Development of a Scalable, High-Throughput-Compatible Assay to Detect Tau Aggregates Using iPSC-Derived Cortical...

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Tau aggregation into neurofibrillary tangles (NFTs) is a primary marker of Alzheimer's disease (AD) progression and cognitive decline.
• Limited success in targeting beta-amyloid necessitates exploring tau-centric therapeutic strategies, such as inhibiting tau phosphorylation and aggregation.
• Developing disease-relevant, scalable in vitro models is crucial for identifying novel AD treatments.

Purpose of the Study:

• To establish a robust and scalable human induced pluripotent stem cell (iPSC)-based model for tau aggregation.
• To adapt the model for high-throughput screening (HTS) to facilitate the discovery of new anti-AD therapies.
• To create a translational tool for identifying treatments targeting tauopathies.

Main Methods:

• Utilized human iPSCs to generate cortical neurons, providing a renewable source.
• Optimized cell culture for a 384-well plate format with Matrigel for enhanced neuronal protection and recapitulation of pathological conditions.
• Integrated AlphaLISA technology for high-throughput detection of tau aggregates.

Main Results:

• Developed a scalable and reproducible tau aggregation assay using iPSC-derived neurons.
• The assay effectively models key pathological features relevant to tauopathies and AD.
• Demonstrated assay compatibility with multiple commercial iPSC lines and across different users.

Conclusions:

• The developed iPSC-based tau aggregation model is a highly translational tool for drug discovery.
• This HTS-compatible assay represents a significant advancement in identifying novel therapeutic strategies for Alzheimer's disease and other tauopathies.
• The model's robustness and scalability offer a promising platform for accelerating the development of effective treatments.