Biology subjects

Becker, M.

Publications and source records attributed to Becker, M..

At least 19 recordsLinked to original sources

bioRxiv2026

An atlas of eukaryotic centromere architecture reveals recurrent evolutionary dynamics

Centromeres evolved at the root of eukaryotes to segregate chromosomes during cell division. Despite their ancient origin, centromeric DNA sequences evolve rapidly and adopt diverse architectures, including point centromeres, satellite arrays, transposon clusters, and holocentrics. To analyse centromere evolution at a broad scale, we characterised architectures across 325 diverse Darwin Tree of Life genome assemblies. Centromere architecture is evolutionarily labile, and similar configurations arise independently across divergent lineages. In plants and animals, we modelled centromere evolution as a recurrent cycle, in which satellite- and transposon-based architectures interconvert, with independent origins of holocentricity. We curated >23 million satellite repeats comprising 263 families from 165 species. Despite sequence divergence between satellite families, higher order repeats are prevalent, indicating constraint on repeat architecture rather than primary sequence. Satellite arrays are heavily invaded by diverse transposon families, consistent with convergent adaptation to the centromeric niche. In 89 species, transposons themselves constitute the primary centromere structure. We observed centrophilic transposons forming tandem arrays, suggesting mechanisms for satellite regeneration. Our sample includes five independent origins of holocentricity in plants and animals, which vary in association with periodic satellite arrays. We propose that genetic instability, centrophilic transposition, and transmission distortion promote recurrent centromere architectural interconversions during evolution.

genomics↗

bioRxiv2026

Chilling Nights Do Not Cause Starch Over-Accumulation and Trigger a Shift in Carbon Partitioning via SPS Toward Sucrose in Arabidopsis - Differing from Acclimation to Permanent Cold

Plants acclimate to low temperatures by remodeling carbohydrate metabolism. Permanent cold at 4/5{whitebullet} C induces well-characterized cold acclimation in plants, including accumulation of starch and soluble sugars. In natural environments, however, annual plants in their vegetative phase more frequently experience chilling nights (0-6{whitebullet} C nights followed by days at least 12{whitebullet} C warmer), whose metabolic consequences remain poorly understood. We investigated Col-0 Arabidopsis thaliana exposed to one or seven chilling nights and quantified central carbohydrate metabolites, starch, photosynthetic parameters, and maximal activities of enzymes linking sucrose synthesis and cleavage. We integrated these time-series data into a biologically constrained augmented neural ordinary differential equation (ANODE) model to infer diurnal reaction-rate dynamics. Chilling nights induced strong accumulation of sucrose, glucose, and fructose, particularly after seven nights. Both measured sucrose phosphate synthase (SPS) capacity and ANODE-predicted SPS rates increased. In contrast to permanent cold acclimation, daytime starch over-accumulation was absent. Thus, lacking starch over-accumulation together with increased SPS rates, chilling nights invoke distinct carbohydrate-partitioning patterns towards sucrose, indicating a fundamentally different acclimation strategy compared to well described permanent cold.

plant biology↗

bioRxiv2026

Weak interactions drive selective proteome demixing and tune the differential response to environmental perturbations

The intracellular space is a crowded environment where macromolecules perform distinct tasks despite pervasive "non-specific" interactions. Whether these interactions are functionally relevant and how they influence cellular organization remains unclear. Here, we developed QuPID-MS, which measures the propensity of proteins to phase separate in native cell extracts proteome-wide. We find that weak interactions drive condensation of half of the proteome in a crowding- and temperature-dependent manner and we present evidence that this proteome demixing occurs in cells. Importantly, protein condensation properties are conserved and broadly change when cells adapt to new environments, demonstrating that weak interactions are regulated and linked to function. Indeed, condensation of the growth regulator TORC1 coincides with its rapid inactivation, while high solubility of the stress-activated Hog1 ensures its activity across conditions. We thus uncover a fundamental organizing principle that allows tuning of cell growth to environmental fluctuations while ensuring other processes function robustly despite perturbations.

cell biology↗

bioRxiv2026

From Sensory Details to Verbal Codes: Visual Memory Reinstatement of Location and Color Features

Successful episodic memory depends on the reinstatement of encoding content and processes during retrieval. However, it remains unclear how such reinstatement (1) differs for various perceptual features, (2) supports subjective versus objective memory retrieval, and (3) relies on linguistic information. To investigate these three issues, we designed an fMRI study in which participants encoded and recalled the colors and spatial locations of object pictures, and provided subjective vividness and objective precision measures. We used encoding-retrieval similarity (ERS) to identify feature-level reinstatement for location or color features, and trial-specific reinstatement for individual location trials or individual color trials. The study yielded three main findings. First, feature-level reinstatement in frontoparietal and visual regions supported both location and color memory, whereas trial-specific reinstatement in early visual cortex contributed to location memory and feature-level reinstatement in lateral/anterior temporal cortices, to color memory. Second, trial-specific reinstatement in early visual cortex supported both location vividness and precision, while feature-level reinstatement in inferior frontal gyrus contributed to color vividness, and trial-specific reinstatement in posterior inferior temporal gyrus (including the color area), to color precision. Finally, color name richness (the number of names associated with a particular color) enhanced color memory precision and modulated trial-specific color reinstatement in right anterior inferior temporal gyrus. Together, these findings suggest that perceptual and linguistic reinstatement play complementary roles in visual episodic memory: perceptual replay provides fine-grained sensory details, whereas linguistic replay can scaffold and refine these representations, especially for features that are easier to verbalize such as colors. Significance StatementNeural reinstatement has been associated with the quality of episodic memory for complex visual images. However, it remains unclear how neural reinstatement varies across perceptual features, memory subjectivity, and linguistic accessibility. Here, we examine how neural reinstatement supports memory for color and location, whether it plays different roles in memory vividness versus precision, and the role of language in color memory. We showed that location memory relies primarily on trial-specific reinstatement in early visual cortex, supporting precise and vivid recall, whereas color memory is supported by a more complex and complementary interplay between perceptual and linguistic reinstatement. Together, these results advance our understanding of how distinct reinstatement mechanisms support the precision and vividness of episodic memory for basic visual features.

neuroscience↗

bioRxiv2026

A personalized eye-tracking system reveals complex state-dependent visual acquisition in lizards

Gaze shifts are fundamental to visual exploration and processing, yet empirical knowledge is largely confined to a small number of model species, limiting our understanding of general principles of visual acquisition across animals. Here, we introduce a versatile, low-cost and open-source framework design for eye tracking in small freely-moving animals. Leveraging photogrammetry, 3D modeling, and 3D-printing, we produce headmounts adaptable to diverse head-eye geometries as we demonstrate for lizards, turtles, and mice. Detailed recordings in Pogona vitticeps, a laterally eyed ectotherm with a high-acuity retina, reveal a rich oculomotor repertoire with kinematics closely resembling the saccadic main sequence in primates. We found both movement-coupled large binocular saccades which exhibited a strong axial bias as well as small, isotropic, and monocular saccades suggesting a capacity for visual exploration of local details. Visual acquisition strategies were strongly tied to behavioral states with periods of active sampling (3-5Hz saccades) separated by periods of ocular stillness lasting many seconds and suggesting divergent visual acquisition strategies for ectotherms. Further, active states were correlated with pupil constriction in contrast to mammals and similarly to birds. Our results demonstrate the utility of our experimental approach for understanding visual acquisition across terrestrial vertebrates. Such a multi-perspective view on natural visual acquisition across species will be essential for developing a generalized understanding of vision, its ecological functions, and its evolutionary trajectory.

animal behavior and cognition↗

bioRxiv2025

Polysialic Acid-Functionalized MAP Scaffolds Promote Regulatory Immune Responses After Ischemic Stroke

Glycosylation regulates immune and neural functions within the central nervous system (CNS), yet biomaterials rarely leverage glycans due to their structural complexity. Polysialic acid (PSA), comprising 2,8-linked sialic acid residues, is a promising candidate owing to its potent immunomodulatory interactions with inhibitory Siglec receptors. Systematic screening of multiple sialic acid derivatives identifies PSA as uniquely effective in inducing anti-inflammatory polarization of bone marrow-derived macrophages (BMDMs). Based on these findings, an injectable microporous annealed particle (MAP) scaffold presenting PSA covalently via its reducing end (MAP-PSA) is engineered, recapitulating physiological glycan orientation. MAP-PSA exhibits robust mechanical properties, stable glycan immobilization, and resistance to enzymatic degradation. Using ischemic stroke as a CNS injury model, MAP-PSA significantly reduces neutrophil infiltration and inflammatory activation while enhancing reparative macrophage and microglial phenotypes. These immunomodulatory effects persist into subacute stages, characterized by sustained reductions in inflammation and enhanced microglial homeostasis. Overall, MAP-PSA scaffolds demonstrate a novel therapeutic paradigm for CNS injuries such as stroke, with translational potential for broader neuroinflammatory and regenerative applications.

bioengineering↗

bioRxiv2025

Excitatory signal processing in early visual areas based on task-relevance and perceptual salience modulates visual perceptual learning

Adaptive visual perceptual learning (VPL) should occur primarily for visual signals relevant to an observers task but not for task-irrelevant signals. However, it is unclear which neural mechanisms reduce VPL for task-irrelevant signals. Here, we repeatedly exposed participants to a task-irrelevant visual signal (coherent motion in one direction) that was perceptually salient (suprathreshold for coherent motion detection) or weak (near threshold for coherent motion detection). The processing of the task-irrelevant signal in early visual areas during the first and final exposure sessions was measured using functional magnetic resonance spectroscopy (fMRS). The behavioral results showed that discrimination sensitivity for the exposed coherent motion direction increased to a greater extent after near threshold than after suprathreshold exposure. The fMRS results showed that excitatory processing in early visual areas, as reflected in the concentration of glutamate, was lower during suprathreshold than near threshold exposure. The lower the level of excitatory processing in the first exposure session, the more deteriorated the discrimination sensitivity for the coherent motion direction after suprathreshold exposure. When the coherent motion direction was rendered task-relevant, levels of glutamate in early visual areas reversed such that excitatory processing was greater when the coherent motion direction was presented suprathreshold than near threshold. This suggests that the level of excitatory processing in early visual areas changes with the task relevance and perceptual salience of a visual signal, which may modulate the extent of VPL for this signal when it is repeatedly exposed. Significance StatementVisual perceptual learning (VPL) enhances the efficiency in processing visual signals and is fundamental to the brains ability to adapt to changing environmental conditions. However, little is known about neural mechanisms that reduce VPL, although such mechanisms are crucial for adaptive VPL, which occurs primarily for visual signals relevant to an observers task but not for task-irrelevant signals. Here we find that early visual areas decrease excitatory processing for a salient task-irrelevant visual signal, which is associated with reduced VPL for this signal. This suggests, first, that a decrease of excitatory activity may be a mechanism that reduces VPL for salient task-irrelevant signals and, second, that this mechanism exerts its effect already at an early stage of cortical visual processing.

neuroscience↗

bioRxiv2025

Goal-directed visual information processing with GABAergic inhibition in parietal cortex

Goal-directed visual information processing involves tracking relevant visual signals (targets) over space and time. However, goal-irrelevant visual signals (distractors) can interfere with the tracking of targets. The neural mechanisms, which promote the tracking of targets in the challenge of interference from distractors remain elusive. Here, we used time-resolved functional magnetic resonance spectroscopy (fMRS) to measure concentrations of {gamma}-aminobutyric acid (GABA), a chief inhibitory neurotransmitter, and glutamate, a chief excitatory neurotransmitter, in parietal and visual cortex while participants performed a visual tracking task for targets among distractors. We found that the more targets had to be tracked, the greater the concentrations of GABA and glutamate in parietal cortex. In visual cortex only the concentration of glutamate increased with the number of targets. Concentration changes of GABA and glutamate only in parietal cortex were differentially associated with tracking performance: Better target tracking was associated with greater increase in GABA concentration and smaller increase in glutamate concentration. The results of control experiments showed that this differential association between tracking performance and metabolite changes in parietal cortex reflected individual differences in distractor suppression: participants with better distractor suppression during tracking tended to have greater increase in GABA concentration and smaller increase in glutamate concentration. This suggests that target-distractor interference during tracking is minimized by GABAergic suppression of goal-irrelevant distractors in parietal cortex, thereby promoting goal-directed visual information processing.

neuroscience↗

bioRxiv2025

Kupffer cells control neonatal hepatic metabolism via Igf1 signaling

During perinatal development, liver metabolism is tightly regulated to ensure energy supply for the newborn. Before birth, glycogen is stored in hepatocytes and later metabolized to glucose, meeting the energy demands of the neonate. Shortly after birth, lipogenesis begins, driven by the transcriptional activation of enzymes involved in fatty acid oxidation. These processes are thought to be largely regulated by systemic insulin and glucagon levels. However, the role of liver-derived local factors in neonatal hepatocyte metabolism remains unexplored. Kupffer cells (KCs), the livers resident macrophages, colonize the fetal liver early in embryogenesis and support liver metabolism in adulthood. Yet, whether KCs influence neonatal hepatocyte metabolism is unknown. Here, using conditional knockout mouse models targeting macrophages, we demonstrate that yolk sac-derived KCs play a critical role in hepatocyte glycogen storage and function by regulating the tricarboxylic acid (TCA) cycle - a role that monocyte-derived KC-like cells cannot substitute. Newborn pups lacking yolk sac-derived KCs mobilize glycogen more rapidly, a process regulated by insulin-like growth factor 1 (Igf1) production. Our findings reveal that macrophages are a major source of Igf1 at birth and that local Igf1 production by KCs is essential for balanced hepatocyte metabolism.

developmental biology↗

bioRxiv2025

Insights into global antimicrobial resistance dynamics through the sequencing of enteric bacteria from U.S. international travelers

Antimicrobial resistance (AMR) is an urgent threat to public health, but gaps in surveillance limit the detection of emergent novel threats and knowledge about the global distribution of AMR genes. International travelers frequently acquire AMR organisms, and thus may provide a window into AMR dynamics in otherwise poorly monitored regions and environments. To assess the utility of travelers as global AMR sentinels, we collected pre- and post-travel stool samples from 608 travelers, which were screened for the presence of extended-spectrum beta-lactamase producing Enterobacterales, carbapenem-resistant Enterobacterales, and mcr-mediated colistin-resistant Enterobacterales. A total of 307 distinct AMR organisms were sequenced in order to determine genotypic patterns and their association with travel region and behavior. Travel-associated AMR organisms were overwhelmingly E. coli, which exhibited considerable phylogenetic diversity regardless of travel region. However, the prevalence of resistance genes varied by region, with blaCTX-M-55 and blaCTX-M-27 significantly more common in travelers returning from South America and South-Eastern Asia, respectively. Hybrid assembly and plasmid reconstruction revealed the genomic neighborhood of blaCTX-M-55 frequently matched a motif previously linked to animal populations. Contact with animals was also associated with virulence factors in acquired AMR organisms, including carriage of the ColV plasmid, a driver of avian pathogenic E. coli. We identified novel variants of the mcr-1 gene in strains acquired from Western Africa, highlighting the potential for traveler surveillance to detect emerging clinical threats. Ongoing efforts to track travel-acquired organisms could complement existing global AMR surveillance frameworks. ImportanceWe collected pre- and post-travel stool samples from 608 U.S. international travelers, which were screened for the presence of three clinically relevant antimicrobial-resistant organisms, with the goal of understanding the utility of travelers as sentinels for emerging AMR and identifying regional resistance patterns. We sequenced 307 organisms and uncovered significant diversity and geographic heterogeneity in AMR organisms. We found significant differences in certain resistance gene alleles of travelers returning from South America and South-Eastern Asia, traveler contact with animals associated with virulence factors, including a plasmid that is a known driver of avian pathogenic E. coli, and novel variants of the colistin resistance mcr-1 gene in strains acquired from Western Africa. This work emphasizes the value of monitoring international travelers as a proxy for understanding AMR patterns globally and could be an important addition to existing global AMR surveillance frameworks.

genomics↗

bioRxiv2024

PyRID: A Brownian dynamics simulator for reacting and interacting particles written in Python

Recent technological developments in molecular biology led to large data sets providing new insights into the molecular organisation of cells. To fully exploit their potential, these developments have to be complemented by computer simulations that allow to gain in-depth understanding on molecular principles. We developed the Python-based, reaction-diffusion simulator PyRID, integrating many features for the efficient simulation of molecular biological systems. Amongst others, PyRID is capable of simulating unimolecular and bimolecular reactions as well as pair-interactions to assess the dynamics resulting from individual interacting proteins to polydisperse substrates consisting of many different molecules. Furthermore, PyRID supports mesh-based compartments and surface diffusion of particles, enabling analyses of the interaction between (trans-)membrane proteins with intra- and extracellular proteins. PyRID is written entirely in Python, which is a programming language being known for its readability and easy accessibility, such that the scientific community can easily extend PyRID to its current and future needs.

neuroscience↗

bioRxiv2024

SNP panel for non-invasive genotyping of leopard (Panthera pardus)

Genetic resources for species monitoring should ideally be relevant for the species full distribution range, feasible economically and logistically, and validated for the range of sample types collected from the field. This is particularly important for large carnivores that are elusive and wide-ranging, where individual and population processes often traverse administrative borders, and where obtaining high-quality samples can be challenging. Here we present a small species-specific SNP panel for leopards. We used whole genome data from across the global range and RAD sequence data from Zambian leopards to select markers for assay development. These were ascertained for 590 individual leopards from eight African countries and final selection was based on marker variation and performance on non-invasive samples. The final 96 marker panel holds 5 mitochondrial markers for species recognition, 3 Y-markers for determination of individual sex, 3 X-markers and 85 somatic markers, with an associated genetic baseline holding nearly 900 individuals. The selected autosomal markers hold variation across the global range with high power to identify individuals (PID=2,45x10-35) and in most cases their provenance with high assignment probability (>95%). Markers were also selected based on their performance on samples with low target DNA content, with distinct genotype separation in the output marker plots. The genotypes from this panel are thus straightforward to analyze and do not require computationally challenging bioinformatic resources, making this a low cost and accessible resource for leopard monitoring and research.

genetics↗

bioRxiv2024

Loss of the Inv(16) Oncogene CBFB::MYH11 Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow

Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, [~]40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.

cancer biology↗

bioRxiv2024

Covalent on-cell conjugation of biomaterials through oxidative phenolic coupling regulates stem cell fate via intracellular biophysical programming

Mechanotransduction is widely used to guide cell fate in hydrogels. Traditionally, hydrogels contain adhesive ligands that dynamically bond with cells to stimulate biochemical signalling axis such as YAP-TAZ. However, the molecular toolbox to achieve mechanotransduction has remained virtually limited to non-covalent bonds, which limits our ability to program engineered living matter. Here, we demonstrate that on-cell chemistry can be leveraged to covalently tether biomaterials directly onto cells, and reveal that mechanotransduction is enabled via intracellular biophysical programming. Specifically, droplet microfluidics produced single-cell microgels in which individual stem cells were extracellularly conjugated to either soft or stiff hydrogels via on-cell oxidative phenolic coupling, which allowed for investigation of mechanotransduction at single-cell resolution. Interestingly, this altered intracellular molecular crowding, calcium signalling, and chromatin organization by regulating cytoplasmic and nuclear volume in a stiffness-dependent yet YAP/TAZ-independent manner. Notably, addition of conventional dynamic adhesive ligands such as RGDs decreased chondrogenic commitment indicating that covalent cell-material tethering is both efficient and sufficient for programming cell fate. Encoding biomaterials with a novel form of mechanotransduction in the form of covalent on-cell chemistry, such as oxidative phenolic coupling, expands our ability to guide cellular behaviour, which can accelerate development of drug-screening models, lab-grown meat, and engineered tissues.

bioengineering↗

bioRxiv2024

Characterizing human CMV-specific CD8+ T cells using multi-layer single-cell omics

In this study we established a comprehensive workflow to collect multi-omics single-cell data using a commercially available micro-well based platform. This included whole transcriptome, cell surface markers (targeted sequencing-based cell surface proteomics), T cell specificities, adaptive immune receptor repertoire (AIRR) profiles and sample multiplexing. With this technique we identified novel paired T cell receptor sequences for three prominent human CMV epitopes. In addition, we review the ability of dCODE dextramers to detect antigen-specific T cells at low frequencies by estimating sensitivities and specificities when used as reagents for single-cell multi-omics. MotivationIn this study, we report the first five-layer multi-omics dataset using the BD Rhapsody single-cell platform for the characterization of human antigen-specific T cells. Modalities include whole transcriptome, T cell receptor (TCR) sequences, T cell antigen specificity measured by dCODE dextramers, surface marker proteins and combinatorial sample multiplexing combining two distinct hashing approaches.

genomics↗

bioRxiv2024

Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8+ T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15-driven neuropathology. Targeting activated microglia, CD8+ T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.

immunology↗

bioRxiv2024

Analysing drivers of worldwide tidal wetland change

Tidal wetlands are dynamic coastal ecosystems that can change in extent in response to a broad range of change drivers. We use high spatial resolution satellite imagery to estimate the relative influence of 18 classes of change drivers on observed tidal wetland gains and losses from 1999 to 2019, differentiating direct drivers as those observable at the site of ecosystem change, and indirect drivers as broader processes that influence changes without being directly visible. We developed a random sample of 2823 change detections from a global dataset of tidal wetland change and allocated each change event to driver classes using high-resolution time-series imagery. We identified that indirect drivers were the most widespread type of driver of tidal wetland change (70.9%), with flooding being the predominant driver for losses (47.5%) and unknown natural processes of change for gains (62.7%). Drivers often associated with climate change were evident in interpretations of wetland drivers, with increases in flooded area and reductions in vegetation cover suggesting the effects of relative sea level rise on tidal wetlands are observable in many areas. Our temporal analysis revealed that over 20 years, indirect drivers consistently contributed to larger proportions of gains and losses compared to direct drivers. Asia was the only continent where direct drivers of loss, such as agriculture (22.9%) and aquaculture (17.1%), outweighed indirect drivers, providing further evidence of the widespread transformation of Asias natural coastal ecosystems to anthropogenic shorelines. Globally, coastal land reclamations were mostly observed in mangrove ecosystems, where more than half of the observed losses were of anthropogenic origin. The most observed direct drivers of gains were altered land management and restoration, but none of them contributed to more than 5% of the total gains over 20 years. Our findings suggest a need for efficient conservation measures that allow the dynamic processes that characterise coastal ecosystems to persist, while simultaneously reducing the worldwide impact of direct human activities.

ecology↗

bioRxiv2024

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimers disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling, we generated a TREM2 reporter mouse model and observed a gradual upregulation of reporter expression with increasing plaque proximity. Isolated microglia were sorted based on reporter expression and their transcriptomic profiles acquired in both wildtype and APP transgenic animals, allowing us to disentangle TREM2 versus pathology-specific effects. Bulk RNA-sequencing highlighted TREM2 level-dependent changes in major immunometabolic pathways, with enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. To confirm these findings, we next analysed uptake of fluorodeoxyglucose (FDG) and examined metabolomic and lipidomic profiles. Again, independent of A{beta} pathology, TREM2 expression correlated with uptake of FDG as well as increased cellular redox, energetics, and cholesterol homeostasis. Finally, we performed chronic treatment with a brain penetrant TREM2 agonist and identified a window of TREM2 expression where microglia are most responsive. Thus, our data provide novel insights into TREM2-mediated regulation of microglial metabolic function and informs current efforts to bring TREM2 agonists into clinical application.

neuroscience↗