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Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation.

Decker JM, Krüger L, Sydow A, Zhao S, Frotscher M, Mandelkow E, Mandelkow EM - Acta Neuropathol Commun (2015)

Bottom Line: Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation.In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation.We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: We used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.

Results: Expression of pro-aggregant Tau(RDΔ) leads to phosphorylation, aggregation and missorting of Tau in area CA3. To test presynaptic pathophysiology we used electrophysiology in the mossy fiber tract. Synaptic transmission was severely disturbed in pro-aggregant Tau(RDΔ) and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant Tau(RDΔ) mice. We observed an increase in bouton size, but a decline in numbers and presynaptic markers. Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant Tau(RDΔ) mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.

Conclusions: We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.

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Related in: MedlinePlus

TauRDΔexpression causes morphological changes of the DG - CA3 postsynapse in hippocampal organotypic slice cultures at DIV 10. (a) A DiI crystal was placed on the dentate gyrus of fixed hippocampal organotypic slices from pro-aggregant mice or control littermates. DiI labeled mossy fibers and CA3 pyramidal neurons were imaged 10 days later. (b) Nuclear counterstaining with TO-PRO was used to visualize hippocampal sub- regions. Arrows indicate DiI labeled mossy fibers. (c) Higher magnification of a single CA3 pyramidal neuron displays thorny excrescences (th.ex.) in the stratum lucidum and stratum oriens as well as projecting mossy fibers (mf) from the dentate gyrus granule cells with large boutons. (d) Examples of thorny excrescences dendritic spines from CA3 pyramidal neurons taken from control (Ctrl), pro-aggregant (Pro) and pro-aggregant slices treated with Tau aggregation inhibitor bb14 (Pro + bb14). (e) Dendritic spine density of CA3 neurons was reduced by ~20% in pro-aggregant (Pro) vs. control littermate slice cultures (Ctrl) (10 slices prepared from 5 different animals per group). This effect is abolished when pro-aggregant slice cultures are treated with the aggregation inhibitor bb14 (Pro + bb14) (One way ANOVA followed by Tukey’s post-hoc test ** p-value < 0.01; * p-value < 0.05). Error bars represent SEM.
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Fig4: TauRDΔexpression causes morphological changes of the DG - CA3 postsynapse in hippocampal organotypic slice cultures at DIV 10. (a) A DiI crystal was placed on the dentate gyrus of fixed hippocampal organotypic slices from pro-aggregant mice or control littermates. DiI labeled mossy fibers and CA3 pyramidal neurons were imaged 10 days later. (b) Nuclear counterstaining with TO-PRO was used to visualize hippocampal sub- regions. Arrows indicate DiI labeled mossy fibers. (c) Higher magnification of a single CA3 pyramidal neuron displays thorny excrescences (th.ex.) in the stratum lucidum and stratum oriens as well as projecting mossy fibers (mf) from the dentate gyrus granule cells with large boutons. (d) Examples of thorny excrescences dendritic spines from CA3 pyramidal neurons taken from control (Ctrl), pro-aggregant (Pro) and pro-aggregant slices treated with Tau aggregation inhibitor bb14 (Pro + bb14). (e) Dendritic spine density of CA3 neurons was reduced by ~20% in pro-aggregant (Pro) vs. control littermate slice cultures (Ctrl) (10 slices prepared from 5 different animals per group). This effect is abolished when pro-aggregant slice cultures are treated with the aggregation inhibitor bb14 (Pro + bb14) (One way ANOVA followed by Tukey’s post-hoc test ** p-value < 0.01; * p-value < 0.05). Error bars represent SEM.

Mentions: Next, we made use of organotypic slice cultures, since this system is particularly advantageous for long distance granule cell-CA3 axonal connections [38,39]. With DiI labeling we detected granule cell-CA3 mossy fiber connections in DIV 10 slices (Figure 4a and b), a time point when we already detected phosphorylated and mislocalized Tau in TauRDΔ slices (Figure 5d1-6), well comparable with results from acute slices. It was possible to label boutons as well as thorny excrescences in area CA3 (Figure 4c). In pro-aggregant slices the dendritic spine density (1.26 ± 0.07 spines/μm) was reduced by ~20% compared to control littermate slices (1.56 ± 0.07 spines/μm). This reduction was prevented by adding the Tau aggregation inhibitor bb14 [31] to pro-aggregant slices at DIV 0 (1.49 ± 0.05 spines/μm; F(2/81) = 5.851; p = 0.0042; Figure 4d,e).Figure 4


Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation.

Decker JM, Krüger L, Sydow A, Zhao S, Frotscher M, Mandelkow E, Mandelkow EM - Acta Neuropathol Commun (2015)

TauRDΔexpression causes morphological changes of the DG - CA3 postsynapse in hippocampal organotypic slice cultures at DIV 10. (a) A DiI crystal was placed on the dentate gyrus of fixed hippocampal organotypic slices from pro-aggregant mice or control littermates. DiI labeled mossy fibers and CA3 pyramidal neurons were imaged 10 days later. (b) Nuclear counterstaining with TO-PRO was used to visualize hippocampal sub- regions. Arrows indicate DiI labeled mossy fibers. (c) Higher magnification of a single CA3 pyramidal neuron displays thorny excrescences (th.ex.) in the stratum lucidum and stratum oriens as well as projecting mossy fibers (mf) from the dentate gyrus granule cells with large boutons. (d) Examples of thorny excrescences dendritic spines from CA3 pyramidal neurons taken from control (Ctrl), pro-aggregant (Pro) and pro-aggregant slices treated with Tau aggregation inhibitor bb14 (Pro + bb14). (e) Dendritic spine density of CA3 neurons was reduced by ~20% in pro-aggregant (Pro) vs. control littermate slice cultures (Ctrl) (10 slices prepared from 5 different animals per group). This effect is abolished when pro-aggregant slice cultures are treated with the aggregation inhibitor bb14 (Pro + bb14) (One way ANOVA followed by Tukey’s post-hoc test ** p-value < 0.01; * p-value < 0.05). Error bars represent SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4384391&req=5

Fig4: TauRDΔexpression causes morphological changes of the DG - CA3 postsynapse in hippocampal organotypic slice cultures at DIV 10. (a) A DiI crystal was placed on the dentate gyrus of fixed hippocampal organotypic slices from pro-aggregant mice or control littermates. DiI labeled mossy fibers and CA3 pyramidal neurons were imaged 10 days later. (b) Nuclear counterstaining with TO-PRO was used to visualize hippocampal sub- regions. Arrows indicate DiI labeled mossy fibers. (c) Higher magnification of a single CA3 pyramidal neuron displays thorny excrescences (th.ex.) in the stratum lucidum and stratum oriens as well as projecting mossy fibers (mf) from the dentate gyrus granule cells with large boutons. (d) Examples of thorny excrescences dendritic spines from CA3 pyramidal neurons taken from control (Ctrl), pro-aggregant (Pro) and pro-aggregant slices treated with Tau aggregation inhibitor bb14 (Pro + bb14). (e) Dendritic spine density of CA3 neurons was reduced by ~20% in pro-aggregant (Pro) vs. control littermate slice cultures (Ctrl) (10 slices prepared from 5 different animals per group). This effect is abolished when pro-aggregant slice cultures are treated with the aggregation inhibitor bb14 (Pro + bb14) (One way ANOVA followed by Tukey’s post-hoc test ** p-value < 0.01; * p-value < 0.05). Error bars represent SEM.
Mentions: Next, we made use of organotypic slice cultures, since this system is particularly advantageous for long distance granule cell-CA3 axonal connections [38,39]. With DiI labeling we detected granule cell-CA3 mossy fiber connections in DIV 10 slices (Figure 4a and b), a time point when we already detected phosphorylated and mislocalized Tau in TauRDΔ slices (Figure 5d1-6), well comparable with results from acute slices. It was possible to label boutons as well as thorny excrescences in area CA3 (Figure 4c). In pro-aggregant slices the dendritic spine density (1.26 ± 0.07 spines/μm) was reduced by ~20% compared to control littermate slices (1.56 ± 0.07 spines/μm). This reduction was prevented by adding the Tau aggregation inhibitor bb14 [31] to pro-aggregant slices at DIV 0 (1.49 ± 0.05 spines/μm; F(2/81) = 5.851; p = 0.0042; Figure 4d,e).Figure 4

Bottom Line: Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation.In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation.We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: We used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.

Results: Expression of pro-aggregant Tau(RDΔ) leads to phosphorylation, aggregation and missorting of Tau in area CA3. To test presynaptic pathophysiology we used electrophysiology in the mossy fiber tract. Synaptic transmission was severely disturbed in pro-aggregant Tau(RDΔ) and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant Tau(RDΔ) mice. We observed an increase in bouton size, but a decline in numbers and presynaptic markers. Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant Tau(RDΔ) mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.

Conclusions: We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.

Show MeSH
Related in: MedlinePlus