Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules

IntroductionTau pathology is a major feature of Alzheimer’s disease (AD) and multiple other adult-onset neurodegenerative diseases. Aberrant exposure of an N-terminal phosphatase-activating domain (PAD) is characteristic of pathological tau, representing a toxic gain of function. Exposure of the PAD in pathological tau leads to dysregulation of protein phosphatase 1/glycogen synthase kinase 3 (PP1/ GSK3β) signaling, inhibition of fast axonal transport, synaptic dysfunction, and altered transcrip