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Alzheimer’s disease (AD), which accounts for ~60% of senile dementia, is a neurodegenerative disorder marked by fibrillar aggregates of Aβ and tau. However, the underlying toxic species appear to be soluble aggregates (oligomers or protofibrils) of Aβ and tau, which may act as prion-like seeds. In human AD tissues, we discovered prion-like oligomeric tau seeds abundantly accumulating at synaptic terminals, which represent promising therapetuic targets. We collaborated with an industrial partner in Taiwan to develop a first-in-class immunotherapy (APNmAb005) against tau oligomers. APNmAb005 is a conformation-specific monoclonal antibody against tau aggregates (oligomers, protofibrils, and fibrils), which recently entered human AD clinical trial. In AD brain extracts, APNmAb005 selectively captures granular oligomers (>40 subunits) that are thioflavin S-positive. In tauopathy mice, APNmAb005 selectively recognizes pathological species arising in neurites instead of neuronal somas. Long-term treatments of APNmAb005 rescues neuronal and synaptic losses in tauoapthy mice. Despite recent advances in tau oligomer therapies, the origins, structures, and properties of tau oligomers in various tauopathies remain poorly understood. Our in vitro data suggest that liquid-liquid phase separation may be a critical first step for tau oligomer formation in the absence of polyanion aggregation inducers, eventually leading to fibrillar aggregates.