Biology subjects

Nagel, J.

Publications and source records attributed to Nagel, J..

6 recordsLinked to original sources

bioRxiv2026

A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology

The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimers disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-{beta} plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.

neuroscience↗

bioRxiv2025

Challenges in Replay Detection by TDLM in Post-Encoding Resting State

Using temporally delayed linear modelling (TDLM) and magnetoencephalography (MEG), we investigated whether items associated with an underlying graph structure are replayed during a post-learning resting state. In these same data, we previously provided evidence for replay during on-line (non-rest) memory retrieval. Despite successful decoding of brain activity during a localizer task, and contrary to predictions, we found no evidence for replay during a post-learning resting state. To better understand this, we performed a hybrid simulation analysis in which we inserted synthetic replay events into a control resting state recorded prior to the actual experiment. This simulation revealed that replay detection using our current pipeline requires an extremely high replay density to reach significance (>1 replay sequence per second, with "replay" defined as a sequence of reactivations within a certain time lag). Furthermore, when scaling the number of replay events with a behavioural measure, we were unable to induce a strong correlation between sequenceness and this measure. We infer that even if replay was present at plausible rates in our resting state dataset, we would lack statistical power to detect it with TDLM. Finally, contrasting our novel hybrid simulation to existing purely synthetic simulations indicated that the latter approaches overestimate the sensitivity of TDLM. We discuss approaches that might optimize the analytic methodology, including identifying boundary conditions under which TDLM can be expected to detect replay. We conclude that solving these methodological constraints will be crucial for optimizing the non-invasive measurement of human replay using MEG.

neuroscience↗

bioRxiv2025

UB-MBX-46 is a potent and selective antagonist of the human P2X7 receptor developed by structure-based drug design

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Interspecies variation among existing antagonists has proven challenging, in part due to the dearth of molecular information on different receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with new and existing structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with picomolar potency and high selectivity, revealing its significant therapeutic potential.

biochemistry↗

bioRxiv2025

High intensity exercise before sleep boosts memory encoding the next morning

The importance of sleep for memory consolidation has been extensively studied, but its role for memory encoding remains less well characterized. At the molecular and cellular level, the renormalization of synaptic weights during sleep has received substantial support, which is thought to free capacity to encode new information at the behavioral level. However, at the systems level and behaviorally, support for this process playing a major role for memory function remains scarce. In the current study, we investigated the utility of moderate- and high-intensity evening exercise as a low-cost low-tech intervention to modulate sleep and its influence on subsequent encoding in the morning. Our findings indicate that high-intensity interval training (HIIT) improved post-sleep memory performance with effects lasting up to 24 hours after initial encoding. In addition, we show that especially the early parts of the encoding task were affected by the HIIT intervention, which is in line with increases in synaptic homeostasis being targeted by the exercise. Intriguingly, low-performing participants seemed to benefit more from the HIIT intervention suggesting it not only as a tool for basic research but also as a candidate for applications to boost memory performance in mental disorders or in the elderly. These results provide first evidence that acute exercise can affect learning processes even hours after it occurs.

neuroscience↗

bioRxiv2024

Unusual migratory strategy a key factor driving interactions at wind energy facilities in at-risk bats

Seasonal movement strategies are poorly understood for most animals, impeding broader understanding of processes underlying migration and limiting practical conservation needs. Here we develop and implement a framework for integrating multiple sources of endogenous markers, in particular stable hydrogen isotope data, that capture and scale dynamics from the movements of individuals to that of continental migration. We assembled and integrated thousands of new isotopic measurements from bat fur with existing datasets and applied this framework to reveal migratory patterns of three broadly distributed bat species most at risk for fatalities at wind energy facilities. Our findings show that the species comprising the lowest proportion of wind turbine fatalities (silver-haired bats) exhibits expected movements to lower latitudes in autumn and higher latitudes in spring. Surprisingly, the two species with higher wind turbine fatality rates (hoary and eastern red bats) have more complex movements, including significant movement to higher latitudes during autumn. We term this unique strategy "pell-mell" migration, during which some individuals are as likely to move to higher latitudes as lower latitudes, relative to their individual summering grounds, in early autumn, after which they move to similar or lower latitudes to overwinter. The pell-mell migratory period corresponds with peak fatalities at wind energy facilities, and bats moving northward during autumn are associated with mortality at those facilities. Our results provide direct support for the hypothesis that bat fatalities at wind energy facilities are related to migration and highlight the importance of migratory distance as an ultimate driver of increased interactions with wind energy facilities, which appears significantly greater for species that travel widely across latitudes in the autumn.

ecology↗

bioRxiv2023

Reactivation strength during cued recall is modulated by graph distance within cognitive maps

Declarative memory retrieval is thought to involve reinstatement of neuronal activity patterns elicited and encoded during a prior learning episode. Furthermore, it is suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained this information over a brief 8-minute consolidation period. During a subsequent cued recall session, participants retrieved the learned information while undergoing magnetoencephalographic (MEG) recording. Using a trained stimulus decoder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not for retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and was most evident in low performers. The results provide evidence for distinct performance-dependent retrieval mechanisms with graded clustered reactivation emerging as a plausible mechanism to search within abstract cognitive maps.

neuroscience↗