Targeting synaptic 'Eat Me' signals to prevent excessive synaptic engulfment by microglia and reduce synaptic loss in Alzheimer’s Disease

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 and for  international co-supervised PhDs.

This project is one of the proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art: In Alzheimer’s disease (AD), synaptic loss is the main driver of cognitive decline.  Recent evidence highlights the pivotal role of microglial reactivity in AD-associated synaptic loss through excessive synaptic engulfment by microglia. This could pave the way for therapeutic applications targeting the aberrant “eat me” signal from synapses to microglia, which is the is the primary objective of this thesis proposal.

Objectives: The global objective is to reduce synaptic loss in Alzheimer’s disease and slow cognitive decline. The first objective involves testing a chimeric molecule developed by the team to convert the aberrant “eat me” signal from synapses to microglia into a “don’t eat me” signal, preventing excessive synaptic engulfment. In the second objective, the student will design and test additional molecules targeting alternative pathways involved in aberrant synaptic in AD.

Methods: 1/ The team has developed a chimeric molecule that converts the aberrant “eat me” signal from synapses to microglia into a “don’t eat me” signal, preventing excessive synaptic engulfment. Based on promising preliminary in vitro results, the student will assess the impact of this molecule on synaptic and neuronal loss in an AD mouse model (P301S), as well as its effects on cognitive function (behavior analysis), synaptic activity (electrophysiology), structure (super-resolution microscopy), and protein changes (proteomics).

2/ The student will design and test additional molecules to protect synapses in AD by targeting pathways involved in aberrant microglial synaptic engulfment, guided by our AD synaptosome proteomic data and current literature. Promising candidates will be tested in vitro (synaptic engulfment assays) and the most effective will be evaluated in vivo using the methods from the first objective.

Expected results: We expect to identify at least one candidate molecule capable of reducing AD-related synaptic degeneration and cognitive decline in an AD mouse model.

Feasibility: All the necessary equipment is available at INP or through a network of collaborators. The team has strong expertise in synaptic loss, and microglial reactivity in Alzheimer’s disease. Mouse models are actively breeding, behavioral tests are optimized, and co-culture models are established in the lab. Promising preliminary in vitro data further support the project’s relevance and potential for success. The first 1.5 years focused on data collection and processing for the first objective, and the following 1.5 years for the second objective.

Within Aix Marseille Université, NeuroMarseille brings together 8 research laboratories and NeuroSchool, a graduate school in neuroscience, to increase the attractiveness of the university, international collaborations, interdisciplinarity, links with the clinical and industrial worlds and the integration of students into professional life. 

Launched in July 2018, NeuroSchool unifies and harmonizes the training of the third year of the Bachelor of Life Sciences (Neuroscience track), the Master's and the PhD in Neuroscience. 

• Master's degree from a non-French university in neuroscience or related field
• Fluent in English

The ideal candidate will have a master’s with a strong background in neuroscience and an interest in neurodegenerative diseases and glial cells. Essential skills include mouse handling, behavioral experiments, molecular biology, teamwork, analytical thinking, and autonomy. Experience in cell culture, histology, microscopy, electrophysiology, and bioinformatics is a plus, along with strong motivation, organization, and collaboration skills.