1. Research Background:

The accumulation of pathological protein aggregates within neurons is a hallmark 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) normally support neuronal function but can aberrantly aggregate, impair intracellular processes, and propagate toxicity across neural networks through prion-like mechanisms. This propagation accelerates neuronal dysfunction and degeneration in interconnected brain regions.

Microglia, the resident immune cells of the central nervous system, are crucial regulators of brain homeostasis. Traditionally viewed through the lens of neuroinflammation and phagocytic clearance, microglia respond to pathogenic stimuli by activating inflammatory pathways and attempting to remove harmful aggregates^1,2. However, inflammatory states can impair microglial clearance mechanisms, thus contributing to continued protein accumulation and disease progression^1,3.

Our lab’s recent work has uncovered a novel neuroprotective mechanism mediated by microglia: the formation of tunneling nanotubes (TNTs) between microglia and neurons, which facilitate direct intercellular transfer of material. This TNT-mediated interaction enables microglia to extract toxic protein aggregates from neurons and deliver functional mitochondria back to damaged neurons, restoring cellular health and function. Importantly, this mechanism is compromised in microglia with disease-associated mutations, demonstrating potential relevance in human pathology.

This research highlights microglia not only as defenders against neuroinflammatory challenges but also as active neuroprotective agents capable of directing intercellular organelle and cargo exchange to support neuronal viability.

2. Research questions addressed by the group:

Despite substantial progress in the field, the cellular and molecular mechanisms governing microglia-neuron crosstalk during aging and neurodegenerative diseases remain incompletely understood. The research of our group is centered on elucidating how microglia contribute to the maintenance of brain homeostasis under physiological conditions and how these regulatory mechanisms become compromised during aging and disease progression. In particular, we are interested in understanding how microglial functions extend beyond classical immune surveillance to directly support neuronal health.

Our recent work has uncovered a previously unrecognized mechanism of microglia-neuron interaction, demonstrating that microglia establish TNTs with neurons burdened by intracellular α-syn and tau aggregates⁴. Through these TNTs, microglia are able to extract toxic protein aggregates from affected neurons while simultaneously delivering functional mitochondria, thereby restoring neuronal metabolic capacity and reducing oxidative stress.

These findings redefine the role of microglia as active neuroprotective partners capable of rescuing distressed neurons through direct intercellular exchange. Building on this concept, our research aims to dissect the molecular pathways that regulate TNT formation and function in microglia, to determine how aging influences TNT-mediated microglia-neuron interactions, and to understand how these processes are altered in different neurodegenerative disease contexts and genetic risk backgrounds. Ultimately, we seek to explore whether targeted manipulation of TNT dynamics can enhance microglial neuroprotective capacity and thereby slow or counteract neurodegenerative disease progression. This research strategy positions microglial TNTs at the intersection of aging, neurodegeneration, and intercellular resilience.

3. Possible projects:

Our primary goal is to uncover the cellular principles by which microglia contribute to brain homeostasis and to understand how these processes deteriorate during aging and in neurodegenerative diseases. Ongoing and future projects in the lab focus on dissecting the signaling pathways and cytoskeletal machinery that regulate TNT formation in microglia and neurons, as well as on characterizing how cellular metabolic state and mitochondrial dynamics influence TNT-mediated cargo transfer. To bridge mechanistic and translational research, we deploy human iPSC-based systems to model microglia-neuron interactions in both physiological and disease contexts. Each project can be tailored to the individual candidate’s interests and expertise and may integrate advanced imaging approaches, molecular and cell biology techniques, omics analyses, or functional assays to address specific mechanistic questions.

4. Applied Methods and model organisms:

We employ a broad array of state-of-the-art experimental approaches to investigate microglial function across multiple biological scales. Our work integrates live-cell and time-lapse imaging with super-resolution microscopy to visualize microglial dynamics and neuron-microglia interactions. These imaging approaches are complemented by molecular and biochemical techniques that allow us to dissect the signaling pathways underlying microglia-neuron interactions, as well as flow cytometry-based methods for detailed cellular phenotyping. In parallel, we employ human iPSC-derived neuronal and microglial models to address translational questions and disease-associated genetic backgrounds.

5. Desirable skills and qualifications:

We seek highly motivated PhD candidates with a strong foundational knowledge in molecular and cell biology and a keen interest in neurobiology, immunology, and intercellular communication. Successful candidates should be enthusiastic about working in an interdisciplinary environment and eager to learn and apply new experimental approaches. Prior experience with cell culture, imaging techniques, or neuroimmunological assays is advantageous but not required, as comprehensive training will be provided.

6. References:

1. Scheiblich, H. et al. Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies. J.I. 207, 2143–2154 (2021).
2. Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019).
3. Friker, L. L. et al. β-amyloid clustering around ASC fibrils boosts its toxicity in microglia. Cell reports 30, 3743–3754 (2020).
4. Scheiblich, H. et al. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 184, 5089-5106.e21 (2021).