Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons

Polanco, Juan Carlos; Li, Chuanzhou; Durisic, Nela; Sullivan, Rodney N.; Götz, Jürgen

doi:10.1186/s40478-018-0514-4

Cited by 140 publications

(154 citation statements)

References 67 publications

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“…EVs are involved in the extracellular enzymatic degradation of Aβ and are shown to promote Aβ aggregation and clearance by microglia [16,17]. On other hand, several researchers have reported the models of neuron-to-neuron transfer of tau seeds by EVs [12,[18][19][20]. Previous work in our lab has shown that microglia spread tau via EV secretion, and that inhibiting EV synthesis significantly reduced tau propagation in vitro and in vivo [10].…”

Section: Introductionmentioning

confidence: 92%

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Muraoka¹,

DeLeo²,

Sethi

et al. 2019

Preprint

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AbstractIntroductionExtracellular vesicles (EVs) from human Alzheimer’s disease (AD) biospecimens contain amyloid-β peptide (Aβ) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.MethodsEVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.ResultsLevels of pS396 tau and Aβ were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.DiscussionIn addition to Aβ and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.

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Section: Introductionmentioning

confidence: 92%

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Muraoka¹,

DeLeo²,

Sethi

et al. 2019

Preprint

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“…Macropinocytosis and HSPGs may also be responsible for the uptake of whole exosomes [196], although it is possible that exosomes are internalized as a result of the unspecificity of micropinocytosis. In general, endocytosis and/or pinocytosis has been reported to be a favored internalization route for exosomes over direct fusion to the PM [197,198].…”

Section: Cellular Uptake and Templated Misfolding Of Tau In Recipientmentioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

209

185

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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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“…The exact mechanism of transmission is not known. Release and trans-synaptic transmission of tau [164,165], tau uptake via exosomes [166][167][168] or nanotubules [169] and free uptake of fibrillar proteins [170,171] have all been suggested as putative mechanisms using cultured neurons. Although astrocyte-to-neuron intercellular transfer mediated by cell-to-cell contact has been postulated for prions [172], no information is available concerning astrocyte-to-neuron transfer in tauopathies.…”

Section: Disease Progression: Seeding and Spreading; Role Of Astrocytesmentioning

confidence: 99%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons

Cited by 140 publications

References 67 publications

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Mechanisms of secretion and spreading of pathological tau protein

Astrogliopathy in Tauopathies

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