Biology subjects

Schroeder, W.

Publications and source records attributed to Schroeder, W..

5 recordsLinked to original sources

bioRxiv2026

Enzyme-Constrained Metabolic Modeling of the Tripartite Synapse Links Astrocyte-Neuron Lactate Shuttle to Lipid Trafficking and Redox Homeostasis

Neuron-astrocyte metabolic coupling sustains synaptic function through coordinated substrate exchange, redox homeostasis, and lipid handling, yet the systems-level mechanism remains poorly understood. Here, we developed an enzyme-constrained, genome-scale metabolic model of the mouse tripartite synapse to test whether protein allocation can reproduce the astrocyte-neuron lactate shuttle (ANLS). Starting from the iMM1865 mouse metabolic model, we corrected mass and charge imbalances, expanded fatty acid and lipid pathways, and standardized annotations to obtain a high-quality, generic mouse model, improving the MEMOTE score from 46% to 83%. Cell type-specific astrocyte and neuron models were reconstructed using the integrative metabolic analysis tool (iMAT) with cell type-resolved mouse brain proteomics, and were further extended to represent the tripartite synapse. Enzyme-constrained resource allocation models (RAMs) were reconstructed for the astrocyte and neuron models using the GECKO 3.0 pipeline and integrated into a tripartite synapse community model via a modified SteadyCom framework. In the stoichiometry-only model, minimum lactate exchange remained at zero across the entire biomass envelope, indicating no coupling between astrocyte lactate secretion and neuronal uptake arising from the metabolic network itself. Imposing enzyme constraints caused growth-coupled lactate secretion above 90% of maximal growth, with corresponding neuronal lactate uptake, indicating that protein limitation partially drives astrocyte-neuron lactate coupling consistent with ANLS. Incorporation of reactive oxygen species (ROS) and lipid peroxidation pathways demonstrated that the brain-type fatty acid binding protein (FABP7) knockout redistributed flux away from astrocytic detoxification, increased neuronal ROS burden, and produced cell-type-specific suppression of lipid-associated reporter metabolites, including prostaglandin J2, hydroxymethylglutaryl-CoA (HMG-CoA), mevalonate, phosphoinositide/DAG intermediates, fatty-acyl-CoA pools, and ceramide-related sphingolipids. Model predictions, including lactate shuttling and lipid metabolic shifts in FABP7 knockout, align with published experimental studies, supporting the biological relevance of this framework. These findings indicate that ANLS emerges from enzyme limitation in the tripartite synapse model and that FABP7-mediated lipid trafficking is essential for lipid-redox homeostasis at the tripartite synapse. Author SummaryThe brain relies on metabolic cooperation between astrocytes and neurons. Astrocytes convert glucose into lactate, which neurons use for energy. This process is known as the astrocyte-neuron lactate shuttle (ANLS). It is still unclear whether this shuttle is just one possible metabolic pathway or is required due to resource limitations. To explore this, we created two detailed mathematical models of the tripartite synapse, where an astrocyte process extends to meet the synapse. The first model consisted only of the stoichiometry of the metabolic network, whereas the second reflected each cells limited ability to make proteins. When these protein limits were imposed, lactate secretion by astrocytes and uptake by the neurons became mandatory, providing a systems-level mathematics-driven demonstration of ANLS. We also examined the role of Fatty Acid Binding Protein 7 (FABP7), a protein primarily expressed in astrocytes that shuttles fatty acids within astrocyte cells. Modeling FABP7 knockout caused astrocytes to lose their ROS detoxification capacity, increased oxidative stress in neurons, and altered lipid metabolism across cell types. Key affected lipid pathways included prostaglandin signaling, HMG-CoA/ketone body metabolism, cholesterol/mevalonate metabolism, phosphoinositide/DAG signaling, fatty acyl-CoA metabolism, and ceramide-related sphingolipid metabolism. These results show how energy supply, lipid trafficking, and oxidative stress control are linked across cell types and provide a way to identify metabolic vulnerabilities in neurological diseases.

Systems Biology↗

bioRxiv2022

Computational modeling of macrophage iron sequestration during host defense against Aspergillus

Iron is essential to the virulence of Aspergillus species, and restricting iron availability is a critical mechanism of antimicrobial host defense. Macrophages recruited to the site of infection are at the crux of this process, employing multiple intersecting mechanisms to orchestrate iron sequestration from pathogens. To gain an integrated understanding of how this is achieved in invasive aspergillosis, we generated a transcriptomic time-series of the response of human monocyte-derived macrophages to Aspergillus and used this and the available literature to construct a mechanistic computational model of iron handling of macrophages during this infection. We found an overwhelming macrophage response beginning 2-4 hours after exposure to the fungus, which included upregulated transcription of iron import proteins transferrin receptor-1, divalent metal transporter-1, and ZIP family transporters, and downregulated transcription of the iron exporter ferroportin. The computational model, based on a discrete dynamical systems framework, consisted of 21 3-state nodes, and was validated with additional experimental data that were not used in model generation. The model accurately captures the steady state and the trajectories of most of the quantitatively measured nodes. In the experimental data, we surprisingly found that transferrin receptor-1 upregulation preceded the induction of inflammatory cytokines, a feature that deviated from model predictions. Model simulations suggested that direct induction of TfR1 after fungal recognition, independent of the Iron Regulatory Protein - Labile Iron Pool system, explains this finding. We anticipate that this model will contribute to a quantitative understanding of iron regulation as a fundamental host defense mechanism during aspergillosis. ImportanceInvasive pulmonary aspergillosis is a major cause of death among immunosuppressed individuals despite the best available therapy. Depriving the pathogen of iron is an essential component of host defense in this infection, but the mechanisms by which the host achieves this are complex. To understand how recruited macrophages mediate iron deprivation during the infection, we developed and validated a mechanistic computational model that integrates the available information in the field. The insights provided by this approach can help in designing iron modulation therapies as anti-fungal treatments.

immunology↗

bioRxiv2021

The Innate Immune Response to Invasive Pulmonary Aspergillosis: A Systems Modeling Approach

Aspergillus species are ubiquitous environmental molds, the spores of which are inhaled daily by most humans. Immunocompromised hosts can develop an invasive infection resulting in high mortality. There is, therefore, a pressing need for host-centric therapeutics for this infection. To address this need, we created a multi-scale computational model of the infection, focused on its interaction with the innate immune system and iron, a critical nutrient for the pathogen. The model, parameterized using published data, was found to recapitulate a wide range of biological features and was experimentally validated in vivo. Conidial swelling was identified as critical in fungal strains with high growth, whereas the siderophore secretion rate is an essential prerequisite for establishment of the infection in low-growth strains. In immunocompetent hosts, high growth, high swelling probability, and impaired leukocyte activation lead to a high conidial germination rate. Similarly, in neutropenic mice, high fungal growth was achieved through synergy between high growth rate, high swelling probability, slow leukocyte activation, and high siderophore secretion. In summary, the model reveals a small set of parameters related to fungal growth, iron acquisition, and leukocyte activation as key determinants of the fate of the infection.

systems biology↗

bioRxiv2019

Feasibility of a surface-coated lung model for the quantification of active agent deposition for preclinical studies

Multiple drug resistance (MDR) of a growing number of bacterial pathogens represents an increasing challenge in conventional curative treatments of infectious diseases. However, the development and testing of new antibiotics is associated with a high number of animal experiments. A symmetrical parametrized lung test rig allowing the exposure of air-passage surfaces to antibiotics was designed and tested to demonstrate proof-of-principle with aerosols containing allicin, which is an antimicrobial natural product from garlic. An artificial lung surface is coated with bacteria embedded in a hydrogel and growth inhibition is visualized by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), that is reduced from colourless to the dark blue formazan in the presence of metabolically active, living cells. A nebulizer is used to generate the aerosols. The results show that allicin has an antibiotic effect as an aerosol and that the deposition pattern of the active agent occurred mainly around the carinal regions. The model represents an integral system for continuous, spatial detection of aerosol deposition and allows the analysis of bacterial behaviour and the toxicity of the active agent. In this way the deposition of antimicrobial aerosols on the bronchial surfaces is characterized in preliminary tests without any animal experiments.

bioengineering↗

bioRxiv2019

NWB:N 2.0: An Accessible Data Standard for Neurophysiology

Neurodata Without Borders: Neurophysiology (NWB:N) is a data standard for neurophysiology, providing neuroscientists with a common standard to share, archive, use, and build common analysis tools for neurophysiology data. With NWB:N version 2.0 (NWB:N 2.0) we made significant advances towards creating a usable standard, software ecosystem, and vibrant community for standardizing neurophysiology data. In this manuscript we focus in particular on the NWB:N data standard schema and present advances towards creating an accessible data standard for neurophysiology.

neuroscience↗