A novel TGFβ1–Hs3st2–tau axis regulates tau pathology and reduces synaptic alterations in hippocampal neurons

Abstract

Tauopathies are neurodegenerative diseases characterized by the pathologic accumulation of tau protein. The hippocampus, a brain region critically involved in memory and learning, is particularly vulnerable to damage in neurodegeneration. However, the molecular mechanisms underlying its susceptibility remain poorly understood. Here, we identify a novel signaling axis, involving TGF-β1, HS3ST2, a 3-O-heparan sulfate (HS) sulfotransferase (HS3ST) and tau that contributes to tau pathology and synaptic dysfunction through accumulation of 3-O-sulfated HS (3S-HS). By using a transgenic murine model of tau pathology, we show that expression of 3S-HS biosynthetic genes — particularly Hs3st1, Hs3st2 and Hs3st4 — is increased early during tau pathology development in the hippocampus. Primary cultures of hippocampal cells from this mouse model allowed to further demonstrate that TGF-β1 signaling is upregulated in this model and enhances Hs3sts expression, linking neuroinflammatory signals to altered 3S-HS biosynthesis and tau pathology. Notably, we found that Hs3st2 plays a key role in abnormal tau phosphorylation and oligomerization in the cultured hippocampal neurons, as that its loss-of-function (LOF) significantly reduced tau pathology. Transcriptomic and immunohistochemical analysis revealed that Hs3st2 LOF specifically decreases 3S-HS levels, reduces tau pathology, and synaptic alterations. These findings define a novel TGF-β1–Hs3st2–tau axis and highlight 3S-HS as a critical and potentially targetable driver of tau pathology and synaptic dysfunction in neurodegeneration.