A novel TGFβ1–Hs3st2–tau axis regulates tau pathology and synaptic integrity

Introduction Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of tau protein. The hippocampus, a brain region crucial for learning and memory, is particularly susceptible to tau-induced damage. However, the molecular mechanisms underlying this vulnerability remain poorly understood. Here, we identified a novel TGFβ1–HS3ST2–tau signaling axis involved in tau pathology and synaptic impairment. Methods We used primary hippocampal neurons from a transgenic mouse model of tauopathy to investigate the relevance of TGFβ1 signaling on Hs3st expression and tau pathology. Loss-of-function (LOF) experiments targeting the neural Hs3st2 were conducted and cells were analyzed using transcriptomics, immunoblotting, and immunohistochemistry. Results TGFβ1 signaling enhanced Hs3st gene expression, linking neuroinflammation to altered HS biosynthesis. TGFβ1 was shown to regulate tau hyperphosphorylation and oligomerization through the accumulation of 3- O -sulfated heparan sulfate (3S-HS) made by Hs3st2 . Hs3st2 LOF significantly reduced 3S-HS levels, tau pathology, and synaptic alterations in hippocampal neurons. Discussion These findings define a new TGFβ1– Hs3st2 –tau axis in the hippocampus and highlight 3S-HS as a key modulator of tau pathology and synaptic dysfunction. Targeting this pathway may offer new therapeutic opportunities in tauopathies and related neurodegenerative disorders.