Biology subjects

Baranes, K.

Publications and source records attributed to Baranes, K..

4 recordsLinked to original sources

bioRxiv2026

Tau aggregate replication occurs at the pre-synapse of cultured human neurons and increases with application of TNFa

Tau aggregation at synapses is a key process driving Alzheimers disease but the mechanism(s) that cause this have not been established. We used a model system of forward-programming induced glutamatergic neurons (iNeurons) with three independent cell lines treated with TNF[a]. Using aggregate-specific SIMOA, STED microscopy, and SynPull to detect nanoscopic tau aggregates in bulk samples and at individual synapses, we found that TNF[a]-driven tau aggregation occurs preferentially at the pre-synapse, forming predominantly non-fibrillar aggregates that are larger than ones in the extra- and post-synaptic regions. Using mathematical models of aggregate formation, we fitted the frequency of AT8-positive tau aggregates in synaptosomes, which showed that aggregate replication is the dominant process and is much faster than de-novo aggregate formation, leading to rapid local amplification once one aggregate is formed. Our results provide direct evidence for tau aggregate replication at the pre-synapse, linking inflammation induced tau aggregation with synaptic pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/728997v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@169dacorg.highwire.dtl.DTLVardef@c9894corg.highwire.dtl.DTLVardef@1551253org.highwire.dtl.DTLVardef@260ae7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

imAgeScore, a Cell Painting-Based Predictor of Cellular Age for High-throughput Drug Screening Applications

Quantifying cellular age in vitro in a scalable and biologically meaningful manner is essential for the discovery of pharmacological interventions that modulate aging. We developed imAgeScore, a machine-learning model trained on high-content Cell Painting features to predict the phenotypic age of primary human dermal fibroblasts. imAgeScore correlates with chronological and DNA methylation-based age estimates and captures coordinated morphological changes across nuclear and cytoplasmic compartments. The model detected age acceleration during serial propagation and age reduction following partial reprogramming. Pharmacological interventions targeting distinct aging hallmarks induced predictable shifts in predicted age and enabled classification of damaging versus rejuvenating cellular states. Application of imAgeScore in an automated high-throughput screening pipeline identified candidate age-modulating compounds, revealed inter-individual variability in response magnitude, and detected additive rejuvenation effects in selected combinatorial treatments. Functional validation in a scratch wound assay confirmed enhanced cellular repair by leading candidates, supporting the biological relevance of morphology-derived age reduction. Together, these results demonstrate that image-based morphological profiling provides a scalable platform for quantifying cellular aging and screening for candidate rejuvenation interventions.

cell biology↗

bioRxiv2025

Drug treatment alters performance in a neural microphysiological system of information processing

Assessment of pharmacological intervention on in vitro neural systems often emphasizes molecular and structural changes. However, neural systems fundamentally process and act on information. For preclinical assays to predict drug efficacy, they must model these physiological functions. DishBrain, an in vitro synthetic biological intelligence (SBI) assay embodying a neural system in a simulated game-world, enables the quantification of this information-processing capacity, however the question remains whether such a system permits classical pharmacological interrogation and dose-response profiling. Hyperactive glutamatergic dysregulation is linked to neurological disorders including epilepsy, and inducible overexpression of neurogenin 2 (NGN2) in human induced pluripotent stem cells (hiPSCs) generates glutamatergic cultures with dysregulated hyperactivity. We therefore tested three anti-seizure medications (ASMs), phenytoin, perampanel, and carbamazepine, on NGN2 neurons from day 21 of differentiation in this system. The key finding was that, while all compounds altered spontaneous firing, carbamazepine 200 {micro}M significantly improved gameplay metrics. This marks the first demonstration of altered SBI following exogenous drug treatment. Notably, only inhibitory compounds enhanced goal-directed activity, linking glutamatergic attenuation to performance. Neurocomputational analysis revealed nuanced pharmacological responses during closed-loop stimulation, highlighting insights beyond spontaneous activity metrics.

neuroscience↗

bioRxiv2024

Circadian clocks in human cerebral organoids

Circadian rhythms result from cell-intrinsic timing mechanisms that impact health and disease1,2. To date, however, neural circadian research has largely focused on the hypothalamic circuitry of nocturnal rodents3. Whether circadian rhythms exist in human brain cells is unknown. Here we show bona fide circadian rhythms in human neurons, glia, cerebral organoids, and cerebral organoid slices (ALI-COs)4-8. Human neural circadian rhythms are synchronised by physiological timing cues such as glucocorticoids and daily temperature cycles, and these rhythms are temperature-compensated across the range of normal human brain temperatures9. Astrocyte rhythms are phase-advanced relative to other cultures and they modulate neuronal clock responses to temperature shift. Cerebral organoid rhythms are more robust at physiological brain temperatures; the relative amplitude of these rhythms increases over time in culture and their resetting capacity recapitulates key neurodevelopmental transitions in glucocorticoid signalling10-14. Remarkably, organoid post-transcriptional bioluminescent clock reporter rhythms are retained even when those of their putative transcriptional drivers are indiscernible15, and electrophysiology recordings confirm circadian rhythms in functional activity of monocultures, organoids, and ALI-COs. Around one third of the cerebral organoid proteome and phosphoproteome are circadian-rhythmic, with temporal consolidation of disease-relevant neural processes. Finally, we show that human brain organoid rhythms can be modulated and disrupted by commonly used brain-permeant drugs and mistimed cortisol exposure, respectively. Our results demonstrate that human brain cells and tissues develop their own circadian oscillations and that canonical mechanisms of the circadian clockwork may be inadequate to explain these rhythmic phenomena. 2D and 3D human neural cultures represent complementary and tractable models for exploring the emergence, disruption, and mechanics of the circadian neural clockwork, with important implications for chronobiology, brain function, and brain health.

neuroscience↗