Using Human iPSC-Derived Neurons to Model TAU Aggregation.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alzheimer's disease and frontotemporal dementia are linked to abnormal TAU protein aggregation in the brain.
• Developing translational models is crucial for screening therapeutic compounds.

Purpose of the Study:

• To create a human TAU aggregation model using induced pluripotent stem cells (iPSC) for drug screening.
• To validate the model's responsiveness to autophagy inducers.

Main Methods:

• hiPSC-derived neural progenitor cells were transduced with a pro-aggregating TAU mutation (P301L).
• TAU aggregation and phosphorylation were quantified using AlphaLISA technology.
• The model was validated by testing the efficacy of autophagy inducers rapamycin and trehalose.

Main Results:

• Seeding with preformed TAU aggregates triggered robust TAU aggregation and hyperphosphorylation in iPSC-derived neurons.
• No spontaneous aggregation was observed without seeding.
• Both rapamycin and trehalose significantly reduced TAU aggregation levels.
• General cell health was not affected by the induced TAU aggregation.

Conclusions:

• iPSC-derived neurons provide a biologically relevant human Tauopathy model.
• This model is highly suitable for screening compounds that modulate TAU aggregation.
• The model shows promise for developing new treatments for neurodegenerative diseases involving TAU pathology.