Etudes des interactions neurones-astrocytes dans le contexte de la maladie d'Alzheimer: modélisation en systèmes microfluidique et microelectrode array

Alzheimer’s disease (AD) is a neurodegenerative proteinopathy characterized by the abnormal accumulation of extracellular β-amyloid (Aβ) deposits and intracellular tau-containing neurofibrillary tangles in the brain. Besides the accumulation of proteins as well as synapse and ultimately neuronal loss, other cellular dysfunctions are observed in the AD brain including neuroinflammation, mediated by reactive microglia and astrocytes. In AD, the latter have been particularly described to exhibit an upregulation of the adenosine A2A receptor (A2AR) which leads to impaired neuronal function. This would explain the protective effect of caffeine, pharmacologically being a non-selective antagonist of A2AR.

It is now obvious that targeting only one pathological aspect of AD is not enough to drastically reduce its progression. To develop efficient (and probably combined) multicellular-based therapies, we need to better understand the interactions between the different cell types and identify associated pathways. In the present project, we will focus on the neuron-astrocyte interactions at the synapse in an AD-like context and through the prism of the dysregulation of A2AR by the astrocytes. In a first attempts, this will be achieved by using a cell culture system encompassing a 3-compartment microfluidic device associated with a microelectrode array (MEA). This system allows us to study the synapse function with regards to the single and combined effects of astrocytic upregulation of A2AR receptors and the presence of tau fibers (and possibly Aβ). Then, we will address these regulations using a more complex network by using organotypic hippocampal slice cultures prepared on MEAs and undergoing tau pathology development. Lastly, we will use both models to assay some therapeutic strategies developed by our collaborators.

This project should allow to better understand how tau pathology and modulation of the expression of A2AR by the astrocytes detrimentally interact together in AD to affect the synaptic function and brain network connectivity.

References:

Lefebvre C, Vreulx AC, Dumortier C, Bégard S, Gelle C, Siedlecki-Wullich D, Colin M, Kilinc D, Halliez S. Integration of Microfluidic Devices with Microelectrode Arrays to Functionally Assay Amyloid-β-Induced Synaptotoxicity. ACS Biomater Sci Eng. 2024 Mar 11;10(3):1856-1868. doi: 10.1021/acsbiomaterials.3c00997. Epub 2024 Feb 22. PMID: 38385618.

Launay A, Nebie O, Vijaya Shankara J, Lebouvier T, Buée L, Faivre E, Blum D. The role of adenosine A2A receptors in Alzheimer's disease and tauopathies. Neuropharmacology. 2023 Mar 15;226:109379. doi: 10.1016/j.neuropharm.2022.109379. Epub 2022 Dec 23. PMID: 36572177.

Bouillet T, Ciba M, Alves CL, Rodrigues FA, Thielemann C, Colin M, Buée L, Halliez S. Revisiting the involvement of tau in complex neural network remodeling: analysis of the extracellular neuronal
activity in organotypic brain slice co-cultures. J Neural Eng. 2022 Dec 6;19(6). doi: 10.1088/1741-2552/aca261. PMID: 36374001.

Centre de Recherche Lille Neuroscience & Cognition (U 1172)

Equipe Alzheimer & Tauopathies

http://lilncog.univ-lille.fr/

http://lilncog.eu

Situé sur le campus hospitalier du CHU de Lille, le Centre de Recherche Lille Neuroscience & Cognition (LilNCog) est dédié aux maladies neurologiques, la psychiatrie et la santé mentale et la neuroendocrinologie. En lien avec l’Université de Lille et le CHU, notre laboratoire est aussi un lieu de formation à la recherche.

Nous accueillons des chercheurs de reconnaissance internationale dans le domaine des neurosciences. Nous travaillons à améliorer les approches diagnostiques et thérapeutiques des maladies du cerveau. Notre qualité scientifique a été reconnue par l’Inserm, Institut National de la Santé et de la Recherche Médicale. Nous appartenons au LiCEND, un des sept centres d’excellence sur les maladies neurodégénératives français. Nous sommes également un des laboratoires fondateurs de l’Institut Cerveau, Société & Technologies de l’Université de Lille.

Les chercheurs et acteurs de la recherche en neurosciences du Centre Lille Neuroscience & Cognition abordent tous les domaines de la recherche du plus moléculaire au plus intégré.

- Master en biologie cellulaire, neurosciences ou sciences de l'ingénieur
- Etudiant(e) Sérieux, motivé et perservérant
- Connaissances en neurobiologie cellulaire
- Expérience en culture primaire