Heparan sulfate sulfotransferases and pathological phosphorylation of tau in Alzheimer’s disease

• Autorzy: Papy Garcia D. , Chantepie S. , Maiza A. , Vera C. , Huynh M.B. , Ouidja O.M.
• Języki publikacji: EN

Abstrakty

EN

Heparan sulfates (HS) are the long and linear glycanic moieties of HS proteoglycans (HSPG). Although HSPG are classically located at the cell membrane and in the extracellular matrix, they are found to accumulate at the intracellular level in Alzheimer’s disease (AD) degenerating neurons, in where they co‑localize with tau in neurofibrillary tangles (NFT). The intracellular accumulation and co-localization of HS with tau in AD neurons suggest a possible role of these complex polysaccharides in the mechanisms leading to the abnormal phosphorylation and aggregation of tau in the neural cells. To explore this possibility, we investigated whether internalization of membrane-associated HS can occur in cell models of tauopathy, and studied the consequences of their internalization in the hyper phosphorylation of tau in vitro and in vivo. We also investigated HS structural insights associated to these events by analyzing the expression of HS biosynthetic enzymes in the AD brain. Our results show that the intracellular interaction of HS with tau induces the tau hyper phosphorylation through a mechanism involving conformational changes in the protein upon contact with HS. Analysis of the HS biosynthetic enzymes in the AD brain suggested the implication of HS 3-O-sulfation in the tau hyper phosphorylation event. Accordingly, inhibition of HS 3-O-sulfotransferase-2 (HS3ST2) in an animal model of tauopathy resulted in a strong reduction of abnormally phosphorylated tau epitopes and animal recovery. These results suggest that HS and their sulfotransferases play critical roles in the development of AD-related tau pathology.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.28

Twórcy

autor

Papy Garcia D.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France

autor

Chantepie S.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France

autor

Maiza A.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France

autor

Vera C.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France

autor

Huynh M.B.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France

autor

Ouidja O.M.

• Cell Growth and Tissue Repair Laboratory (CRRET) CNRS 9215, Faculty Sciences and Technology, Universite Paris Est Creteil, Paris, France