1. Research Background:

The accumulation of pathological protein aggregates within neurons is a central feature of many age-related neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Proteins such as tau and alpha-synuclein (α-syn) can misfold and aggregate, disrupting essential neuronal processes and spreading pathology through interconnected brain regions. As neurons are highly dependent on intact protein and energy homeostasis, the accumulation of such aggregates is closely linked to mitochondrial dysfunction, cellular stress, and ultimately neuronal degeneration.

Microglia, the resident immune cells of the central nervous system, play a key role in maintaining brain homeostasis. They continuously survey their environment, respond to neuronal damage, and remove cellular debris and pathogenic protein aggregates. However, microglial function changes substantially during ageing and neurodegenerative disease. Chronic inflammatory activation and disease-associated alterations can impair their homeostatic and protective functions and thereby contribute to progressive neuronal dysfunction.

Our recent work has identified an additional and unexpected way in which microglia can protect neurons. We showed that microglia and neurons form direct cellular connections through tunneling nanotubes (TNTs), enabling the exchange of material between the two cell types. Through these connections, microglia can remove aggregated α-syn and tau from stressed neurons while simultaneously transferring functional mitochondria to them. This mitochondrial support improves neuronal metabolic function and reduces cellular stress. Importantly, disease-associated alterations in microglia can impair the protective outcome of this interaction,suggesting that the ability of microglia to support neurons depends strongly on their own cellular and metabolic state.

These findings expand the classical view of microglia as primarily immune and phagocytic cells. Instead, they suggest that microglia can act as active support cells that sense neuronal stress and directly provide damaged neurons with cellular components required for recovery. Understanding how this intercellular communication is regulated, and how it changes during ageing and disease, may therefore reveal fundamental mechanisms that determine neuronal resilience in the ageing brain.

2. Research questions addresses by the group:

Building on our discovery of TNT-mediated communication between microglia and neurons, our group aims to understand the mechanisms that regulate this direct intercellular exchange and how they change during ageing and neurodegenerative disease.

We are particularly interested in how microglia sense neuronal stress and initiate contact with distressed neurons, which signaling and cytoskeletal pathways control TNT formation, and what determines the type and direction of cargo transferred between the two cell types. A central question is how the metabolic state of both neurons and microglia influences these interactions, and whether mitochondrial dysfunction limits the ability of microglia to provide effective support.

We further investigate how ageing, chronic inflammation, and disease-associated genetic alterations affect microglial responsiveness and TNT-mediated communication. Ultimately, our goal is to identify the cellular mechanisms that determine whether microglia can successfully support stressed neurons or whether this protective interaction fails during disease progression.

3. Possible projects:

Possible PhD projects may focus on different aspects of microglia-neuron communication, including the signaling pathways and cytoskeletal mechanisms that regulate TNT formation, the role of mitochondrial dynamics and cellular metabolism in cargo transfer, or the impact of ageing and disease-associated alterations on these processes.

Depending on the specific research question, projects may use primary cell cultures, human iPSC-derived neurons and microglia, or more complex cellular models of neurodegeneration. Experimental approaches can include advanced live-cell imaging, molecular and cell biology, metabolic and functional assays, and omics-based analyses.

Projects can be adapted to the interests and expertise of the individual candidate while remaining closely integrated into the overall research program of the group.

4. Applied Methods and model organisms:

We use a broad range of experimental approaches to study microglia-neuron interactions across different levels of complexity. Live-cell and time-lapse imaging, confocal and super-resolution microscopy are used to visualize cellular dynamics, TNT formation, and intercellular cargo transfer. These approaches are combined with molecular and biochemical methods to investigate the signaling and cytoskeletal mechanisms underlying microglia-neuron communication.

To assess the functional consequences of these interactions, we employ metabolic and mitochondrial assays, flow cytometry, and proteomic and other omics-based approaches. Our experimental models include primary neuronal and microglial cultures as well as human iPSC-derived neurons and microglia, including genetically modified and disease-associated backgrounds. Where appropriate, more complex three-dimensional or tissue-based models are used to study these processes in a physiologically relevant environment.

5. Desirable skills and qualifications:

We are looking for highly motivated PhD candidates with a background in molecular and cell biology and a strong interest in neurobiology, immunology, and intercellular communication. Candidates should enjoy working in an interdisciplinary research environment and be motivated to apply a broad range of experimental approaches.

Previous hands-on experience with mammalian cell culture is highly desirable. In particular, experience working with primary cells and/or human iPSC-derived cell models would be a strong advantage. Experience with advanced imaging techniques, molecular biology, or neuroimmunological methods would also be beneficial.

6. References:

Scheiblich H, Eikens F, Wischhof L, Opitz S, Jüngling K, Cserép C, Schmidt SV, Lambertz J, Bellande T, Pósfai B, Geck C, Spitzer J, Odainic A, Castro-Gomez S, Schwartz S, Boussaad I, Krüger R, Glaab E, Di Monte DA, Bano D, Dénes Á, Latz E, Melki R, Pape HC, Heneka MT (2024) Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes, Neuron, 112:1-20. doi: 10.1016/j.neuron.2024.06.029

Scheiblich H, Dansokho C, Mercan D, Schmidt SV, Bousset L, Wischhof L, Eikens F, Odainic A, Spitzer J, Griep A, Schwartz S, Bano D, Latz E, Melki R, Heneka MTH (2021) Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes, Cell, 184(20):5089-5106.e21. doi: 10.1016/j.cell.2021.09.007

Scheiblich H, Bousset L, Schwartz S, Griep A, Latz E, Melki R, Heneka MTH (2021) Microglial NLRP3 inflammasome activation upon TLR2 and TLR5 ligation by distinct a-synuclein assemblies, J Immunol, 207(8):2143-2154. doi: 10.4049/jimmunol.2100035