A5011151201- Neuroinflammation and Neurodegeneration Mechanisms
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Adenosine and Purinergic Signaling
- Alzheimer's disease research and treatments
- Barrier Structure and Function Studies
- Neurological Disease Mechanisms and Treatments
- Inflammation biomarkers and pathways
- Retinal Development and Disorders
- Chemical Synthesis and Analysis
- Stress Responses and Cortisol
- Photoreceptor and optogenetics research
- Protein Kinase Regulation and GTPase Signaling
- Neuroscience of respiration and sleep
- Immune cells in cancer
- Tryptophan and brain disorders
- Connexins and lens biology
- Neurogenesis and neuroplasticity mechanisms
- Neuroendocrine regulation and behavior
- Membrane-based Ion Separation Techniques
- Clusterin in disease pathology
- Olfactory and Sensory Function Studies
- Inflammasome and immune disorders
- IL-33, ST2, and ILC Pathways
Charité - Universitätsmedizin Berlin
2017-2025
Humboldt-Universität zu Berlin
2021-2023
Freie Universität Berlin
2021-2023
University College London
2010-2023
MSB Medical School Berlin
2017-2020
Max Planck Institute for Brain Research
2006-2016
University of North Texas
2003-2008
University of North Texas Health Science Center
2003-2008
Max Planck Society
2007
Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most vascular resistance within brain capillaries, this could reflect dysfunction contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish relevance, rodent experiments define mechanism. found that humans with cognitive decline, amyloid β (Aβ) constricts capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which...
Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but also send out targeted envelop sites tissue damage. We now show that these motility differ mechanistically. identify two-pore domain channel THIK-1 as main K+ expressed in microglia situ. is tonically active, its activity potentiated by P2Y12 receptors. Inhibiting function pharmacologically or gene knockout depolarizes microglia, which decreases microglial ramification thus...
Abstract Microglia sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, removing apoptotic neurons, and promoting neuronal survival. To elucidate the role of microglia during embryonic postnatal brain development, we used mouse model deficient throughout life deletion fms-intronic regulatory element (FIRE) Csf1r locus. Surprisingly, young adult ΔFIRE/ΔFIRE mice display no changes excitatory inhibitory synapse number spine density CA1...
Abstract Neuroinflammation is highly influenced by microglia, particularly through activation of the NLRP3 inflammasome and subsequent release IL-1β. Extracellular ATP a strong activator inducing K + efflux as key signaling event, suggesting that -permeable ion channels could have high therapeutic potential. In these include ATP-gated THIK-1 P2X7 receptors, but their interactions potential role in human brain are unknown. Using novel specific inhibitor combination with patch-clamp...
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic-lipid-activated two-pore domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders, example Alzheimer’s disease amyothropic lateral sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16-Å-resolution cryo-EM structure human that reveals several distinct...
Abstract Microglia sense their environment using an array of membrane receptors. While P2Y 12 receptors are known to play a key role in targeting directed motility microglial processes sites damage where ATP/ADP is released, little about the 13 , which transcriptome data suggest second most expressed neurotransmitter receptor microglia. We show that, patch‐clamp recordings acute brain slices from mice lacking receptors, THIK‐1 K + current density evoked by ADP activating was increased ~50%....
N-Methyl-d-aspartate (NMDA) receptors are tetrameric protein complexes composed of the glycine-binding NR1 subunit with a glutamate-binding NR2 and/or NR3 subunit. Tri-heteromeric containing NR1, NR2, and subunits reconstitute channels, which differ strikingly in many properties from respective glycine- glutamate-gated NR1/NR2 NR1/NR3 gated by glycine alone. Therefore, an accurate oligomerization process different has to assure proper NMDA receptor assembly, been assumed occur via...
Microglia, the brain's innate immune cells, have highly motile processes which constantly survey brain to detect infection, remove dying and prune synapses during development. ATP released by tissue damage is known attract microglial processes, but it controversial whether an ambient level of needed promote constant surveillance in normal brain. Applying ATPase apyrase, enzyme hydrolyzes ADP, reduces process ramification surveillance, suggesting that ATP/ADP maintains surveillance. However,...
Neuronal gap junctional hemichannels, composed of pannexin-1 subunits, have been suggested to play a crucial role in epilepsy and brain ischaemia. After few minutes anoxia or ischaemia, neurons slices show rapid depolarization ∼−20 mV, called the anoxic depolarization. Glutamate receptor blockers can prevent depolarization, suggesting that it is produced by cation influx through glutamate-gated channels. However, isolated hippocampal pyramidal cells, simulated ischaemia evokes large inward...
The <i>N</i>-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (iGluRs) is a tetrameric protein composed homologous NR1 and NR2 subunits, which require the binding glycine glutamate, respectively, for efficient channel gating. extracellular N-terminal domains (NTDs) iGluR subunits show sequence homology to bacterial periplasmic leucine/isoleucine/valine (LIVBP) have been implicated in assembly, trafficking, function. Here, we investigated how deletion NR1- NR2-NTDs affects...
Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing purified cell types from human post-mortem brain tissue, demonstrated highly specific expression tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) microglia compared to other glial...
The activity of cells critically depends on the control their cytosolic free calcium ion (Ca2+) concentration. objective present study was to identify mechanisms action underlying gain intracellular Ca2+ release by circulating gonadal steroid hormones. Acute stimulation isolated neurons with progesterone led IP3R-mediated transients that depend activation PI3 kinase/Akt/PKB signaling pathway. These results were confirmed at molecular level and phosphorylation IP3R type 1 Akt/PKB identified...
Coassembly of the glycine-binding NMDA receptor subunits NR1 and NR3A results in excitatory glycine receptors low efficacy. Here, we report that micromolar concentrations divalent cation Zn 2+ produce a 10-fold potentiation NR1/NR3A responses, which resembles seen upon antagonizing binding to subunit. Coapplication both antagonist caused supralinear potentiation, resulting >120-fold increase glycine-activated currents. At >50 μM, alone generated currents with similar efficacy as...
Abstract Aims Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia that diverts blood flow from poorly ventilated better aerated lung areas optimize ventilation-perfusion matching. Yet, the exact sensory and signalling mechanisms by which triggers remain incompletely understood. Recently, ATP release via pannexin 1 (Panx1) subsequent purinergic P2Y receptors has been identified as regulator of in systemic arterioles. Here, we probed for role Panx1-mediated...
Glycine has diverse functions within the mammalian central nervous system. It inhibits postsynaptic neurons via strychnine-sensitive glycine receptors (GlyRs) and enhances neuronal excitation through co-activation of N-methyl-D-aspartate (NMDA) receptors. Classical Ca2+-permeable NMDA are composed glycine-binding NR1 glutamate-binding NR2 subunits, hence require both glutamate for efficient activation. In contrast, recombinant binding NR3A and/or NR3B subunits lack sites can be activated by...
purpose. The most recently identified metabotropic glutamate receptor (mGluR), type 8 mGluR (mGluR8), has been functionally as a presynaptic autoreceptor in rod photoreceptors. This study analyzed the mechanism of action underlying mGluR8 activity and modulation cytosolic Ca2+ concentration mouse methods. acutely isolated photoreceptors was monitored optically with microspectrofluorimetry presence modulators G protein activity. results. activation by group III agonists...
Inositol (1,4,5)-trisphosphate receptors (IP3Rs) contribute substantially to cytosolic free calcium ion (Ca2+) concentration transients and thereby modulate neuronal function. The present study was undertaken determine the contribution of IP3Rs function rod bipolar cells in retina.Immunoreactivity for from mouse retinas detected by immunocytochemical methods. Intracellular Ca2+ concentrations were optically recorded acutely isolated cells, biophysical properties analyzed with single channel...
Abstract THIK-1 ( KCNK13 ) is a halothane-inhibited and anionic lipid-activated Two-Pore Domain (K2P) K + channel implicated in microglial activation neuroinflammation, current target for the treatment of neurodegenerative disorders such as Alzheimer’s Amyothropic Lateral Sclerosis (ALS). However, compared to other K2P channels, little known about structural functional properties THIK-1. Here we present 3.16 Å resolution cryoEM structure human that reveals several unique features,...
N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits identical or different non-GluN1 that include six gene products; four GluN2 (A-D) GluN3 (A-B) subunits. The heterogeneity subunit combination facilities the distinct NMDARs. All GluN contain an extracellular N-terminal Domain (NTD) ligand binding domain (LBD), transmembrane...
Vascular compromise occurs early in Alzheimer’s disease (AD) and other dementias 1–3 . Amyloid β (Aβ) reduces cerebral blood flow 4–6 and, as most of the vasculature resistance is capillaries 7 , Aβ might mainly act on contractile pericytes capillary walls 8–10 Employing human tissue to establish disease-relevance, rodent experiments define mechanism, we now show that constricts brain at pericyte locations subjects with cognitive decline. Applying soluble 1-42 oligomers live cortical...