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PubMed: 29590627

Title
Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways.
Journal
Cell reports
Volume
22
Issue
None
Pages
3612-3624
Date
2018-03-27
Authors
Billinton A | Evans LD | Fraser G | Livesey FJ | Perkinton M | Smith J | Wassmer T

Evidence 7c20488891
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Inhibition of actin polymerization with Cytochalasin D disrupts several clathrin-independent endocytic processes, including bulk endocytosis/ macropinocytosis (Mooren et al., 2012)

bp(GO:"actin filament polymerization") positiveCorrelation bp(GO:"bulk synaptic vesicle endocytosis") View Subject | View Object

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a(CHEBI:"cytochalasin D") decreases bp(GO:"actin filament polymerization") View Subject | View Object

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a(CHEBI:"cytochalasin D") negativeCorrelation bp(GO:"bulk synaptic vesicle endocytosis") View Subject | View Object

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a(CHEBI:"cytochalasin D") negativeCorrelation bp(GO:macropinocytosis) View Subject | View Object

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bp(GO:"actin filament polymerization") positiveCorrelation bp(GO:macropinocytosis) View Subject | View Object

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bp(GO:"bulk synaptic vesicle endocytosis") negativeCorrelation a(CHEBI:"cytochalasin D") View Subject | View Object

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bp(GO:"bulk synaptic vesicle endocytosis") positiveCorrelation bp(GO:"actin filament polymerization") View Subject | View Object

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bp(GO:macropinocytosis) negativeCorrelation a(CHEBI:"cytochalasin D") View Subject | View Object

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bp(GO:macropinocytosis) positiveCorrelation bp(GO:"actin filament polymerization") View Subject | View Object

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Evidence 7d49e2c5fd
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Entry of monomeric tau was markedly reduced in the presence of 1 mM Cytochalasin D, as reflected in the 95% reduction in the number of monomeric tau-pHrodo-positive objects after 3-hr incubation in the presence of 1 mMCytochalasinD (Figure 5C)

a(CHEBI:"cytochalasin D") decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 286b52c124
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In contrast, disruption of actin polymerization with Cytochalasin D had little effect on the entry of aggregated tau (total fluorescent intensity and number of objects; Figures 5D–5F; Figure S5)

a(CHEBI:"cytochalasin D") causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 78886be917
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Conversely, dynamin inhibition significantly reduced the entry of aggregated tau, with no significant effects of Cytochalasin D (Figure S6) at this relatively high molar concent of aggregated tau

a(CHEBI:"cytochalasin D") causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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a(CHEBI:dynasore) decreases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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act(p(HGNC:DNM1)) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 6eb732dfe7
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These kinetics of aggregated tau-pHrodo entry are similar to that of both lower concentrations of monomeric tau (2.5 nM) and of low-molecular weight (10-kDa) dextran-pHrodo (same molarity as monomeric tau samples; Figures S5A–S5C

a(CHEBI:dextran) increases tloc(a(CHEBI:dextran)) View Subject | View Object

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Annotations
MeSH
Neurites
MeSH
Neurons

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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MeSH
Neurites
MeSH
Neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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Annotations
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Neurites
MeSH
Neurons

Evidence bb60ae5108
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The amount of monomeric tau entering neurons, as measured by total fluorescent intensity of intracellular monomeric tau-pHrodo vesicles, was significantly reduced by dynamin inhibition, as shown at 1 and 3 hr after the addition of extracellular tau (Figure 4B)

a(CHEBI:dynasore) decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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act(p(HGNC:DNM1)) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 76e41952c7
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The effect of dynamin inhibition on the entry of aggregated tau was more pronounced than on monomeric tau (Figures 4D–4F). The total fluorescent intensity of intracellular aggregated taupHrodo was consistently reduced by more than 70% at 1 and 3 hr after tau addition (Figure 4E), and the number of taupHrodo- positive objects was reduced by 95% (Figure 4F)

a(CHEBI:dynasore) decreases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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act(p(HGNC:DNM1)) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 16a5384c45
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We confirmed that heparin within the aggregated tau preparations did not contribute to tau entry into neurons, finding that uptake of both monomeric and aggregated tau was unaffected in the presence of heparin (Figures S4C and S4D

a(CHEBI:heparin) causesNoChange tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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a(CHEBI:heparin) causesNoChange tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 658f6161cf
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As early as 1 hr after the addition of extracellular tau, monomeric and aggregated tau-Dylight were co-localized in EEA1+ early endosomes

a(GO:"early endosome") association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

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a(GO:"early endosome") association a(HBP:"Tau aggregates") View Subject | View Object

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a(HBP:"Tau aggregates") association a(GO:"early endosome") View Subject | View Object

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p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:"early endosome") View Subject | View Object

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Evidence 5998bdf778
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Monomeric and aggregated tau-Dylight were also detected in LAMP1+late endosomes and lysosomes, consistent with endocytosed proteins first reaching early endosomes, before late endosomes and lysosomes

a(HBP:"Tau aggregates") association a(GO:"late endosome") View Subject | View Object

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a(HBP:"Tau aggregates") association a(GO:lysosome) View Subject | View Object

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a(GO:"late endosome") association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

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a(GO:"late endosome") association a(HBP:"Tau aggregates") View Subject | View Object

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a(GO:lysosome) association p(HGNC:MAPT, var("p.Pro301Ser")) View Subject | View Object

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a(GO:lysosome) association a(HBP:"Tau aggregates") View Subject | View Object

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p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:"late endosome") View Subject | View Object

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p(HGNC:MAPT, var("p.Pro301Ser")) association a(GO:lysosome) View Subject | View Object

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Evidence d06b6c0f01
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Thus, monomeric and aggregated tau both efficiently enter neurons via the endosome/lysosome system, and they are actively trafficked within vesicles over long distances within neurons over several hours

a(GO:lysosome) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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a(GO:lysosome) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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bp(GO:endocytosis) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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bp(GO:endocytosis) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 326635e03b
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After extensive washing, monomeric and aggregated tau-Dylight were both detected within cells expressing the neuron-specific microtubule-associated protein MAP2, confirming that both forms of tau enter neurons

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 4126d89d11
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Tau-Dylight was found predominantly within the somatic compartment of neurons (Figure 1A)

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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Evidence 40d0201959
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After a 4-hr incubation with extracellular tau, flow cytometry analysis (Figures 1B and 1C) revealed that 83% and 73% of dissociated cells contained monomeric or aggregated tau-Dylight, respectively, demonstrating that extracellular tau efficiently enters human neurons in culture

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence ffd8929c4b
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Internalization of aggregated tau-pHrodo (Figure 2D) was also found to be concentration dependent (Figure 2E)

a(HBP:"Tau aggregates") increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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Neurites
MeSH
Neurons

Evidence da6b228f6e
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Disruption of actin polymerization has previously been shown to inhibit entry of fibrils formed of the tau repeat domain (Holmes et al., 2013)

bp(GO:"actin filament polymerization") increases tloc(a(HBP:"Tau fibrils"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 6aabff68ec
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These data indicate that, at the concentrations studied, aggregated tau enters neurons almost entirely via endocytosis

bp(GO:endocytosis) increases tloc(a(HBP:"Tau aggregates"), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 3e45fa17a6
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These independent assays confirmed the same differential effects of the two inhibitors observed by live imaging of pHrodo-tau: at the 3-hr assay point, dynamin inhibition had no effect on the number of monomeric tau-Dylightpositive punctae within neurons, whereas inhibition of actin polymerization reduced the amount of intracellular tau by over half (Figure S6).

composite(a(CHEBI:"cytochalasin D"), p(HGNC:MAPT, var("p.Pro301Ser"))) decreases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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composite(a(CHEBI:dynasore), p(HGNC:MAPT, var("p.Pro301Ser"))) causesNoChange tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence ddb41b5004
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We used the tau P301S variant, an autosomal dominant mutation that causes early onset FTD with high penetrance (Bugiani et al., 1999; Guo et al., 2017)

p(HGNC:MAPT, var("p.Pro301Ser")) increases path(MESH:"Frontotemporal Dementia") View Subject | View Object

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Evidence b52d591674
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Internalization of monomeric tau (P301S) and wild-type tau was comparable and concentration dependent (Figure S3A), confirming that the P301S mutation does not confer the ability to efficiently enter neurons, nor is this form of tau likely to aggregate in extracellular media during the 3- to 4-hr incubation period

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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p(HGNC:MAPT) increases tloc(p(HGNC:MAPT), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 695c9a99f7
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Incubation of tau-pHrodo with human neurons at a range of concentrations from 2.5 to 25 nM (0.12–1.2 µg.mL-1, diluted in culture medium) showed that tau entry to neurons is rapid, as visualized by live imaging

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 205ea7fa06
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We found that FLAG-tagged tau enters neurons efficiently and that internalized tau persists at detectable levels within neurons for at least 4 days (Figure S4A)

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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Evidence 4b9d9dbb0d
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Intracellular fluorescent punctae were observed within the first 10 min of exposure of neurons to monomeric tau-pHrodo (Figure 2A; Video S1). Tau-pHrodo-positive structures increased in size and intensity over the 4-hr course of the assay. These structures were present within neurites and accumulated in the cell bodies of neurons

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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Annotations
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Neurites
MeSH
Neurons

Evidence 9be37637d0
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In the presence of 15 and 25 nM monomeric tau-pHrodo, the number of tau-pHrodo-positive objects approached a plateau (>90% of final measurement) after approximately 1 hr (Figure 2C)

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(GO:"cell body")) View Subject | View Object

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Annotations
MeSH
Neurites
MeSH
Neurons

Evidence 4d2e726166
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In agreement with the monomeric tau-pHrodo experiments, monomeric tau-Dylight was rapidly taken up into neurons (Figure 3C

p(HGNC:MAPT, var("p.Pro301Ser")) increases tloc(p(HGNC:MAPT, var("p.Pro301Ser")), fromLoc(GO:"extracellular region"), toLoc(MESH:Neurons)) View Subject | View Object

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