PubMed: 29202785

Anti-aggregant tau mutant promotes neurogenesis.
Molecular neurodegeneration
Anglada-Huguet M | Joseph M | Mandelkow E | Mandelkow EM | Paesler K

Evidence 2d1b30eb15

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)

Evidence e1b663ce6f

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

Evidence 84cfee5a50

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)

Evidence ebf5a9bd24

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

Evidence 31f7847402

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)

Evidence b2ce8be98b

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

Evidence 370de481ae

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)

Evidence 493845462b

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)

Evidence beea1317d4

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)

Evidence caf7df093f

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)

Evidence 23e0bfcc8a

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)

Evidence a426526a19

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)

Evidence dc02ed5596

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

Evidence a292ece65b

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

Evidence e82a233ccf

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

Evidence 6c1dc6c139

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).

Evidence 9b868e813e

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

Evidence 3d3e65fb9c

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)

Evidence 98c13fadb9

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)

Evidence fe3b49e091

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)

Evidence e254ca7294

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)

Evidence 43647b7bc1

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

Evidence efbb7ef1fb

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).

Evidence 19183049dd

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)

Evidence 9217337452

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

Evidence dc504dadc8

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)

Evidence ce558732ce

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)

Evidence c4f2adea5d

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)

Evidence 54c2426c0b

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)

Evidence 9d840709cc

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

Evidence b04c32d8e7

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)

Evidence d99c166fbc

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)


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