Heparan sulfates involved in early Alzheimers disease

Heparan sulfates (HS) are classically located in cell membranes and extracellular matrices, from where they participate to in the regulation of tissue homeostasis. However, in Alzheimers disease, HS accumulate in neurites and intracellularly colocalize with neurofibrillary tangles. Previously, we showed that the neural 3-O HS sulfotransferase-2 (HS3ST2), which produces 3-O-sulfated HS (3S-HS), is critically involved in the process leading to the abnormal phosphorylation of tau. However, whether 3S-HS are implicated in tauopathy development at the synapse, where tauopathy likely starts, remains unknown. Here, we used rTg4510 mice primary hippocampal neurons and synaptosomes to demonstrate that 3S-HS are involved in tauopathy development and at the synapse. In vivo, we showed that at early disease stages Hs3st2 loss of function reverses tau pathology. Our results illustrate the Hs3st2 and 3S-HS implication in tauopathy development in hippocampal neurons and at the synapse, opening a new field to better understand the processes leading to Alzheimers disease-related tauopathy.