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09:22
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Are tau aggregates toxic or protective in tauopathies?
Catherine M Cowan1, Amrit Mudher
1Centre for Biological Sciences, University of Southampton , Southampton , UK.
Frontiers in Neurology
|August 22, 2013
Summary
Highly phosphorylated tau causes toxicity in tauopathies, independent of aggregation. Some insoluble tau aggregates, like oligomers, may be protective, challenging current therapeutic strategies targeting aggregate dissolution.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Tauopathies, including Alzheimer's disease, are characterized by aggregated tau.
- Therapeutic strategies often target tau phosphorylation or aggregation.
- Emerging evidence suggests soluble, hyper-phosphorylated tau species drive toxicity.
Purpose of the Study:
- To investigate the role of soluble hyper-phosphorylated tau in tauopathy.
- To determine the impact of GSK-3β inhibition on tau species and toxicity.
- To assess the toxicity of different tau aggregate forms.
Main Methods:
- Utilized a Drosophila model expressing wild-type human tau.
- Administered pharmacological and genetic inhibition of GSK-3β.
- Assessed behavioral deficits, synaptic function, axonal transport, and cytoskeletal stability.
- Analyzed tau phosphorylation, aggregation state, and species solubility.
Main Results:
- Highly phosphorylated wild-type human tau induced behavioral deficits, synaptic dysfunction, and axonal transport disruption without neuronal death or filament formation.
- GSK-3β inhibition rescued tau phenotypes but increased tau levels and generated insoluble tau oligomers.
- Not all insoluble tau aggregates were toxic; some tau oligomers appeared non-toxic or even protective.
Conclusions:
- Tau toxicity in tauopathies is mediated by soluble, hyper-phosphorylated tau species, not necessarily insoluble aggregates.
- Inhibiting tau aggregation may be counter-productive if it leads to the formation of toxic soluble species.
- Future therapies should focus on identifying and targeting specific toxic tau species rather than broadly dissolving all aggregates.
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