Impact of CSGALNACT1-mediated structural changes in chondroitin sulfate on tau seed uptake and pathological progression

Chondroitin sulfate (CS) plays essential roles in neurodevelopment and brain aging. Alterations in glycosaminoglycan composition on the neuronal cell surface and within the extracellular matrix (ECM) contribute to the progression of tauopathies, including Alzheimer's disease (AD). Disease-associated changes in CS sulfation patterns have been linked to tau pathology, and administration of CS-specific antibodies has been shown to improve cognitive function in AD model mice. CSGALNACT1 catalyzes the initial step of CS chain elongation by transferring N-acetylgalactosamine residues to the linkage tetrasaccharide. Although csgalnact1-deficient mice exhibit structural alterations in perineuronal nets-specialized ECM structures surrounding neurons-as well as suppression of inflammatory diseases, the relevance of CSGALNACT1 to human neurodegenerative disorders remains unclear. Here, we investigated the role of CSGALNACT1 in AD by integrating human brain transcriptomic analyses with cell-based assays. We found that CSGALNACT1 expression decreased during healthy aging but was maintained or upregulated in AD brains in association with pathological progression. In Neuro2a cells, we observed CS-dependent tau seed uptake, which was significantly enhanced by CSGALNACT1 overexpression. Disaccharide analysis further revealed that CSGALNACT1 expression increased the abundance of non-sulfated CS disaccharide units (O units). Moreover, CS synthesized by CSGALNACT1 exhibited high affinity for both tau seeds and wild-type tau monomers and promoted tau aggregation in vitro. Together, these findings demonstrate that O unit-enriched CS chains generated by CSGALNACT1 facilitate extracellular tau capture, cellular uptake, and aggregation, thereby promoting tau pathology progression. This study identified CS structural regulation as a critical determinant of AD onset and progression.