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PubMed: 28528849

Title
Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability.
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
Volume
13
Issue
None
Pages
1270-1291
Date
2017-11-01
Authors
Chandupatla RR | Kaniyappan S | Mandelkow E | Mandelkow EM

Evidence 92aedf7b59
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In our hands, these aggregated tau species formed in different conditions did not show any significant release of LDH when applied on the differentiated SH-SY5Y cells (Supplementary Fig. 8A), and they did not show a significant reduction in cell viability by the MTTassay (Supplementary Fig. 8B).

a(HBP:"Tau aggregates") causesNoChange bp(GO:"cell death") View Subject | View Object

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a(HBP:"Tau aggregates") causesNoChange a(GO:membrane) View Subject | View Object

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Evidence 198b8ed8a7
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The fibril-treated cells (cross-linked with GA or not) did not reduce the spine density significantly (Fig 4C, bars 8 and 9).

a(HBP:"Tau fibrils") decreases a(MESH:"Dendritic Spines") View Subject | View Object

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Evidence 19312cedc6
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Recently, extracellular tau oligomers were shown to impair long term potentiation (LTP) and memory [40].

a(HBP:"Tau oligomers") decreases bp(GO:"long-term synaptic potentiation") View Subject | View Object

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MeSH
Extracellular Space

a(HBP:"Tau oligomers") decreases bp(GO:memory) View Subject | View Object

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MeSH
Extracellular Space

Evidence 98bb9dc014
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For comparison, in the case of Ab oligomers, only higher concentrations (w1 mM) cause an appreciable spine reduction of w30% (Fig. 4C, bar 3) (Zempel et al., 2010 [30]).

a(HBP:AβOs) decreases a(MESH:"Dendritic Spines") View Subject | View Object

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Evidence e52a09492d
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We reasoned that microglia and other cell types in the hippocampus might act as mediators for the cytotoxicity caused by TauRDΔK oligomers, which could explain why cytotoxicity was not observed in the cell culture systems.

a(MESH:Microglia) regulates act(p(HBP:"Tau oligomers", var("p.Lys280del"))) View Subject | View Object

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Evidence 636278b6d4
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We indeed found that there is an overexpression (w15%) of Nox1 protein (a component of NADPH oxidase complex) by Western blot, suggesting the role of NADPH oxidase complex as a potential source of ROS

act(complex(GO:"NADPH oxidase complex")) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases p(HGNC:NOX1) View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases act(complex(GO:"NADPH oxidase complex")) View Subject | View Object

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Evidence dc4255b3e1
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These findings suggest that the ROS production induced by extracellular TauRDΔK oligomers might cause the activation of NADPH oxidase complex

act(complex(GO:"NADPH oxidase complex")) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases act(complex(GO:"NADPH oxidase complex")) View Subject | View Object

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Evidence 60cd28c964
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TauRDΔK comprises the structural elements required for the pathologic assembly of tau filaments, and it causes reversible memory deficits and synapse loss in regulatable transgenic mice [11,25].

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) decreases bp(GO:memory) View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) decreases a(GO:synapse) View Subject | View Object

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p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases a(HBP:"Tau fibrils") View Subject | View Object

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Evidence a2ed343c07
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Analysis of sarkosyl extracts of brain homogenates of mice expressing the pro-aggregant repeat domain TauRDΔK revealed that oligomers are present, partly in a disulfide–cross-linked form (Supplementary Fig. 1).

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases a(HBP:"Tau oligomers") View Subject | View Object

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Evidence e7532b818f
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During early stages of assembly, there is some increase in ThS intensity, combined with a pronounced increase in ANSfluorescence (Fig. 2Aand B), which is due to oligomers, indicating a change in conformation without increase in beta-structure

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases p(HBP:"Tau oligomers", var("p.Lys280del")) View Subject | View Object

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Evidence 38cf7c2b70
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As shown earlier, TauRDΔK-expressing mice display loss of neurons in the CA3 and other regions of the hippocampus [11,24].

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) decreases a(MESH:Neurons) View Subject | View Object

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MeSH
CA3 Region, Hippocampal

Evidence 8f346d206e
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By contrast, monomers of TauRDΔK even at 10 mM concentration did not cause any significant ROS increase (Fig. 5B).

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) causesNoChange a(CHEBI:"reactive oxygen species") View Subject | View Object

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Evidence 3510e11a78
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By contrast, there was no significant increase in the calcium level in cells treated with TauRDΔK monomers even at higher concentration (10 mM) (Fig. 5E and F, green curves).

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) causesNoChange bp(GO:"cellular calcium ion homeostasis") View Subject | View Object

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Evidence 681bd72ff1
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During the transition from oligomers to polymers, the ANS fluorescence remains roughly constant, whereas ThS fluorescence increases strongly (Fig. 2B)

p(HBP:"Tau oligomers", var("p.Lys280del")) increases p(HBP:"Tau fibrils", var("p.Lys280del")) View Subject | View Object

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Evidence 91ea9a176c
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To address this question, we first applied the oligomers directly after the purification of the protein eluting from the Butyl FF 16/ 10 column (without buffer exchange; 1, 5, and 10 mM) to SHSY5Y cells and observed a variety of toxic effects, including pronounced reduction in the cell viability (by MTT assay, Fig. 3A), increase in apoptotic cells (by Hoechst staining, Supplementary Fig. 4A), loss of mitochondrial membrane potential (by JC1 assay, Supplementary Fig. 4B), caspase 3/7 activation (Supplementary Fig. 4C-D), and cytochrome-c release (Supplementary Fig. 4), within 5 hours of incubation.

p(HBP:"Tau oligomers", var("p.Lys280del")) increases bp(GO:"cell death") View Subject | View Object

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Experimental Factor Ontology (EFO)
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p(HBP:"Tau oligomers", var("p.Lys280del")) increases bp(GO:"apoptotic process") View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases bp(GO:"negative regulation of mitochondrial membrane potential") View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases act(p(HGNC:CASP3)) View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) increases act(p(HGNC:CASP7)) View Subject | View Object

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Experimental Factor Ontology (EFO)
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p(HBP:"Tau oligomers", var("p.Lys280del")) increases sec(p(HGNC:CYCS)) View Subject | View Object

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Evidence 32181c287b
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Consistent with this, NeuN staining of the slices fixed after 48 hours of treatment with TauRDΔK oligomers revealed no reduction in the neuronal number in all regions of the hippocampus (CA1, CA3, and DG) (Fig. 3C and D, Supplementary Fig. 7), confirming that TauRDΔK oligomers do not cause cell death in the OHSC model as well.

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA2 Region, Hippocampal
MeSH
CA3 Region, Hippocampal

Evidence f2db971ceb
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There was no significant change in the LDH release in oligomer-treated cells compared with controls indicating that TauRDΔK oligomers do not compromise the membrane integrity (Supplementary Fig. 5G-H).

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange a(GO:membrane) View Subject | View Object

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Experimental Factor Ontology (EFO)
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Evidence 648e367450
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In this case, there was a dramatic loss (up to 50%) of spines in TauRDΔK oligomer-treated cells compared with monomer-treated cells (Fig. 4A and B, bar 3).

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(MESH:"Dendritic Spines") View Subject | View Object

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Evidence d34a9cdeec
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Drebrin, a neuronal actin-binding protein involved in spinogenesis and synaptogenesis, was decreased by up to 60% consistent with the reduced number of spines (Fig. 4D, bars 3, 6, and 9).

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(MESH:"Dendritic Spines") View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) decreases p(HGNC:DBN1) View Subject | View Object

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p(HGNC:DBN1) increases bp(GO:"synapse assembly") View Subject | View Object

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Evidence 586c269393
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Endogenous tau protein retained its normal axonal localization and did not missort into the cell body and dendrites (Fig. 6A8), although there was a reduction in the spine density (Fig. 6B6) in the TauRDΔK oligomer-treated neurons.

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(MESH:"Dendritic Spines") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(GO:"cell body")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Neurons

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange tloc(p(HGNC:MAPT), fromLoc(GO:axon), toLoc(MESH:"Dendritic Spines")) View Subject | View Object

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MeSH
Neurons

Evidence 87b7a2e411
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The results revealed that both TauRDΔK and TauFLΔK oligomers reduce the density of spines up to 50% compared with the buffer-treated cells.

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(MESH:"Dendritic Spines") View Subject | View Object

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Evidence 305c0a3a6b
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PSD-95, a marker of postsynaptic spines, decreased up to 50% in the TauRDΔK oligomer-treated cells, compared with buffer- and monomer-treated cells

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(GO:postsynapse) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Dendritic Spines

Evidence 95a97e747f
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Similarly, the GluR1 subunits of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (characteristic of mature spines and necessary for LTP and calcium signaling) decreased in the oligomer-treated samples up to 60%.

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases p(HGNC:GRIA1) View Subject | View Object

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Evidence fb65c59803
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We also looked at the presynaptic protein synaptophysin, which was not significantly altered in TauRDΔK oligomer-treated cells compared with buffer- or monomer-treated cells (Fig 4D, bar 12). However, at higher concentration, synaptophysin tends to be reduced.

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases p(HGNC:SYP) View Subject | View Object

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Evidence 5d713c393c
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We observed an oligomer-dependent increase in the ROS production in the mature rat primary hippocampal neurons in all cellular compartments (Fig. 5A).

p(HBP:"Tau oligomers", var("p.Lys280del")) increases a(CHEBI:"reactive oxygen species") View Subject | View Object

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MeSH
Hippocampus
MeSH
Neurons

Evidence 9af7c1f38a
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However, we did not find significant changes in the expression level of Nox2 protein (another component of NADPH oxidase complex) (Fig. 5C).

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange p(HGNC:CYBB) View Subject | View Object

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Evidence 051fe75527
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The ratio of 340 to 380 nm in TauRDΔK oligomer-treated cells showed a steady concentration-dependent increase in the intracellular calcium with a maximum reached at 20 minutes of incubation with oligomers (10 mM) occurring in all cell compartments (Fig. 5D; arrows).

p(HBP:"Tau oligomers", var("p.Lys280del")) increases bp(GO:"cellular calcium ion homeostasis") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Neurons

Evidence 85a27ec17b
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We did not observe any increase in the phosphorylation of the tau repeat domain (as seen by the antibody 12E8) after treating the neurons with TauRDΔK oligomers.

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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Evidence 5cddf60302
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We also checked the phosphorylation of tau at other sites (e.g., using the antibody AT8, reacting only with the endogenous tau) and did not observe an increase in the phosphorylation.

p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

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p(HBP:"Tau oligomers", var("p.Lys280del")) causesNoChange p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

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Evidence 5831b2734b
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Tau oligomers from TauRDΔK and TauFLΔK mice reduced the density of the synapses by w50%, whereas tau from wild-type mice had no effect on the density (Fig. 7G).

p(HBP:"Tau oligomers", var("p.Lys280del")) decreases a(GO:synapse) View Subject | View Object

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p(HGNC:MAPT) causesNoChange a(GO:synapse) View Subject | View Object

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