AbstractBackgroundTau pathologies contribute to neurodegeneration in Alzheimer’s Disease (AD) and other disorders via a variety of mechanisms. In tauopathy mouse models, administration of LM11A‐31 (C31), a small molecule modulator of the p75 neurotrophin receptor (p75NTR), reduced tau post‐translational modifications, accumulation of pathological tau species and microglial activation; restored synaptic plasticity, and reversed synaptic spine loss. We examined long‐term dosing with C31 at the single‐cell transcriptional level to further elucidate cell types and cellular mechanisms affected by treatment.MethodTauopathy model tauP301S mice (PS19) and age‐matched wildtype (Wt) mice were dosed by oral gavage with C31 or vehicle once daily for 3 months from 6 months of age, when tau pathology was well established. Whole cortex single‐nucleus RNA‐sequencing was analyzed using Seurat, with automated cell type annotation, followed by manual curation. Additional analyses compared AD‐associated biodomains and risk scored genes from TREAT‐AD with individual cell types. Finally, cell‐to‐cell communication was assessed via Liana ligand‐receptor (LR) interaction analysis.ResultSeveral neuronal, glial, and vascular cell types showed inverse correlations between C31 differential expression and both PS19 differential expression and TREAT‐AD biodomains (Figure 1), suggesting shifts in expression profiles in the opposite direction from those in human AD cohorts and mouse tauopathy models. In LR interaction analysis, vascular and leptomeningeal cells (VLMCs) were highly active as a signaling source to most other cells—particularly neurons—in the PS19 vehicle mice compared to all other groups (Figure 2). VLMC LR signals that were stronger in PS19 vehicle mice versus Wt vehicle were enriched for Focal Adhesion/PI3K‐Akt signaling, TGF‐beta signaling, AD‐presenilin pathways and regulation of synapse organization (Figure 3). VLMC LR signals that were stronger in PS19 C31 versus PS19 vehicle showed similar pathway enrichments and included several neuropilin‐semaphorin‐plexin complexes which may direct neuronal wiring and development.ConclusionThese findings demonstrate that broad patterns of expression and LR signaling in multiple cell types impacted by tauopathy show substantial reversion to wildtype‐like patterns when treated with C31. Further they indicate a possible role for VLMC signaling in the pathogenesis of tauopathies.