Development of a robust, physiologically relevant neuronal tau aggregation assay for tau-related drug discovery

Therapeutic interventions to block extracellular tau seeding to prevent endogenous tau aggregation and progression of Alzheimer's disease pathology are currently being investigated in clinical trials. However, the translation of promising preclinical findings to benefit clinical outcomes remains problematic due to the lack of pathophysiological models that recapitulate key features of sporadic Alzheimer's disease-related tauopathies. We developed a primary neuronal tau (hTau) seeding and propagation model. Neurons expressing wild-type human tau protein at a physiological level, seeded with a sub-nanomolar tau derived from Alzheimer's disease brain tissues, rapidly and robustly form tau aggregates and develop impaired mitochondrial function. Resulting aggregates are quantitatively measured using automated high-content algorithms. The considerable pathophysiological relevance, coupled with a highly sensitive dynamic range, makes this assay a valuable model system for studying tau pathobiology and an efficient screening tool for modulators of tau aggregation. Using this model, we demonstrate that by targeting a phosphorylation-specific epitope of tau, an antibody effectively stops tau aggregation.