The propagation of pathological tau protein in neuronal cells is a critical driver of neurodegeneration in tauopathies, including Alzheimer's disease. Heparan sulfate (HS) critically regulates pathological tau seeding and cellular uptake processes closely linked to the development of tau pathology in tauopathies, identifying HS as a key potential therapeutic target. Here, we focused on targeting Exostosin-1 (Ext1), an essential enzyme for HS biosynthesis, in the tau P301S transgenic (PS19) tauopathy mouse model. Conditional knockdown of neuronal Ext1 in PS19 mice by delivering an adeno-associated viral vector expressing Ext1 shRNA decreased neuronal HS levels, resulting in reduced pathological tau phosphorylation, enhanced synaptic function, and restored cognitive performance. Notably, decreasing neuronal Ext1 impeded the intercellular spread of human tau in the mouse brain. Furthermore, treating disease-onset PS19 mice with an antisense oligonucleotide targeting Ext1 ameliorated tau aggregation, improved behavioral deficits, and attenuated neurodegeneration and neuroinflammation. These results suggest that inhibiting tau propagation by targeting Ext1-mediated HS production could be a promising gene therapy approach for tauopathies.
Huang et al. (Thu,) studied this question.