3-O-sulfated heparan sulfates tailored by the 3-O-sulfotransferase-2 are essential for the pathologic phosphorylation of tau in Alzheimer s disease-related tau pathology

SEPULVEDA DIAZ, J.; OUIDJA O.; CHANTEPIE S.; HUYNH B.; SOCIAS B.; VILLARES J.; RAISMAN VOZARI R.; PAPY GARCÍA D.

Londres

Congreso; Alzheimer´s Disease Congress. 2014; 2014

European Scientific Conferences - Euroscicon

The accumulation of abnormally phosphorylated tau is a central event in Alzheimer?s disease. Although in vivo the critical pathologic phosphorylation of tau is assumed to be mediated by the same kinases that phosphorylate tau in normal brain, in vitro, these kinases abnormally phosphorylate tau at diseasespecific sites only if the enzymatic reaction takes place in the presence of certain polyanions such as heparin, a highly sulfated analogue of the complex heparan sulfates family of glycosaminoglycans. Currently, it is unknown whether this complex family of molecules, which structural and functional diversity in brain results from the action of several heparan sulfate sulfotransferases, is involved in the cellular mechanism leading to tau pathology. Recently, we have observed that specific heparan sulfate sulfotransferases are increased in Alzheimer?s disease brain and that the products of these enzymes are critically involved in the biochemical and cellular mechanisms leading to the pathologic phosphorylation of tau. Inhibiting the expression of one of these enzymes strongly attenuates the pathologic phosphorylation of tau induced in cells by oxidative stress or by expression of hTauP301L, indicating an essential role of specific heparan sulfates domains in the mechanism leading to the abnormal phosphorylation of tau at Alzheimer?s disease characteristic sites. We propose a novel hypothesis for the better comprehension of the pathophysiological mechanisms leading to Alzheimer?s disease related tauopathy, with groundbreaking therapeutic outcomes.