Our group focuses on understanding how the immune system responds to changes in the brain's microenvironment during healthy aging and neurodegeneration. We also investigate how immune cells can influence the onset, progression, and severity of neurodegenerative disorders. To uncover the mechanisms behind these reciprocal interactions, we utilize state-of-the-art methods, including high-dimensional flow cytometry, single-cell (multi-)omics techniques, and spatial imaging and transcriptomics.

T Cells in the CNS during neurodegeneration and ageing

A central aim is to understand how various pathological or subclinical changes in the CNS are driven by T cells. This includes exploring how T cells transcriptionally and phenotypically adapt to their presence within brain tissue, and identifying the signaling pathways and transcription factors that govern the formation and function of these brain-resident T cells. Using disease models of neurodegeneration, such as 5xFAD and SPG15, as well as models for physiological changes like accelerated aging, we focus on the origin and function of T cells in the CNS, their developmental trajectories, clonality, and interactions with other cell types, including microglia.

Single-cell (multi)-omic atlases of the brain in inflammation and neurodegeneration

Our group is dedicated to unravel the mechanisms underlying neurodegenerative diseases at the single-cell level. To achieve this, we utilize decentralized approaches to create cell atlases and leverage multi-modal omics data, including single-nucleus RNA sequencing (snRNA-seq), single-cell ATAC sequencing (scATAC-seq), spatial transcriptomics, and MultiOmics data from techniques such as SHARE-seq, 10X, and BD Rhapsody single-cell sequencing. Our current projects include a multi-center collaboration with the DFG-NGS competence network to create a cell atlas of the human striatum. Additionally, we are investigating transcriptional changes in Parkinsonian striatal neurons to gain a deeper understanding of the molecular basis of the loss of dopaminergic input in Parkinson's disease.

Moreover, we aim to uncover how acute infections and chronic inflammation throughout life can shape the reactivity of the brain's immune system. Microglia, the brain's innate immune cells, can "remember" previous stimuli and adapt their reactivity, with potentially life-altering implications for the progression of neurodegenerative diseases like Alzheimer's disease. To explore this "innate immune memory," we employ state-of-the-art single-cell multi-omics techniques, uncovering the gene expression profiles and epigenetic states of microglia in response to different immune challenges.

Understanding microglia heterogeneity in the CNS

An additional area of our research is CRISPR-Cas9 induced genome editing. It has been utilized as a dynamic lineage tracing tool, inheritable by descendant cells during division. This system was employed to develop a mouse model referred to as LINC, capable of linking cell state to cell fate at single-cell resolution, thereby identifying myeloid and microglial lineages under both homeostatic and pathological conditions. Our LINC mouse represents a promising tool to better understand the function of microglia in neurodegenerative disorders.

Role of peripheral immunity for neuropathology

Another focus of our research is the systemic implications of Alzheimer’s disease. We utilize high-resolution techniques in a large DZNE cohort study to characterize the interplay between neurodegenerative processes and peripheral immunity. We are examining how immune processes in early dementia patients and individuals at risk for Alzheimer’s disease may contribute to disease progression and the development of biomarkers for early treatment interventions.

As part of the European research project NeuroCOV, we aim to identify immune signatures in peripheral blood that are associated with long-term neurological complications of COVID-19. To achieve this, we conduct an in-depth, high-throughput multidimensional single-cell analysis of peripheral blood mononuclear cells at both the protein and transcriptomic levels. This approach enables us to uncover the cellular and molecular mechanisms underlying cognitive decline and neurodegenerative processes that form the basis of neurological and neuropsychiatric symptoms observed in NeuroCOVID patients.