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Oulfa Ben Abdelouahab: Prix du meilleur poster "biologie" des 3èmes journées scientifiques du GDR

 

 

Heparan sulfates and sulfotransferases: importance in the diagnosis of Alzheimer’s disease

Oulfa Ben Abdelouahab1, Nicolas Rebergue1, Audrey Ridoux1, Nadjia Younsi2, Sandrine Chantepie-Laborde1, Gael Le Douaron1, Gilles Carpentier1, Fabrice Allain3, Bruno Dubois2, Dulce Papy-Garcia1*, Alexandre Fifre1*

1 Laboratoire CRRET CNRS ERL 9215 - EA 4397

2 Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A)

Université de Lille CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France

* PhD supervisors

 

Alzheimer's disease (AD) is a neurodegenerative pathology of the central nervous system characterized by a progressive and irreversible decrease in memory and cognitive functions. Despite the identification of several genetic and/or environmental risk factors, the exact causes of the disease as well as the cellular and molecular origins of its evolution are currently still largely unknown. This pathology is characterized by two types of lesions: neurofibrillary tangles (NFT) and amyloid or senile plaques (SP), which are also associated with an inflammatory process that undeniably contributes to the evolution of the pathology. In addition, some studies show that abnormal intracellular accumulation of heparan sulfates (HS) in the neurons of AD patients occurs well before NFT and SP.  However, there is currently no molecular or structural mechanism to explain this abnormal intracellular accumulation of HS or its potential link to the development of AD characteristics.

HS are part of the glycosaminoglycan’s family (GAGs linked to protein bodies thus forming proteoglycans (PG) with heparan sulfate chain (HSPG)). HSPG has long been considered as only localized on the cell surface and composing the extracellular matrix. However, we have demonstrated the intracellular co-location of HS with the hyperphosphorylated Tau protein, a major component of NFT. In addition, we have shown that some sulfotransferases (ST), a key enzymes family in the biosynthesis of HS, are directly involved in the regulation of Tau hyperphosphorylation and its aggregation. In that way, we have described an overexpression of the ST isoform in the hippocampus of the brain of AD patients and that an inhibition of its expression in tauopathy models allowed a stop in the progression of the disease and the recovery of the motor functions of the animals.

Recently, we have observed that the disturbance of the location of HS may also be present in some circulating cells of AD patients (Figure 1). Indeed, we have demonstrated by immunostaining in circulating cells from blood samples taken from patients with AD (mild / moderate AD stage - average age 63.6 years) a particular phenotype characterized by the same membrane accumulation and especially abnormal intracellular accumulation of HS found in neurons. Indeed, in healthy subjects (mean age: 54.2 years), HS is found only at the membrane level. ST, which normally have a membrane and a Golgi distribution (place of synthesis), is delocalized at the cytoplasmic level in AD subjects circulating cells. The evaluation of the prognostic and/or diagnostic character is currently carried out by the longitudinal study in collaboration with the Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A) led by Prof. Bruno DUBOIS as part of the European project H2020 FET-OPEN ArrestAD (Figure 2). These results would pave the way for the possible use of these glycanic targets in circulating cells as a potential tool for early AD diagnosis.

 

 Figure poster .jpg

 MCI: Mild Cognitive Impairment        PET-FDG18: Positron Emission Tomography fluorodesoxyglucose 18  
INSIGHT and SOCRATES are French cohorts, MCI WARSAW and AD WARSAW are Polish cohorts

 

“This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 737390.”