Our Research Focus
Our research projects are organized into four Research Areas, each targeted at one specific pathomechanistic “nexus” and its translational part. The research within these research areas is structured as Tandem Projects. The Research Areas are complemented by Technology Hubs that provide critical methodological support.
Our four Research Areas:
Projects in Research Area A investigate the reciprocal interactions between two of the most complex cellular systems in our body: the immune system and the nervous system. While the structural appearance and cellular composition of both systems are quite different, there are also important commonalities. Both are highly interconnected systems that depend on the timed integration of signals both locally and over longer distances.
In recent years, we have learned that such communication happens not only within a given system but also across these systems as a number of shared molecular mediators of neuro-immune cross-talk have emerged. Cytokines such as tumor necrosis factor alpha (TNF-alpha) and Interleukin 6 (IL-6), for example, are not only key signaling molecules within the immune system but also regulate the neuronal response to injury. On the other hand, classical signaling molecules of the nervous system, including neuropeptides and neurotrophic factors, regulate immune responses throughout the body.
The nervous and immune systems are also highly intertwined in disease as, on the one hand, neurodegenerative conditions like AD are critically modulated by inflammatory reactions and, on the other hand, the outcome of inflammatory CNS conditions, such as MS, is determined by neurodegenerative sequelae. Here, we aim to uncover how neuro-immune interactions shape the course of both neurodegenerative and neuroinflammatory conditions, define the critical mediators and markers of this cross-talk in CNS disease, and identify novel therapeutic strategies to improve the outcome of neuro-immune interactions.
Tandem Projects Research Area A
A1: TREM2 dependent microglial function and dysfunction in Alzheimer's disease
Haass*, Simons*, Herms, Lichtenthaler, Feederle
A2: Neuronal pathology and its compensation in the inflamed nervous system
Kerschensteiner*, Misgeld*, Bareyre, Konnerth, Portugues
A4: Axonal mitophagy – local quality control to restrict inflammation
A5: Investigating pathogenic protein seeding in human iPSC-derived models of AD and FTD
Paquet*, Herms*, Hartl, Haass
A6: Trio infernal: The role of glia-glia-neuron interaction in ALS/FTD pathology
Edbauer*, Liebscher*, Ninkovic
Neurons, due to their unique geometry and cell biology, are among the most energy-consuming cells in the body. Not surprisingly, they depend on an extensive and tightly regulated support structure of glial and vascular cells to satiate their energetic needs. Glio-vascular pathologies commonly have neurodegenerative sequels, which is reflected in the widespread comorbidity of vascular changes and neuronal loss. Indeed, the vasculature is a predilection site for accumulation of aggregation-prone proteins linked to neurodegeneration, and can itself be the primary site of protein aggregation in familial small vessel diseases (SVD). Moreover, glial and vascular cells have evolved into complex and highly specialized cells with their own unique vulnerabilities to subcellular damage and subsequent degeneration. Finally, glial and vascular cells – similar to immune cells – often play Janus-faced roles in disease, some supportive, others disruptive: Oligodendrocytes support axons metabolically, but can also suffocate them if myelin is disconnected; astrocytes provide essential support to synapses, but can also strip them away.
Whether neuro-glial interactions are beneficial or detrimental depends in part on diversity within glial cell types, both at rest, as well as in their stress response. For instance, a newly defined oligodendrocytes subset appears critical for remyelination, while a distinct subset of juxtavascular astrocytes expand during gliosis after a range of neurological insults. Subspecialization also applies to microglia. Such subtype-specific responses also open therapeutic options: Glial and perivascular cells that – in contrast to neurons – retain proliferative potential make the perivascular niche a potential source of cells for endogenous repair, e.g., capitalizing on new in situ reprogramming strategies. These approaches focus on proliferating cells in the neurovascular niche, including human brain-derived pericytes in vitro, and now aim to target specifically neurotoxic or scar-forming glial populations to minimize damage to preexisting neurons, while replacing those that were lost. Together these observations reveal an intimate, but damage-prone relationship between neurons and their glio-vascular support structures – a relationship of disease-spanning significance that is the topic of SyNergy’s Research Area B.
Tandem Projects Research Area B
B1: Systems neurology of cell-type specific mitochondrial pathology in neurodegeneration
Misgeld*, Perocchi*, Harbauer
B2: Identifying key regulators of neuronal replacement after neurodegeneration and stroke
Götz*, Liesz*, Dichgans, Ninkovic
B3: Small vessel disease (SVD) – multiscale imaging from models to patients
Dichgans*, Plesnila*, Ertürk
B4: Exploring and exploiting proteostasis network dynamics for treatment and repair
Behrends*, Hartl*, Edbauer, Götz
B5: Cellular mechanisms of prolonged functional impairment after transient ischemic attacks
B6: Cellular mechanisms of β-amyloid dependent astrocytic dysfunction in vivo
Konnerth*, Misgeld*, Haass
B7: Neural circuit remodeling after acute hearing loss
Grothe*, Liebscher*, Ninkovic
B8: Systems-wide characterization of astrocyte-neuron crosstalk - relevance for Parkinson’s disease
Burbulla*, Perocchi*, Lichtenthaler, Misgeld
Research Area C focuses on the interaction between the immune system and glio-vascular pathophysiology. The glio-vascular unit, together with constituents of the immune system defines distinct anatomical and functional niches within the CNS. This concept extends beyond the classical BBB and comprises small vessels with their local immune cell outfit in the CSF space and the plexus choroideus. The vascular immune niche has gate-keeping functions for immune surveillance of the CSF space and the CNS parenchyma in steady state. Moreover, it impacts the development and resolution of lesions within the CNS during inflammatory and vascular diseases. In addition, it is increasingly recognized that peripheral immune compartments (including the systemic immune system and the immune system at mucosal surfaces) have an impact on the glio-vascular unit.
Conversely, the vascular immune niche exerts widespread effects within the CNS, including during neural development, and also feeds back on the systemic compartment via the egress of immune cells from the CNS and the release of soluble mediators. Immune-vascular interactions are multi-layered even under physiological conditions: Dedicated macrophages screen the peri-vascular space and are critical in maintaining microvascular function. For instance, these perivascular macrophages contribute to vascular dysfunction caused by systemic alterations, such as high blood pressure. Monocytes, T cells, and CNS macrophages also reside in substantial numbers in the choroid plexus and the meninges, where they get in close contact with the vascular compartment and extravasating cells. Thereby, inflammatory CNS diseases also cause secondary cerebrovascular complications, such as impaired neurovascular coupling, microthrombosis, and vascular inflammation. In turn, cerebrovascular injuries induce inflammatory reactions, both locally, as well as affecting systemic immune homeostasis.
In Research Area C, we will analyze how cells populate emerging vascular immune niches, which molecular signals are involved, and how these niches sense or emit systemic cues. We will explore how immune cells control CNS vascular homeostasis and execute immune surveillance during steady state, as well as their roles in the development and resolution of inflammatory or vascular CNS lesions.
Tandem Projects Research Area C
C2: Lipid metabolism, phagocyte function and remyelination
Simons*, Hemmer*, Haass
C3: Exploring neurovascular disorders in isogenic human iPSC-derived in vitro models involving APP, Notch3, and Foxf2 mutations
Paquet*, Dichgans*, Plesnila
C4: Glia-neuron-vascular crosstalk governing systemic metabolism
García-Cáceres*, Tschöp*, Götz, Misgeld, Perocchi
C5: Pharmacological inhibition of HDAC9 for atheroprotection and its effects on neuroprotection
Dichgans*, Weber*, Liesz, Bernhagen, Plesnila
C6: Role of Sensory Neuroimmune Cardiovascular Interfaces in Atherosclerosis
Weber*, Dichgans*, Bernhagen*, Lichtenthaler, Herms
C7: IL-6 signaling in T cell subsets - Advanced models
C8: Cell-type specific mitochondrial plasticity in neural cells of the inflamed CNS
Misgeld*, Kerschensteiner*, Perocchi, Harbauer
Research Area D provides a versatile platform for SyNergy scientists to collaborate on translational projects. The pathomechanistic studies of SyNergy’s first funding period already yielded results directly relevant for disease monitoring or modulation – and we expect more such results as SyNergy’s disease-spanning research program unfolds further. Among these results are novel insights into disease mediators and hence potential new therapeutic targets (e.g., derived from GWAS, such as HDAC in stroke; from neuropathological studies, such as DPRs; or from animal studies, such as lipotoxicity in MS), pathomechanism-based biomarkers (ranging from miRNAs, to shed or secreted proteins, and histological markers) and imaging indicators). Such new disease-relevant leverage points with translational potential now require rigorous testing in preclinical and clinical settings. To address this growing need, we have implemented Translational Tandem Projects.
The key feature of these new Tandems is to bring clinicians and basic researchers together centered on a specific clinical topic. Indeed, the SyNergy’s collaborative spirit across the “bench-to bedside chiasm”, enables basic researchers to evolve their research towards translation, and that we intend to amplify further. This allows basic researchers to explore the clinical potential of new discoveries together with expert neurologists or even initiate new clinical projects, thus providing new targets and a robust pathomechanistic basis for investigator-initiated studies and trials in SyNergy’s clinics.
Tandem Projects Research Area D
D1: Microglial activity markers: from mouse models to humans
Haass*, Lichtenthaler*, Brendel, Perneczky
D2: Environmental and immunological disease triggers in the German National Twin Cohort
Kerschensteiner*, Hemmer*, Gerdes, Korn, Simons
D3: Therapeutic modulation of TREM2
Haass*, Simons*, Herms, Lichtenthaler, Feederle
D6: PET radiotracer development for in vivo imaging of neurodegeneration, neuroinflammation and neurovascular diseases
D7: Preparing for clinical trials of immunotherapy and nucleoside analogs in C9orf72 ALS
Edbauer*, Klopstock*, Levin, Lingor
Our Technology Hubs for methodological support:
Tandem Projects are highly collaborative research projects aimed at improving our understanding of degenerative, inflammatory, and glio-vascular disease. The projects combine expertise across traditional pathomechanisms, as well as systems biology and systems neuroscience tools. Furthermore, in many projects, the research efforts of scientists and clinicians are bundled. This allows us to combine approaches that range from in vitro models to investigator-initiated trials. The portfolio of projects within the cluster is dynamic: new projects and investigators can be added as topics and techniques in systems neurology emerge.
The Hubs provide access for SyNergy members to two arcs of ‘omics’- and imaging-oriented technologies across different levels and scales of analysis from systems to clinics.
The Hubs are organized as institutions-spanning units – all Hubs are coordinated by three SyNergy experts from at least two different institutions.
Array Tomography Training & Network
This initiative aims at developing an international array tomography user community via courses and an online hub to increase skills and accessibility and reveal the scale of biology in health and disease