Job ID: 118121
PhD project: Role of oligodendroglial cells in Alzheimer’s Disease pathology
Position: Ph.D. Student
Deadline: 14 April 2024
Employment Start Date: 1 October 2024
Contract Length: 3 years
City: Marseille
Country: France
Institution: Aix-Marseille Université
Department: INP
Description:
The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master’s degree in a non-French university. This project is one of the 13 proposed projects. Not all proposed projects will be funded, check our website for details.
State of art
Alzheimer’s Disease (AD), by its exceptional prominence in people aged 75 and above, represents a major public health issue worldwide (Hebert et al., 2013). Unfortunately, compared to other neurodegenerative diseases, the failure rate in clinical trials of AD drugs in one of the highest (Cummings et al., 2014). One explanation could be that we still do not completely understand disease onset and progression. Past studies have mainly been focused on the repercussions of amyloid plaque and neurofibrillary tangles accumulation around and within neuronal cells only. Recently, new evidence, on human post-mortem tissues and AD murine models, have highlighted the importance to extend our research to glial cells, such as oligodendroglial cells.
Objectives
If many data support an oligodendroglial contribution in AD pathology, how oligodendroglial cell lineage could have a causal role in AD onset and progression is still largely unknown. We will test whether age-related dysregulation of oligodendroglial functions could result in defective neuro-oligodendroglial communication, thereby impacting neuronal function, inducing early neurodegeneration and disease onset in AD models.
Methods
1/ Test whether oligodendroglial aging directly induces early cognitive deficits in an AD mouse model. By taking advantage of the Tet1cKO mouseline (Moyon et al., 2021), presenting an aging-like phenotype restricted to the oligodendroglial cell lineage, we will functionally characterize the oligodendroglial contribution to cognitive deficits onset in an AD mouse model (5xFAD) (Oakley et al., 2006).
2/ Which pathways are dysregulated in aging-like oligodendroglial cells in an AD mouse model? Using spatial transcriptomic analysis, we will identify neuronal-oligodendroglial communication pathways dysregulated in aging-like oligodendroglial cells in an AD model.
3/ Test whether ablation of specific neuro-oligodendroglial pathways in oligodendroglial cells can impact neuronal function and/or survival, hence accelerate AD onset in a mouse model. We will validate their functional roles during neuronal activity in vitro and during learning and memory abilities in vivo.
Expected results
This project will better characterize the molecular and phenotypic mechanisms underlying oligodendroglial dysfunction in AD. It should determine how oligodendroglial aging could directly affect their support to neurons, inducing neurodegeneration and accelerating disease onset.
Feasibility
We have the scientific expertise on oligodendroglial lineage, aging biology, and AD pathology. Collaborators at the INP also complement our tools and knowledge on AD. Sequencing expertise is available at the MMG (Dr. V. DELAGUE). The mouse models are breeding in our animal facility. Behavioral tests are being set up and optimized. Co-culture models are set-up in the lab.
Expected candidate profile
The ideal candidate should have a master (or equivalent) in cell biology or neurosciences, an interest in glial cells, aging, and in neurodegenerative diseases.
Required skills: Mouse handling, team player, motivation, organization skills, communication skills.
Appreciated skills: cell culture, histology, microscopy and/or live-imaging, animal behavior, electrophysiology, bioinformatics.