Development of iPSC-based assays for drug development in neuroscience: tauopathies as an entry point

Tau aggregation is the pathological hallmark that best correlates with the progression of Alzheimer's Disease (AD). The presence of neurofibrillary tangles (NFTs), formed of hyperphosphorylated tau, leads to neuronal dysfunction and loss, and is directly associated with the cognitive decline observed in AD patients. The limited success in targeting ?-amyloid pathologies has reinforced the hypothesis of blocking tau phosphorylation, aggregation and/or spreading as alternative therapeutic entry points to treat AD. Identification of novel therapies requires disease-relevant and scalable assays capable of reproducing key features of the pathology in an in vitro setting. Here we will present our work using induced pluripotent stem cells (iPSC) as a virtually unlimited source of human cortical neurons to develop a robust and scalable tau aggregation model compatible with high throughput screening (HTS). We have downscaled cell culture conditions to 384-well plate format and used matrigel to introduce an extra physical protection against cell detachment that reduces shearing stress and better recapitulates pathological conditions. We complemented the assay with AlphaLISA technology for the detection of tau aggregates in a high throughput-compatible format. The assay is reproducible across users and works with different commercially available iPSC-lines, representing a highly translational tool for the identification of novel treatments against tauopathies including AD. In addition, we will be presenting the current efforts made in Europe to validate and consolidate iPSC technology as a robust tool for biomedical research: the European Bank of iPSCs (EBiSC).