Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice

Baker, Siân; Polanco, Juan Carlos; Gotz, Juergen

doi:10.3233/jad-160371

Cited by 75 publications

(62 citation statements)

References 27 publications

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“…Exosomes are generated in multivesicular bodies, a type of late endosomes, following inward budding of the outer endosomal membrane. Tau has been reported to be found in exosomes purified from brains of tau(P301L) transgenic mice [143,144] and in exosomes isolated from neuroblastoma cells and from cerebrospinal fluid of AD patients [145]. Importantly, exosomes may deliver pathological tau to unaffected cells, seeding further tau pathology.…”

Section: Vesicle-mediated Mechanisms Of Tau Secretionmentioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

191

171

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Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-tocell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

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Section: Vesicle-mediated Mechanisms Of Tau Secretionmentioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

191

171

View full text Add to dashboard Cite

show abstract

“…In this regard, are the propagons in a free form or membrane associated? It is known that exosomes containing tau with seeding activity have been isolated from the brains of tau transgenic mice [9]. In addition, seed-competent tau species, in both free and vesicular forms, have been detected in CSF and ISF from experimental models and CSF from AD patients [85,171].…”

Section: Tau Seedingmentioning

confidence: 99%

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

et al. 2019

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The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.

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“…In addition, pathogens use the endolysosomal system for entry into cells and their replication; therefore the action of the ISGylation machinery on the endosomal system will facilitate its encounter with viral components and thus affect their degradation at sites of virus entry, replication and egress. Protein aggregates and prions are also enriched in and spread through exosomes (Guo et al, 2016), which has been suggested to contribute to the progression of prion diseases and aggregopathies (Baker et al, 2016;Eitan et al, 2016;Quek and Hill, 2017). In addition, ISGylated proteins interact with the aggresome marker p62 (Nakashima et al, 2015), which in turn interacts with LC3-II (the activated lipidated form of LC3) in the membrane of autophagosomes, thereby facilitating the clearance of protein aggregates.…”

Section: Effects Of Isg15 On Secretionlocking the Cell Gatesmentioning

confidence: 99%

ISGylation – a key to lock the cell gates for preventing the spread of threats

Villarroya-Beltrí

Guerra

2017

Journal of Cell Science

122

115

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Interferon stimulated gene 15 (ISG15) is an ubiquitin-like protein whose expression and conjugation to targets (ISGylation) is induced by infection, interferon (IFN)-α and -β, ischemia, DNA damage and aging. Attention has historically focused on the antiviral effects of ISGylation, which blocks the entry, replication or release of different intracellular pathogens. However, recently, new functions of ISGylation have emerged that implicate it in multiple cellular processes, such as DNA repair, autophagy, protein translation and exosome secretion. In this Review, we discuss the induction and conjugation of ISG15, as well as the functions of ISGylation in the prevention of infections and in cancer progression. We also offer a novel perspective with regard to the latest findings on this pathway, with special attention to the role of ISGylation in the inhibition of exosome secretion, which is mediated by fusion of multivesicular bodies with lysosomes. Finally, we propose that under conditions of stress or infection, ISGylation acts as a defense mechanism to inhibit normal protein translation by modifying protein kinase R (PKR, also known as EIF2AK2), while any newly synthesized proteins are being tagged and thus marked as potentially dangerous. Then, the endosomal system is re-directed towards protein degradation at the lysosome, to effectively 'lock' the cell gates and thus prevent the spread of pathogens, prions and deleterious aggregates through exosomes.

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Extracellular Vesicles Containing P301L Mutant Tau Accelerate Pathological Tau Phosphorylation and Oligomer Formation but Do Not Seed Mature Neurofibrillary Tangles in ALZ17 Mice

Cited by 75 publications

References 27 publications

Mechanisms of secretion and spreading of pathological tau protein

Mechanisms of secretion and spreading of pathological tau protein

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

ISGylation – a key to lock the cell gates for preventing the spread of threats

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