Intracellular heparan sulfates and tauopathy development in Alzheimer's Disease
Prof. Dulce Papy-Garcia
Unité de Recherche sur la Croissance, Réparation et Régénération Tissulaire (CRRET)
ERL CNRS 9215, Université Paris Est Créteil (UPEC).
Place: CEA Fontenay-aux-Roses, Building 52, Auditorium
Live broadcasting: Evry, Monod Room
Date and schedule: 14 June, 2018 - From 11am to 12:30pm
Organized by Bénédicte MARTIN
This seminar, organized by the François Jacob Institute of Biology (IBFJ), will focus on a new breaking hypothesis in which heparan sulfates (HS) are centrally involved in the early mechanims leading to Alzheimer's disease (AD).
Recent results
will be presented, supporting this new concept that highlights 3-O-sulfated HS, and their neural HS sulfotransferases, as new diagnostic and therapeutic targets in AD.
It will be followed by a discussion.
Alzheimer's disease (AD) is a slowly progressing non-linear brain disease in which pathophysiological abnormalities precede overt clinical symptoms by many years to decades. The best-known AD hallmarks are brain deposition of amyloid plaques (Aβ-peptides) and of neurofibrillary tangles (NFT) made essentially of abnormally phosphorylated tau.
Nevertheless, an established key abnormality that occurs decades before amyloid and NFTs deposition is the anomalous intracellular accumulation of heparan sulfates (HS) in the AD neurons.
Interestingly, this aberrant HS accumulation appears decades before the deposition of amyloids and NFTs in brain of Down syndrome patients, which inexorably evolve to AD. HS constitutes the sugar chains of HS proteoglycans (HSPG), which are classically located at the cell surface and in the extracellular matrix. Importantly, their intracellular accumulation in neurons of AD breaks the dogma of their extracellular location.
During biosynthesis, HSPG undergo numerous post-translational modifications leading to different HS structures that vary depending on the cell type or organ in which they are expressed. In brain, and more specifically in neural cells, HS are sulfated in the position "3" of their glucosamine. This sulfation is assured by neural HS 3-O-sulfotransferases that generate the 3-O-sulfated HS (3S-HS), rarely expressed or absent in other tissues. In AD neurons, 3S-HS are translocated into the intracellular compartment.
Our ongoing experiments strongly suggest a tight correlation between this event and the onset of tauopathy. In this talk, I will discuss a new breaking hypothesis in which HS are centrally involved in the early mechanisms leading to AD. I will present recent results supporting this new concept that highlights 3S-HS, and their neural HS sulfotransferases, as new diagnostic and therapeutic targets in AD.