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PubMed: 22817713

Title
Tau oligomers and tau toxicity in neurodegenerative disease.
Journal
Biochemical Society transactions
Volume
40
Issue
None
Pages
667-71
Date
2012-08-01
Authors
Binder LI | Himmelstein DS | Lancia JK | Ward SM

Evidence a7b40274fe
JSON

Employing recombinant full-length hT40, we observe the presence of oligomers approximately 15 min after the addition of the anionic inducer arachidonic acid, whereas filament formation requires 5–6 h to attain steady state (Figures 1A–1C)

a(CHEBI:"arachidonic acid") increases a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(CHEBI:"arachidonic acid") increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 1a858548e9
JSON

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of senile plaques composed of Aβ (amyloid β-peptide) and the intracellular accumulation of the MAP (microtubuleassociated protein) tau into both non-filamentous and filamentous inclusions, such as NFTs (neurofibrillary tangles), NTs (neuropil threads) and NPs (neuritic plaques) [1,2]

a(GO:"neurofibrillary tangle") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(MESH:"Neuropil Threads") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") association a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") association a(MESH:"Neuropil Threads") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Plaque, Amyloid") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

Evidence 8b77f2a043
JSON

AD (Alzheimer’s disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid beta-peptide and the intracellular accumulation of tau

a(HBP:"Tau aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"amyloid-beta aggregates") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"amyloid-beta aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

Evidence cb1644afff
JSON

Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 298ed2888f
JSON

We discovered that aggregated tau inhibits FAT only in the anterograde direction at physiological tau levels, whereas tau monomers had no effect on FAT in either direction, even at concentrations of tau >10-fold higher than

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

Evidence a0fc9379b4
JSON

However, when tau aggregates, this conformation is altered, exposing PAD and allowing activation of the PP1/GSK3 signalling pathway facilitating FAT inhibition [21]

a(HBP:"Tau aggregates") decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") increases act(p(HGNC:PPP1CA)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") increases act(p(HGNC:GSK3A)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 7de7530d8a
JSON

TNT1 also co-localizes in tissue with the phospho-epitope defined by the AT8 antibody, indicating that PAD exposure represents an early event in AD pathology

a(HBP:"Tau aggregates") association p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau aggregates") association p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau oligomers") association p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

a(HBP:"Tau oligomers") association p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Ser, 202)) association a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Ser, 202)) association a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Thr, 205)) association a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Thr, 205)) association a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 3886577992
JSON

Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease

a(HBP:"Tau oligomers") increases bp(HBP:neurotoxicity) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 07dc5753ca
JSON

This indicates that tau oligomers represent the main toxic species responsible for neurodegeneration associated with AD

a(HBP:"Tau oligomers") increases bp(HBP:neurotoxicity) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

a(HBP:"Tau oligomers") increases bp(HP:Neurodegeneration) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

Evidence 28d96f17ba
JSON

Time-course aggregation analysis revealed that dimerization precedes tau oligomerization which, in turn, is an earlier event than the formation of full-length filaments

a(HBP:"Tau oligomers") increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

complex(p(HGNC:MAPT), p(HGNC:MAPT)) increases a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence f990a9e5a6
JSON

TOC1’s immunoreactivity is greatly elevated in AD brains compared with healthy controls, but co-localizes best with early-stage markers for AD pathogenesis such as pS422 [16]

a(HBP:"Tau oligomers") association p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

p(HGNC:MAPT, pmod(Ph, Ser, 422)) association a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") increases a(HBP:"Tau oligomers") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

Evidence 8e56771422
JSON

Tau’s primary role within neurons is thought to be the regulation and stabilization of microtubule dynamics [1,2]

bp(GO:"regulation of microtubule cytoskeleton organization") association p(HGNC:MAPT) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT) association bp(GO:"regulation of microtubule cytoskeleton organization") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 227f470f5d
JSON

We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition observed with a mixture of both forms of aggregated tau

complex(a(HBP:"Tau oligomers"), p(HGNC:HSPA1A)) decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence e3e12f53f8
JSON

However, our data indicate that Hsp70 preferentially binds to oligomeric as opposed to fibrillar tau aggregates and prevents anterograde FAT inhibition [31]

complex(a(HBP:"Tau oligomers"), p(HGNC:HSPA1A)) increases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Intracellular Space

Evidence 8d0521be29
JSON

Previous findings indicate that Hsp70 prevents tau toxicity by preserving tau in its soluble form and preventing it from aggregating by binding to exposed hydrophobic residues [33]

p(HGNC:HSPA1A) decreases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence d06b28cad5
JSON

It has also been demonstrated that Hsp70 can facilitate the degradation of pre-formed aggregates [33]

p(HGNC:HSPA1A) increases deg(a(HBP:"Tau aggregates")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence e47a5590ea
JSON

Tau reportedly exerts an effect on axonal transport by interfering and reducing the attachment frequency of the motor proteins to the microtubules [28]

p(HGNC:MAPT) decreases complex(a(GO:microtubule), a(MESH:Kinesin)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:MAPT) decreases complex(a(GO:microtubule), a(MESH:Dyneins)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 79b490c2a6
JSON

Furthermore, when Hsp70 was pre-incubated with the PAD peptide and introduced to the squid axoplasm, inhibition of FAT was still observed [31]

composite(p(HGNC:HSPA1A), p(HGNC:MAPT, frag("2_18"))) decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence 22aa2f1a22
JSON

Deletion analyses demonstrate that FAT inhibition requires a small stretch of amino acids (residues 2–18) located within the N-terminus that we have termed the PAD (phosphataseactivation domain) [21]

p(HGNC:MAPT, frag("2_18")) decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Intracellular Space

Evidence c06009f2d2
JSON

Further investigation illustrated that this inhibition occurs via activation of a signalling cascade involving PP1 (protein phosphatase 1) and GSK3 (glycogen synthase kinase 3) [24]

p(HGNC:GSK3A) decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

p(HGNC:PPP1CA) decreases bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

Evidence cf0d83bf4f
JSON

The tau protein becomes highly phosphorylated in AD and this is likely to induce a conformational change causing its detachment from microtubules and its accumulation in aggregates [3]

p(HGNC:MAPT, pmod(Ph)) increases a(HBP:"Tau aggregates") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space

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