Investigating the effects of tau mutations on the activity of VQIVYK-targeting agents on tau seeding in neurodegenerative diseases

Tauopathies, including Alzheimer's disease and frontotemporal dementia, are a group of neurological disorders characterised by intracellular deposits of tau aggregates. Evidence suggests that pathogenic tau develops early in patients' brains and spreads in a prion-like manner between neurons. There is a recent interest in inhibitors targeting the VQIINK or VQIVYK motifs in tau's repeat 2-3 (R2R3) interface due to their role in tau prion-like seed formation. Notably, targeting VQIVYK blocks proteopathic seeding by tau fibrils. In humans, several missense mutations linked to genetic tau pathology occur within the tau repeat domain clustering near the R2R3 interface. The mutations near the R2R3 interface contribute to tau conformational rearrangement, transforming it from an inert to an early seed-competent form by perturbing the structure. Given the structural changes induced by mutations around the R2R3 interface and the location of VQIVYK, it is unclear how these mutations would influence the efficacy of VQIVYK-targeting inhibitors.