Background: Deposition of amyloid plaques and neurofibrillary tangles composed of abnormally phosphorylated tau are the neuropathological hallmarks of Alzheimer's disease (AD). However, years before the accumulation of protein aggregates, the abnormal intraneuronal accumulation of heparan sulfates (HS) is observed. This phenomenon breaks a dogma, since HS are classically located on the cell surface and in the extracellular matrix, leading to a new cell autonomous concept in tauopathy, which is the conceptual core of the FET-OPEN ArrestAD 737390 project. Previously, we provide evidence that inside the cell, HS act as molecular chaperones inducing in Tau conformational changes favoring its abnormal phosphorylation and aggregation (Sepulveda-Diaz JE. Brain 2015, 138(Pt 5):1339-54). Thus, molecules able to act on heparan sulfate pathway could represent a new class of compounds for the treatment of AD-related tauopathies.Method: PAPS is the universal sulfate donor involved in HS biosynthesis and structurally related to ATP. Thus, we first screened kinase inhibitor libraries in a sulfotrans-
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