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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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Ultramicroscopy of mossy fiber boutons reveal severe synaptic vesicle reduction in mice expressing pro-aggregant TauRDΔ. (a-b) Electron micrographs of mossy fiber synapses from a control littermate (a) and pro-aggregant TauRDΔ transgenic mouse (b). While the presynaptic mossy fiber bouton of the control animal is densely filled with clear synaptic vesicles (a, arrow), vesicle accumulations are rare in presynaptic mossy fiber boutons from pro-aggregant TauRDΔ mice (b, arrow). Rather, large parts of the presynaptic bouton area in the mutant are almost free of vesicles (asterisks). S = postsynaptic complex spines protruding into the presynaptic bouton. Scale bar: 300 nm. (c) Length of active zones and (d) number of synaptic vesicles/μm2 in mossy fiber synapses from control (Ctrl) and TauRDΔ transgenic animals. While there is no statistically significant difference in the length of active zones of mossy fiber synapses between control mice and mutants, the number of vesicles/μm2 bouton area is dramatically decreased in TauRDΔ transgenic mice. Data expressed as mean ± standard deviation. 4 animals per group ***p < 0.001; n.s. not significant; az = active zone.
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Fig6: Ultramicroscopy of mossy fiber boutons reveal severe synaptic vesicle reduction in mice expressing pro-aggregant TauRDΔ. (a-b) Electron micrographs of mossy fiber synapses from a control littermate (a) and pro-aggregant TauRDΔ transgenic mouse (b). While the presynaptic mossy fiber bouton of the control animal is densely filled with clear synaptic vesicles (a, arrow), vesicle accumulations are rare in presynaptic mossy fiber boutons from pro-aggregant TauRDΔ mice (b, arrow). Rather, large parts of the presynaptic bouton area in the mutant are almost free of vesicles (asterisks). S = postsynaptic complex spines protruding into the presynaptic bouton. Scale bar: 300 nm. (c) Length of active zones and (d) number of synaptic vesicles/μm2 in mossy fiber synapses from control (Ctrl) and TauRDΔ transgenic animals. While there is no statistically significant difference in the length of active zones of mossy fiber synapses between control mice and mutants, the number of vesicles/μm2 bouton area is dramatically decreased in TauRDΔ transgenic mice. Data expressed as mean ± standard deviation. 4 animals per group ***p < 0.001; n.s. not significant; az = active zone.

Mentions: Mossy fiber boutons in the stratum lucidum of CA3 were easily identified by their unique fine-structural characteristics. Thus, the thin unmyelinated preterminal mossy fiber axons gave rise to giant boutons that were densely filled with clear synaptic vesicles. Postsynaptic complex spines protruded deeply into the presynaptic boutons. At low magnification, no major differences in the fine structure of mossy fiber boutons were noticed between control littermate animals and pro-aggregant mice (13 ± 1 month, 4 mice per group). In fact, an estimation of the lengths of synaptic contact zones (active zones; az, Figure 6a and b) did not reveal statistically significant differences between genotypes (control: 153.2 ± 31.8 nm; pro-aggregant mice 150.7 ± 36.1 nm; p = 0.80876, Figure 6c). However, we regularly noticed a reduction in the number of synaptic vesicles in the mossy fiber boutons of pro-aggregant animals. While vesicles were densely packed and almost completely filled the mossy fiber terminals of control littermates (Figure 6a), vesicle accumulations were rare in the boutons from transgenic mice, and there were frequent bouton areas containing only a few scattered vesicles (Figure 6b). Indeed, the number of synaptic vesicles/μm2 bouton area was significantly decreased in TauRDΔ transgenic mice when compared to control littermates (control: 206.1 ± 47.0 vesicles/μm2; transgenic mice 77.3 ± 21.5 vesicles/μm2; p = 7.4487 ×10−10, Figure 6d).Figure 6


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)

Ultramicroscopy of mossy fiber boutons reveal severe synaptic vesicle reduction in mice expressing pro-aggregant TauRDΔ. (a-b) Electron micrographs of mossy fiber synapses from a control littermate (a) and pro-aggregant TauRDΔ transgenic mouse (b). While the presynaptic mossy fiber bouton of the control animal is densely filled with clear synaptic vesicles (a, arrow), vesicle accumulations are rare in presynaptic mossy fiber boutons from pro-aggregant TauRDΔ mice (b, arrow). Rather, large parts of the presynaptic bouton area in the mutant are almost free of vesicles (asterisks). S = postsynaptic complex spines protruding into the presynaptic bouton. Scale bar: 300 nm. (c) Length of active zones and (d) number of synaptic vesicles/μm2 in mossy fiber synapses from control (Ctrl) and TauRDΔ transgenic animals. While there is no statistically significant difference in the length of active zones of mossy fiber synapses between control mice and mutants, the number of vesicles/μm2 bouton area is dramatically decreased in TauRDΔ transgenic mice. Data expressed as mean ± standard deviation. 4 animals per group ***p < 0.001; n.s. not significant; az = active zone.
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Fig6: Ultramicroscopy of mossy fiber boutons reveal severe synaptic vesicle reduction in mice expressing pro-aggregant TauRDΔ. (a-b) Electron micrographs of mossy fiber synapses from a control littermate (a) and pro-aggregant TauRDΔ transgenic mouse (b). While the presynaptic mossy fiber bouton of the control animal is densely filled with clear synaptic vesicles (a, arrow), vesicle accumulations are rare in presynaptic mossy fiber boutons from pro-aggregant TauRDΔ mice (b, arrow). Rather, large parts of the presynaptic bouton area in the mutant are almost free of vesicles (asterisks). S = postsynaptic complex spines protruding into the presynaptic bouton. Scale bar: 300 nm. (c) Length of active zones and (d) number of synaptic vesicles/μm2 in mossy fiber synapses from control (Ctrl) and TauRDΔ transgenic animals. While there is no statistically significant difference in the length of active zones of mossy fiber synapses between control mice and mutants, the number of vesicles/μm2 bouton area is dramatically decreased in TauRDΔ transgenic mice. Data expressed as mean ± standard deviation. 4 animals per group ***p < 0.001; n.s. not significant; az = active zone.
Mentions: Mossy fiber boutons in the stratum lucidum of CA3 were easily identified by their unique fine-structural characteristics. Thus, the thin unmyelinated preterminal mossy fiber axons gave rise to giant boutons that were densely filled with clear synaptic vesicles. Postsynaptic complex spines protruded deeply into the presynaptic boutons. At low magnification, no major differences in the fine structure of mossy fiber boutons were noticed between control littermate animals and pro-aggregant mice (13 ± 1 month, 4 mice per group). In fact, an estimation of the lengths of synaptic contact zones (active zones; az, Figure 6a and b) did not reveal statistically significant differences between genotypes (control: 153.2 ± 31.8 nm; pro-aggregant mice 150.7 ± 36.1 nm; p = 0.80876, Figure 6c). However, we regularly noticed a reduction in the number of synaptic vesicles in the mossy fiber boutons of pro-aggregant animals. While vesicles were densely packed and almost completely filled the mossy fiber terminals of control littermates (Figure 6a), vesicle accumulations were rare in the boutons from transgenic mice, and there were frequent bouton areas containing only a few scattered vesicles (Figure 6b). Indeed, the number of synaptic vesicles/μm2 bouton area was significantly decreased in TauRDΔ transgenic mice when compared to control littermates (control: 206.1 ± 47.0 vesicles/μm2; transgenic mice 77.3 ± 21.5 vesicles/μm2; p = 7.4487 ×10−10, Figure 6d).Figure 6

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