Abstract In Alzheimer’s disease (AD) and related tauopathies, tau neuropathology correlates with severity of dementia. However, interventions for AD and AD related dementias (ADRDs) are limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration. This underscores the need for tau-targeted disease-modifying therapeutics. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy involves the MSUT2 CCCH domain binding to poly(A) RNA, as deletion of the CCCH domain suppresses neurodegeneration in mouse models of tauopathy. The identification of single chain antibody or nanobody leads that inhibit MSUT2 from binding to poly(A) RNA will provide a biologic means of intervening against tauopathy. We hypothesize that biologic antagonism of MSUT2/poly(A) RNA-binding after onset of pathological tau deposition will reverse the toxic consequences of pathological tau. The specific aims of this proposal will develop potent and specific brain-penetrant biologic based approaches to target MSUT2 and use them to dissect the temporal and mechanistic relationship between MSUT2 activity and tauopathy. Completion of the project as proposed will also further demonstrate the importance of MSUT2 in tauopathy. This knowledge will set the stage for future translational studies by both generating MSUT2 specific lead biologic agents and further validating a novel candidate therapeutic target for intervention in tauopathy disorders.