Stacked binding of a small molecule PET tracer to Alzheimer’s tau paired helical filaments

Neurodegenerative diseases (NDs) are characterized by the formation of amyloid filaments that adopt disease-specific conformations in the brain. Recently developed small molecules hold promise as diagnostics and possible therapeutics for NDs, but their binding mechanisms to amyloid filaments remain unknown. Here, we used cryo–electron microscopy (cryo-EM) to determine a 2.7 Å structure of Alzheimer’s disease patient-derived tau paired-helical filaments incubated with the GTP-1 PET probe. GTP-1 is bound stoichiometrically along an exposed cleft of each protofilament in a stacked arrangement that matches the fibril’s symmetry. Multiscale modeling revealed favorable pi-pi aromatic stacking interactions between GTP-1 molecules that, together with small molecule–protein contacts, result in high affinity binding. This binding mode offers new insight into designing compounds for diagnosis and treatment of specific NDs. One Sentence Summary Cryo-EM structure reveals a novel stacked arrangement of the GTP-1 PET ligand bound to Alzheimer’s disease tau filaments. ### Competing Interest Statement S.B.P. is the founder of Prio-Pharma, which did not contribute support for this study. W.F.D. is a member of the scientific advisory boards of Alzheon Inc., Pliant, Longevity, CyteGen, Amai, and ADRx Inc., none of which contributed support for this study.