the brain would result from prion-like cell-to-cell transmission. Consistent with this new concept, recent studies have reported that human tau can be released in the extracellular space by an active process of secretion, and can be endocytosed both in vitro and in vivo. Most importantly, it was reported that the spreading of tau pathology was observed along synaptically connected circuits in a transgenic mouse model where human tau overexpression was restricted in the entorhinal cortex. This indicates that secretion of tau by presynaptic neurons and its uptake by postsynaptic neurons could be the sequential events leading to the propagation of tau pathology in the brain.
Laboratory Investigation
Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2–10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed ...
Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein
PLoS ONE, 2014
Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
Cryo-EM structures of tau filaments from Alzheimer’s disease
Nature
Alzheimer's disease (AD) is the most common neurodegenerative disease, and there are no mechanism-based therapies. AD is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in cerebral cortex. Neurofibrillary lesions are made of paired helical and straight Tau filaments (PHFs and SFs), 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 PHFs and SFs from AD brain. Filament cores are made of two identical protofilaments comprising residues 306-378 of Tau, which adopt a combined cross-β/βhelix structure and define the seed for Tau aggregation. PHFs and SFs differ in their interprotofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patientderived material, and pave the way to study a range of neurodegenerative diseases. Neurofibrillary lesions strongly correlate with cognitive deficits, making them an important therapeutic target for AD 1. Dominantly inherited mutations in MAPT cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), showing that dysfunction of Tau is sufficient to cause neurodegeneration and dementia 2. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: