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

<h4>Introduction</h4>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.<h4>Methods</h4>We used primary hippocampal neurons from a transgenic mouse model of tauopathy to investigate the relevance of TGFβ1 signaling on <i>Hs3st</i> expression and tau pathology. Loss-of-function (LOF) experiments targeting the neural <i>Hs3st2</i> were conducted and cells were analyzed using transcriptomics, immunoblotting, and immunohistochemistry.<h4>Results</h4>TGFβ1 signaling enhanced <i>Hs3st</i> gene expression, linking neuroinflammation to altered HS biosynthesis. TGFβ1 was shown to regulate tau hyperphosphorylation and oligomerization through the accumulation of 3-<i>O</i>-sulfated heparan sulfate (3S-HS) made by <i>Hs3st2</i>. <i>Hs3st2</i> LOF significantly reduced 3S-HS levels, tau pathology, and synaptic alterations in hippocampal neurons.<h4>Discussion</h4>These findings define a new TGFβ1-<i>Hs3st2</i>-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.