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Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration. • P-tau217 correlates with brain atrophy and cognitive impairment in AD patients • Antibody against p-tau217 attenuates pathology and neuronal loss in tauopathic mice • P-tau217 antibody restores brain function and proteostasis in tauopathic mice • An antibody targeting total tau leads to motor deficits in tauopathic mice Zhang et al. demonstrate that passive immunotherapy targeting p-tau217 is an effective strategy for intervening in tau-associated pathology and neurodegeneration in a mouse model of tauopathy, with potentially little side effect. [ABSTRACT FROM AUTHOR]