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PubMed: 29202785

Title
Anti-aggregant tau mutant promotes neurogenesis.
Journal
Molecular neurodegeneration
Volume
12
Issue
None
Pages
88
Date
2017-12-04
Authors
Anglada-Huguet M | Joseph M | Mandelkow E | Mandelkow EM | Paesler K

Evidence 2d1b30eb15
JSON

However, when the expression of the antiaggregant TauRDΔKPP was switched off by DOX, there was an even more pronounced reduction in Wnt5a level (Fig. 10a, lane 3, bar 3)

a(CHEBI:doxycycline) decreases p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) View Subject | View Object

Appears in Networks:

a(CHEBI:doxycycline) decreases p(MGI:Wnt5a) View Subject | View Object

Appears in Networks:

Evidence e1b663ce6f
JSON

Remarkably, this caused a 40% reduction of the Wnt3 level compared to control slices (Fig. 10b, lane 3, bar 3)

a(CHEBI:doxycycline) decreases p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) View Subject | View Object

Appears in Networks:

a(CHEBI:doxycycline) decreases p(MGI:Wnt3) View Subject | View Object

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases p(MGI:Wnt3) View Subject | View Object

Appears in Networks:

Evidence 84cfee5a50
JSON

In controls and anti-aggregant TauRDΔKPP slices, the microglia were mainly in the ramified form, in contrast to the pro-aggregant TauRDΔK slices where microglia were more of the reactive form (Fig 3b)

act(a(MESH:Microglia)) negativeCorrelation p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) negativeCorrelation act(a(MESH:Microglia)) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence ebf5a9bd24
JSON

On the contrary, microglia in proaggregant TauRDΔK slices, were increased in number and were also observed with 2-3 branches on an average compared to age-matched controls and also the antiaggregant TauRDΔKPP slices (Fig. 3d, bar 3). This indicates that in the pro-aggregant TauRDΔK slices the microglia are in a reactive form, indicating that there is also enhanced inflammation

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence 31f7847402
JSON

Microscopic analysis revealed a remarkable overall increase (30%) in the size of the hippocampus of anti-aggregant TauRDΔKPP OHSCs, compared to controls and the age-matched proaggregant TauRDΔK slices (Fig. 2a)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:

Evidence b2ce8be98b
JSON

Additionally, there was an increase by 25% of the hippocampal volume in anti-aggregant TauRDΔKPP mice, compared to controls at P8 (Fig. 8c, bar 2), presumably due to the increased number of neurons

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence 370de481ae
JSON

The anti-aggregant TauRDΔKPP mice had an increased hippocampal volume of ~15% compared to agematched controls but it was not a significant increase as analyzed by bonferroni post hoc test (Fig. 9a, bar 2) in contrast mice expressing pro-aggregant TauRDΔK had a 25% reduced hippocampal volume (Fig. 9a, bar 3)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Hippocampus) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence 493845462b
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This revealed an impressive increase in mature neurons in all regions of the hippocampus (47% in CA1; 69% in CA3 and 81% in DG) in the anti-aggregant TauRDΔKPP slices compared to age-matched controls (Fig. 2c, bars 2, 5 and 8)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence beea1317d4
JSON

Notably, after switch-off of antiaggregant TauRDΔKPP there was a change in the number of BrdU stained cells in all regions of the hippocampus (CA1 region 32%, CA3 region 22% and DG 33% reduction) compared to switch-ON conditions (Fig. 7a, bars 4, 8 and 12)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence caf7df093f
JSON

Similarly in the number of NeuN positive cells, there was a 22% reduction in CA1, 33% in CA3 and 37% reduction in DG compared to switch-On conditions (Fig. 7b, bars 4, 8 and 12)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:

Evidence 23e0bfcc8a
JSON

BrdU positive cells were present in CA1, CA3 and DG in both the controls and antiaggregant TauRDΔKPP groups (Fig. 8a, b), but their numbers were increased strongly by 80% only in the CA3 region of the anti-aggregant TauRDΔKPP mice (Fig. 8b, bar 4), with 20% change in the CA1 and no change in the DG (Fig. 8b, bar 2 and 6)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence a426526a19
JSON

Surprisingly, the anti-aggregant TauRDΔKPP mice had an increased neuronal number significantly in the CA3 region (20%, Fig. 9b, bar 5), in contrast to the pro-aggregant TauRDΔK mice where neuronal loss (e.g. CA1 ~50%, CA3 ~10%, DG ~25%) was observed in all regions of the hippocampus (Fig. 9b, bar 3, 6, 9)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

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

Appears in Networks:
Annotations
MeSH
Hippocampus

Evidence dc02ed5596
JSON

This suggests that the expression of anti-aggregant TauRDΔKPP is needed for the increased proliferation of newborn neurons, and since these new born neurons need endogenous mouse Tau for their migration, differentiation, and maturation, there is enhanced expression of endogenous mouse Tau

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:Neurons) View Subject | View Object

Appears in Networks:

p(MGI:Mapt) increases bp(GO:"neuron maturation") View Subject | View Object

Appears in Networks:

p(MGI:Mapt) increases bp(GO:"neuron migration") View Subject | View Object

Appears in Networks:

p(MGI:Mapt) increases bp(GO:"neuron differentiation") View Subject | View Object

Appears in Networks:

Evidence a292ece65b
JSON

Thus, pro-aggregant TauRDΔK causes neurodegeneration, whereas anti-aggregant TauRDΔKPP leads to neurogenesis, even in regions outside the DG

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases bp(GO:neurogenesis) View Subject | View Object

Appears in Networks:

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

Appears in Networks:

Evidence e82a233ccf
JSON

Total numbers of Iba1 positive microglial cells were reduced to 50% in anti-aggregant TauRDΔKPP slices when compared to controls (Fig. 3c, bar 2)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) decreases a(MESH:Microglia) View Subject | View Object

Appears in Networks:

Evidence 6c1dc6c139
JSON

The antiaggregant TauRDΔKPP slices had ramified form of microglia with 6-7 branches on an average indicating that the microglial cells were in their normal physiologically active form and there is no sign of inflammation (Fig 3d, bars 1 and 2).

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) causesNoChange act(a(MESH:Microglia)) View Subject | View Object

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) causesNoChange path(MESH:Inflammation) View Subject | View Object

Appears in Networks:

Evidence 9b868e813e
JSON

In the controls and the antiaggregant TauRDΔKPP slices there was a uniform axonal distribution of Tau in the hippocampus (Fig. 5, A1 and 2)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases p(MGI:Mapt) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Axons
MeSH
Hippocampus

Evidence 3d3e65fb9c
JSON

Surprisingly, there was an ~80% increase in the endogenous mouse Tau level in slices obtained from pups expressing anti-aggregant TauRDΔKPP (Fig. 5b lane 2 and 5c bar 2), compared with age matched non-transgenic controls and pro-aggregant TauRDΔK (Fig. 5b lane 1 and 3; and 5c lane 1 and 3)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases p(MGI:Mapt) View Subject | View Object

Appears in Networks:

Evidence 98c13fadb9
JSON

In spite of this increase, there was little mislocalization of Tau (endogenous or exogenous) into the somatodendritic compartment in the anti-aggregant TauRDΔKPP (Fig. 5, A2)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases tloc(p(MGI:Mapt), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) View Subject | View Object

Appears in Networks:

Evidence fe3b49e091
JSON

From DIV15 until DIV30 the anti-aggregant slices were treated with DOX to switch off the expression of the anti-aggregant Tau. This lead to a strong reduction (~70%) of the endogenous mouse Tau (Fig. 10c, lane3)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases p(MGI:Mapt) View Subject | View Object

Appears in Networks:

Evidence e254ca7294
JSON

However, in case of the anti-aggregant TauRDΔKPP slices there was a remarkable 30% increase in the number of BrdU positive cells in the CA1 and CA3 regions and almost 100% increase in DG (Fig. 6b, bar 2, 5, and 8)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases a(MESH:"Stem Cells") View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence 43647b7bc1
JSON

In particular in the CA3 and DG regions almost 70% and in CA1 almost 50% of the new born cells got differentiated into NeuN positive neurons in the anti-aggregant TauRDΔKPP slices (Additional file 2: Figure S1A, bars 4, 8, 12).This reveals an increase in proliferation followed by an increase in neuronal differentiation in the anti-aggregant TauRDΔKPP slices

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases bp(GO:"neuron differentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence efbb7ef1fb
JSON

Surprisingly there was a 50% reduction in the amount of Wnt5a protein in anti-aggregant TauRDΔKPP slices compared to controls (Fig. 10a, lane 2, bar 2).

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) decreases p(MGI:Wnt5a) View Subject | View Object

Appears in Networks:

Evidence 19183049dd
JSON

Unexpectedly the Wnt3 levels in the anti-aggregant TauRDΔKPP slices were increased substantially (up to 85%) compared to the agematched control slices (Fig. 10b, lane 2, bar 2)

p(HBP:"Tau isoform F (441 aa)", var("p.Ile277Pro"), var("p.Ile308Pro"), var("p.Lys280del")) increases p(MGI:Wnt3) View Subject | View Object

Appears in Networks:

Evidence 9217337452
JSON

This may be due to the strong Tau pathology of the toxic pro-aggregant TauRDΔK leading to Tau aggregation, loss of synapses and loss of neurons

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

Appears in Networks:

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

Appears in Networks:

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

Appears in Networks:

Evidence dc504dadc8
JSON

By contrast, the pro-aggregant TauRDΔK slices showed a pronounced reduction in neuronal numbers, particularly in the CA1 (-44%), CA3 (-33%) and DG (-22%) regions compared to controls (Fig. 2c, bars 3, 6 and 9)

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

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence ce558732ce
JSON

The opposite result was observed in the pro-aggregant TauRDΔK slices where the microglial number was increased by 100% compared to controls (Fig. 3c, bar 3)

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

Appears in Networks:

Evidence c4f2adea5d
JSON

On the contrary the proaggregant TauRDΔK slices showed hypertrophic astrocytes with prominent cell bodies with 1-3 processes ranging from 3-5μm in length, which can be compared to the degrading forms of astrocytes (Fig. 4a3)

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

Appears in Networks:
Annotations
Cell Ontology (CL)
astrocyte

Evidence 54c2426c0b
JSON

The pro-aggregant TauRDΔK slices showed intense mislocalization of Tau in the somato-dendritic compartment, the most affected being the CA3 pyramidal neurons (Fig. 5, A3)

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases tloc(p(MGI:Mapt), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) View Subject | View Object

Appears in Networks:

Evidence 9d840709cc
JSON

By contrast, pro-aggregant TauRDΔK slices showed no overall increase in endogenous mouse Tau (rather a 20% decrease), yet pronounced mislocalization (Fig. 5, A3).

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) causesNoChange p(MGI:Mapt) View Subject | View Object

Appears in Networks:

p(HBP:"Tau isoform F (441 aa)", var("p.Lys280del")) increases tloc(p(MGI:Mapt), fromLoc(GO:axon), toLoc(GO:"somatodendritic compartment")) View Subject | View Object

Appears in Networks:

Evidence b04c32d8e7
JSON

This was in striking contrast to the pro-aggregant TauRDΔK slices where there was no significant difference in the number of BrdU positive cells compared to the age matched controls (Fig. 6b, bar 3, 6, and 9)

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

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal
MeSH
CA3 Region, Hippocampal
MeSH
Dentate Gyrus

Evidence d99c166fbc
JSON

This also resulted in a 30% increase in the rate of differentiation in the CA1 region of the pro-aggregant TauRDΔK slices (Additional file 2: Fig. S1B, bars 2 and 4)

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

Appears in Networks:
Annotations
MeSH
CA1 Region, Hippocampal

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