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Updated: Apr 15, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation
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.
Insights
Pro-aggregant Tau oligomers cause presynaptic damage and calcium dysregulation, impairing synaptic plasticity. Inhibiting Tau aggregation prevents these deficits, offering a potential therapeutic target for tauopathies.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Investigated presynaptic Tau pathology using a mouse model with inducible pro-aggregant Tau repeat domain (Tau(RDΔ)) mutation.
- Focused on Tau pathology in the hippocampus, specifically area CA3.
Purpose of the Study:
- To analyze presynaptic Tau pathology and its impact on synaptic function.
- To investigate the role of Tau aggregation in synaptic deficits and calcium dysregulation.
Main Methods:
- Utilized an inducible mouse model expressing pro-aggregant Tau(RDΔ).
- Performed electrophysiology in the mossy fiber tract and calcium imaging in neurons.
- Conducted ultrastructural analysis of synaptic vesicles and presynaptic markers.
Main Results:
- Pro-aggregant Tau(RDΔ) induced Tau phosphorylation, aggregation, and missorting in CA3.
- Synaptic transmission was impaired, and long-term depression failed in Tau(RDΔ) mice.
- Observed bouton size increase, decreased bouton numbers, presynaptic marker decline, and synaptic vesicle depletion.
- Showed Tau(RDΔ) caused calcium dysregulation in neurons, even without tangles.
- Demonstrated that inhibiting Tau(RDΔ) aggregation prevented structural deficits.
Conclusions:
- Oligomer formation by Tau(RDΔ) leads to pre- and postsynaptic structural deterioration.
- Tau(RDΔ) oligomers cause calcium dysregulation, resulting in synaptic plasticity deficits.
- Inhibition of Tau aggregation is a potential strategy to prevent Tau-induced synaptic pathology.
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