Neuroscience Publications

Wanqing Jiang, Cecilia Skoug, Ian Rodrigues, Ernesto Ciabatti, Fiona M. Gribble, Frank Reimann, Daniel I. Brierley, Marie K. Holt, Stefan Trapp

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, known as preproglucagon (PPG) neurons, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if chronic stimulation of PPG neurons is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that PPG neurons in the NTS and intermediate reticular nucleus (IRT) determine meal size, and that their total number is inversely correlated with bodyweight gain. We report that PPGNTS and PPGIRT neurons receive distinct monosynaptic inputs, but have convergent efferent projection targets throughout the brain, and that combined ablation of both populations delays the onset of physiological satiation to a degree sufficient to promote weight gain under ad libitum chow fed conditions. Crucially, chronic daily chemogenetic activation of PPGNTS+IRT neurons drives robust and sustained hypophagia and weight loss in obese mice without notable adverse effects, demonstrating their value as targets for obesity pharmacotherapy.

Molecular Metabolism, May 2026

Roisin Murphy, Julia A. Fairbairn, Becca W.A. Baileeves, Phillip J. Stansfeld, Timothy D.H. Bugg

A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage ϕX174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF3) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19606 (MIC 8 μg/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 μg/mL). The analogues showed 33–47% inhibition of particulate E. coli MraY at 200 μM concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC50 210 μM). Docking against the structure of E. coli MraY revealed a possible binding site in the “elbow” of bent helix 9, close to Phe-288. This work identifies the MraY-protein E interaction site as a possible target for the antimicrobial activity of bromoageliferin, and establishes a new skeleton for design of non-nucleoside MraY inhibitors.

Bioorganic & Medicinal Chemistry Letters, July 2026

Boltze J., Fisher M

Recanalization therapies for ischemic stroke, in particular endovascular thrombectomy, have revolutionized acute stroke management. Cytoprotective approaches were unsuccessfully tested in the pre-recanalization era but have seen a renaissance in translational research and early clinical trials as a potential intervention to augment the impact of recanalization therapies. The new clinical trial approaches in which cytoprotective therapies are now being applied require refinement of cytoprotective application strategies. This has a profound impact on both preclinical translational and clinical research. This review summarizes current cytoprotection concepts and explains their rationale based on ischemic stroke pathophysiology and provides an overview of cytoprotection approaches currently under clinical assessment. Preclinical assessment of novel cytoprotective paradigms will require advanced in vivo testing in models resembling human stroke patients as much as possible. The review therefore also describes ways to improve preclinical and translational research with respect to comorbidities and other aspects impacting stroke pathophysiology. Moreover, the role of modern brain imaging approaches is discussed including their use as potential biomarkers or patient selection tools. The review further provides detailed considerations of novel clinical trial design features for cytoprotection trials in the context of recanalization therapies and provides an outlook on potential future research approaches.

Advanced Science, February 2026

Ling Cai, Yan Li, Chong Wang, Tim Magnus, Chengye Yao, Xiaoming Hu, Ann M. Stowe, Anna Rosell, Sunghee Cho, Stuart M. Allan, Jieqing Wan, Yulong Ma, Yang Liu, Daniel I. Sessler, Johannes Boltze, Tianlong Wang, Weifeng Yu, Yueman Zhang, Peiying Li,

Ischemic stroke is a major global health burden, leading to considerable mortality and long-term disability. Endovascular thrombectomy and mechanical recanalization have revolutionized acute stroke care. Nonetheless, many patients experience poor long-term neurological outcomes, which are often attributed to the no-reflow phenomenon and activation of inflammatory cascades. The perioperative period of endovascular thrombectomy, managed under either general anesthesia or conscious sedation, represents a critical window where anesthetic strategies may influence recovery through hemodynamic control and possibly immune modulation. This consensus review was generated by an international multidisciplinary expert group and synthesizes preclinical and clinical evidence to evaluate the promise of various immunomodulatory strategies for improving functional outcomes in patients with ischemic stroke following endovascular thrombectomy. Our goal is to provide a foundational reference for future research and development of novel perioperative immune therapies for patients with endovascular thrombectomy.

Stroke, February 2026

Matthew J Padgett , Nela Fucelova , Johannes Boltze, Timothy J England , Tuuli Hietamies , Karen Horsburgh , Terence J Quinn , Emily S Sena , Lorraine M Work, Marietta Zille, Rebecca C Trueman, Tracy D Farr

Hypoperfusion via bilateral carotid artery stenosis is the most common mouse model of vascular cognitive impairment, but the literature varies surrounding which behavioural tests are most appropriate to detect cognitive deficits in this model. We aimed to address this via a systematic review and meta-analysis. We also aimed to provide a recommendation that also considers how the tests cover the different cognitive domains. We identified 1714 publications and extracted data from 56. Interestingly, only six cognitive behavioural tests were employed across the literature with the most common being the Morris water and radial arm mazes, followed by the Y maze, novel object recognition, open field, and the Barnes maze. While all examined tests were able to detect cognitive impairments in hypoperfused mice, there was a high degree of heterogeneity across the publications, highlighting that not all research groups consistently observed cognitive deficits in the model. There was also evidence of publication bias, and occasionally some publications with extremely high effect sizes were influential. We recommend all tests, but ideally experiments should be complemented with additional approaches that examine a greater range of cognitive functions.

Journal of Cerebral Blood Flow & Metabolism, January 2026

Amol Mohan Bhandare, Adwoa Boaten, Dylan Dunkwu, Jade Hill, Biborka Balazs, Nicholas Dale

Impaired CO₂ responsiveness in epilepsy can result in hypoventilation and hypercapnia and these respiratory disturbances are key contributors to Sudden Unexpected Death in Epilepsy (SUDEP). While mild to moderate inflammation is known to modulate respiratory function, its specific role in regulating respiratory responses in the context of epilepsy remains unclear. We studied the effects of lipopolysaccharide (LPS)-induced inflammation and microglial inhibition via minocycline during the acute and chronic phases of epilepsy on hypercapnic ventilatory responses (HCVR) in the intrahippocampal kainic acid model of temporal lobe epilepsy in male C57BL/6 mice. LPS treatment during acute seizures and minocycline during spontaneous seizures in the chronic phase of epilepsy restored the impaired HCVR in mice. Notably, LPS treatment during acute seizures also reduced the frequency of spontaneous seizures. In contrast, minocycline given during acute seizures and LPS administered during chronic epilepsy further exacerbated HCVR impairment. Immunohistochemical analysis of chemosensitive retrotrapezoid nucleus (RTN) revealed varied effects of different treatments in epileptic mice on microglia density, morphology and their expression of triggering receptor expressed on myeloid cells 2 (TREM2), P2Y12 receptor, and astrocytic adenosine 2A receptor (A2AR). Overall, the inflammation during epileptogenic or acute phase preserves HCVR and reduces spontaneous seizure frequency in chronic epilepsy, whereas in chronic phase it worsens HCVR. Although not yet fully validated, changes in microglial and astrocytic receptor expression could contribute to this HCVR impairment and may represent a mechanistic target for preserving HCVR in epilepsy; a dysfunction that could potentially lead to SUDEP.

Journal of Neuroinflammation, January 2026

Xuming Zhang, Mitali Malhotra

Mutual interaction between the nervous and immune systems underpins many pathophysiological processes. Transient Receptor Potential Melastatin 2 (TRPM2) channels are abundantly expressed in both systems, acting as a critical interface of neuroimmune interaction. TRPM2 channels in immune cells participate in innate immunity and immune inflammation by acting as an oxidative stress and metabolic sensor. TRPM2 in neurons functions not only as an oxidative sensor but also a temperature sensor and a pain transducer critical to neuronal death, temperature sensing, thermoregulation, and chronic pain. Cooperation between immune and neuronal TRPM2 influences the outcome of neuroimmune interaction and many diseases such as infection, inflammation, ischemic stroke, pain, and neurodegenerative diseases. Improved understanding of neuronal and immune TRPM2 interaction is essential for therapeutic interventions for the treatment of diseases mediated by TRPM2 channels.

Cells, 2026

Piotr Walczak, Shen Li, Xunming Ji, Johannes Boltze

Most conditions of the central nervous system (CNS) and the peripheral nervous system are not stand-alone disorders but are modulated and influenced by other pathobiological processes. For instance, the impact of frequent comorbidities such as hypertension or dyslipidemia as factors contributing to and aggravating CNS diseases has been much better understood in recent years. Another prominent disease-modifying factor is the gut microbiome which can exert both protective and detrimental effects on the nervous system in health and disease. An even better understanding of these factors will contribute to the development of individualized treatment approaches, a major research objective in the era of precision medicine. The current issue of Neuroprotection presents articles focusing on disease-modifying factors or novel treatment approaches for a broad spectrum of conditions. This provides a wide perspective but also novel insights into disease mechanisms and targeted treatment approaches. Priority has been given to articles reporting, reviewing or meta-analyzing clinical data as well as articles providing results of translationally relevant preclinical work.

Neuroprotection, December 2025

Emma Short, Ramzi Ajjan, Thomas M Barber, Sunil Bhandari, Paul Chazot, Jennifer L. Garrison, Anushka Goyal, Robert Huckstepp, Noordin Jamal, Venkateswarlu Kanamarlapudi, Alpar Lazar, Thomas Lee, Adriana A. S. Tavares, Jeremy J Tree, Jack Wellington, Stuart RG Calimport, Barry Bentley

An ageing-related pathology has recently been described as one that develops and/or progresses with increasing chronological age, that is associated with, or contributes to, functional decline and that is evidenced by studies in humans. The pineal gland is a photo-neuroendocrine organ whose primary function is to produce and secrete melatonin in response to light-dark cycle environmental cues. The gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion. Pineal gland senescence describes the ageing-related decline in neuroendocrine function, with reduced secretion of melatonin, which may contribute to ageing-related sleep disorders and disruption of other circadian-driven physiological functions and may have secondary effects such as contributing to cognitive and mood disorders related to sleep disturbance.

Hormones, December 2025

Bertil B. Fredholm, Lauren May, Christa E. Müller, Joel Linden, Karl-Norbert Klotz, Kenneth A. Jacobson, Adriaan P. IJzerman, Rebecca Hills, Bruno G. Frenguelli, Gary L. Stiles

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [114]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [155]. More recently, structures for the A2B receptor [58, 48] and the A3 receptor [279, 47] were elucidated. The A2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank (www.rcsb.org). istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson's disease, while caffeine's mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A1 and A3 receptors, have been explored chemically and structurally.

IUPHAR/BPS Guide to Pharmacology CITE, December 2025

Sean Savitz, Edgar Samaniego, David Liebeskind, Johannes Boltze

A STAIR XIII workshop was held to discuss aspects of trials likely to have the greatest impact on detecting meaningful treatment effects of cerebroprotection in acute stroke. Intended goals for hyperacute protection should be focused on preserving penumbral tissue and delaying infarct core growth to augment the impact of reperfusion therapies. Infarct volume is a biologically and clinically meaningful surrogate imaging marker to assess the treatment effects of cerebroprotection. Lastly, clinical outcome measures for cerebroprotection should include domain-specific and patient-centered outcomes to detect clinically meaningful changes across multiple functional domains.

Stroke, November 2025

Alexandra Lovatt, Jack Butler, Nicholas Dale

Connexins can act either as hemichannels to facilitate ion and small-molecule movement from the cytosol to the extracellular space or as gap junction channels to provide a pathway for solute exchange between cells. Connexins are ubiquitously expressed throughout the body and are implicated in a wide range of processes. The permselectivity of connexin hemichannels for small neurochemicals remains poorly understood. By coexpressing genetically encoded fluorescent sensors for ATP, glutamate, and lactate with a range of connexins, we examined the ability of different hemichannels to permit the release of these compounds under physiological conditions and in response to physiological stimuli (small changes in partial pressure of CO2 and transmembrane depolarization). We found that some connexin hemichannels were relatively nonselective (Cx26, Cx32, Cx43, and Cx31.1) allowing passage of ATP, glutamate, and lactate. By contrast, other connexin hemichannels (Cx36, Cx46, and Cx50) were highly selective. Cx36 and Cx46 hemichannels allowed the release of ATP but not glutamate or lactate. The size of the permeating molecule cannot be the sole determinant of permselectivity. By contrast, Cx50 hemichannels permitted the release of lactate and glutamate but not ATP. We also found that the nature of the opening stimulus could alter the permselectivity of the hemichannel—for some of the relatively nonselective connexins, hemichannel opening via depolarization was ineffective at allowing the release of lactate. By performing a mutational analysis, informed by the differential selectivity of the closely related Cx46 and Cx50 hemichannels, we found that the charge on the N terminus and N terminus–transmembrane 2 interactions are key contributors to permselectivity for ATP.

Journal of Biological Chemistry, December 2025

Piotr Walczak, Shen Li, Xumming Ji, Johannes Boltze

Central nervous system (CNS) disorders are usually characterized by a complex pathophysiology. The last issue of Neuroprotection featured reviews and research articles looking at peripheral factors such as the gut microbiome or a history of pre-eclampsia and their impact on CNS conditions. Articles presented in the current issue of Neuroprotection will shift the focus back to the CNS but will continue to provide insights from recent research that help to better understand the pathophysiological complexity of CNS conditions.

Neuroinflammation is known to be a hallmark and major contributor to many CNS diseases. It comprises both peripheral and central immune cells and can be modulated by frequent comorbidities such as hypertension. Moreover, neuroinflammatory processes can involve cell populations not primarily characterized as immune cells. Psychiatric conditions, including major depressive disorders (MDD), are increasingly recognized to be linked to neuroinflammation but also to systemic comorbidities, stress and aging. A better understanding of neuroinflammatory processes in the context of psychiatric conditions may help to identify novel therapeutic targets for better and potentially causal treatment strategies.

Neuroprotection, September 2025

Emma Short, Robert T.R. Huckstepp et al

It is paramount that the language used in the scienitifc and medical literature is clear and unambiguous to ensure shared understanding amongst researchers, clinicians, and policymakers. The aim of the ICCARP is to develop a systematic and comprehensive classifcation system for ageingrelated changes including pathologies, diseases, and syndromes. Currently, the ICCARP is in the process of identifying all phenomena that meet the criteria for ageing-related pathologies, to develop proposals for grouping and naming them within a comprehensive classification system. We expect that these defnitions, and subsequent classifcations, will contribute to improving discourse, research methodologies, clinical diagnostics, and public health planning.

Geroscience. February 2025

Tohidul Islam et al, including Emily Hill & Mark J Wall

Patients with Alzheimer’s disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking. Our findings inform about the status of early-stage tau aggregation, reveal aggregation-relevant phosphorylation epitopes in tau and offer a diagnostic biomarker and targeted therapeutic opportunities for AD.

Nature Medicine. February 2025 

Press Release

Sarbjit Nijjar, Deborah Brotherton, Jack Butler, Valentin-Mihai Dospinescu, Harry G Gannon, Victoria Linthwaite, Martin Cann, Alexander Cameron, Nicholas Dale 

CO2 directly modifies the gating of connexin26 (Cx26) gap junction channels and hemichannels. This gating depends upon Lys125, and the proposed mechanism involves carbamylation of Lys125 to allow formation of a salt bridge with Arg104 on the neighbouring subunit. We demonstrate via carbamate trapping and tandem mass spectrometry that five Lys residues within the cytoplasmic loop, including Lys125, are indeed carbamylated by CO2 . Our findings directly demonstrate carbamylation in connexins, provide further insight into the differential action of CO2 on Cx26 hemichannels and gap junction channels, and increase support for the role of the N-terminus in gating the Cx26 channel. KEY POINTS: Direct evidence of carbamylation of multiple lysine residues in the cytoplasmic loop of Cx26. Concentration-dependent carbamylation at lysines 108, 122 and 125. Only carbamylation of lysine 125 is essential for hemichannel opening to CO2. Carbamylation of lysine 108 along with lysine 125 is essential for CO2-dependent gap junction channel closure.

Journal of Physiology. February 2025

Julia A. Fairbairn, Rachel V. Kerr, Nika-Kare A. Pierre-White, Anthony Jacovides, Becca W. A. Baileeves, Phillip J. Stansfeld, Gerhard Bringmann, Andrew T. Merritt and Timothy D. H. Bugg

Escherichia coli translocase MraY is the target for bacteriolytic protein E from bacteriophage fX174, interacting at a site close to Phe-288 on helix 9, on the extracellular face of the protein. A peptide motif Arg-Trp-x-x-Trp from protein E was used to design a set of triazinedione peptidomimetics, which inhibit particulate MraY (6d IC50 48 µM), and show antimicrobial activity against Gram-negative and Gram-positive antibiotic-resistant clinical strains (7j MIC Acinetobacter baumannii 16 µg/mL, Staphyloccoccus aureus MRSA 2-4 µg/mL). Docking against a predicted structure for E. coli MraY revealed two possible binding sites close to helix 9, the binding site for protein E. Antimicrobial activity of analogue 6j was found to be synergistic with bacitracin in Micrococcus flavus, consistent with a link between this inhibition site and undecaprenyl phosphate uptake. Alkaloid michellamine B, also predicted to bind in the cleft adjacent to helix 9, was also found to be synergistic with bacitracin. These data provide experimental evidence that the unusual hydrophobic cleft adjacent to helix 9 in MraY is involved in uptake of undecaprenyl phosphate, in addition to recently identified transporters UptA and PopT, and that this process can be targetted by small molecules as a novel antibacterial mechanism.

RSC Medicinal Chemistry. January 2025

Prakash R., Waseem A., Siddiqui A.J., Naim M., Khan M.A., Robertson A.A.B., Boltze J., Raza S.S.

after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.

Biomedicine and Pharmacotherapy. January 2025

Pawel K Lysyganicz, Antonio D Barbosa, Shoily Khondker, Nicolas A Stewart, George M Carman, Phillip J Stansfeld, Marcus K Dymond, Symeon Siniossoglou

Here we demonstrate that a lipid-degradation pathway inhibits expansion of the endoplasmic reticulum (ER) membrane. Phospholipid diacylglycerol acyltransferases (PDATs) use endogenous phospholipids as fatty-acyl donors to generate triglyceride stored in lipid droplets. The significance of this non-canonical triglyceride biosynthesis pathway has remained elusive. We show that active Lro1 mediates retraction of ER membrane expansion driven by phospholipid synthesis. Furthermore, subcellular distribution and membrane turnover activity of Lro1 are controlled by diacylglycerol produced by the activity of Pah1, a conserved member of the lipin family. Collectively, our findings reveal a lipid-metabolic network that regulates endoplasmic reticulum biogenesis by converting phospholipids into storage lipids.

EMBO Journal. January 2025

Marie K. Holt, Natalia Valderrama, Maria J. Polanco, Imogen Hayter, Ellena G. Badenoch, Stefan Trapp, Linda Rinaman

Stress-induced behaviours are driven by complex neural circuits and some neuronal populations concurrently modulate diverse behavioural and physiological responses to stress. Glucagon-like peptide-1 (GLP-1)-producing preproglucagon (PPG) neurons within the lower brainstem caudal nucleus of the solitary tract (cNTS) are particularly sensitive to stressful stimuli and are implicated in multiple physiological and behavioural responses to interoceptive and psychogenic threats. However, the afferent inputs driving stress-induced activation of PPG neurons are largely unknown, and the role of PPG neurons in anxiety-like behaviour is controversial. Through chemogenetic manipulations we reveal that cNTS PPG neurons have the ability to moderately increase anxiety-like behaviours in mice in a sex-dependent manner. Our findings reveal sex differences in behavioural responses to PPG neural activation and highlight a hypothalamic-brainstem pathway in stress-induced hypophagia.

Molecular Metabolism. January 2025

Kołodziej, Marta, Tsapras, Panagiotis, Cameron, Alexander and Nezis, Ioannis P

LC3 (microtubule-associated protein 1 light chain 3, called Atg8 in yeast and Drosophila) is one of the most well-studied autophagy-related proteins. LC3 controls the selectivity of autophagic degradation by interacting with LIR (LC3-interacting region) motifs also known as AIM (Atg8-interacting motifs) on selective autophagy receptors that carry cargo for degradation. Although the function of Atg8 family proteins is primarily cytoplasmic, they are also enriched in the nucleus. Here, we used yeast two-hybrid screening, and we identified transcription factor Deformed wings (Dwg) as an Atg8a-interacting protein in Drosophila. Dwg-Atg8a interaction is LIR motif-dependent. We have created Dwg Y129A/I132A LIR mutant flies and shown that they exhibit elevated autophagy, improved resistance to oxidative stress, and starvation. Our results provide novel insights into the transcriptional regulation of autophagy in Drosophila.

Cells. November 2024

Williams G.K., Akkermans J., Lawson M., Syta P., Staelens S., Adhikari M.H., Morton A.J., Nitzsche B., Boltze J., Christou C., Bertoglio D., Ahamed M.

The major goal of our preliminary cross-sectional study is to demonstrate the feasibility and utility of the unique transgenic sheep model of HD (OVT73) in positron emission tomography (PET) imaging. In this first-of-its-kind study, we showed the usefulness and validity of HD sheep model in imaging cerebral glucose metabolism and dopamine uptake using PET imaging. The identification of discrete patterns of metabolic abnormality using [18F]FDG and decline of [18F]FDOPA uptake may provide a useful means of quantifying early HD-related changes in these models, particularly in the transition from presymptomatic to early symptomatic phases of HD.

ACS Chemical Neuroscience. October 2024

Lorenzo Morè, Lucia Privitera, Marcia Lopes, J. Simon C. Arthur, Julie C. Lauterborn, Sonia A.L. Corrêa, Bruno G. Frenguelli

One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. To establish whether MSK1 converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.

Neuropharmacology. 2024

Mireia Montaner, Jessica Denom, Vincent Simon, Wanqing Jiang, Marie K. Holt, Daniel I. Brierley, Claude Rouch, Ewout Foppen, Nadim Kassis, David Jarriault, Dawood Khan, Louise Eygret, Francois Mifsud, David J. Hodson, Johannes Broichhagen, Lukas Van Oudenhove, Xavier Fioramonti, Victor Gault, Daniela Cota, Frank Reimann, Fiona M. Gribble, Stephanie Migrenne-Li, Stefan Trapp, Hirac Gurden & Christophe Magnan

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Nature Communications. August 2024

Jake Brooks, James Everett, Emily Hill, Kharmen Billimoria, Christopher M. Morris, Peter J. Sadler, Neil Telling & Joanna F. Collingwood

Neuromelanin-pigmented neurons of the substantia nigra are selectively lost during the progression of Parkinson’s disease. These neurons accumulate iron in the disease state, and iron-mediated neuron damage is implicated in cell death. Here, scanning transmission x-ray microscopy (STXM) is used to probe iron foci in relation to the surrounding ultrastructure in melanised neurons of human substantia nigra from a confirmed Parkinson’s case. The findings show that STXM is a powerful label-free tool for the in situ, nanoscale chemical characterisation of both organic and inorganic intracellular components. Future applications are likely to shed new light on incompletely understood biochemical mechanisms, such as metal dysregulation and morphological changes to cell nucleoli, that are important in understanding the pathogenesis of Parkinson’s.

Communications Biology. August 2024

Peter Wotherspoon, Hannah Johnston, David J. Hardy, Rachel Holyfield, Soi Bui, Giedrė Ratkevičiūtė, Pooja Sridhar, Jonathan Colburn, Charlotte B. Wilson, Adam Colyer, Benjamin F. Cooper, Jack A. Bryant, Gareth W. Hughes, Phillip J. Stansfeld, Julien R. C. Bergeron & Timothy J. Knowles

The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD.

Nature Communications. July 2024

Okinaka Y, Maeda M, Kataoka Y, Nakagomi T, Doi A, Boltze J, Claussen C, Gul S, Taguchi A

Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. Following transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 minutes after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In-vitro investigations revealed that BM-MNC abolish the expression of HIF1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying repair of brain function.

Stem Cells & Development. July 2024

Shefeeq M. Theparambil, Olga Kopach, Alice Braga, Shereen Nizari, Patrick S. Hosford, Virag Sagi-Kiss, Anna Hadjihambi, Christos Konstantinou, Noemi Esteras, Ana Gutierrez Del Arroyo, Gareth L. Ackland, Anja G. Teschemacher, Nicholas Dale, Tobias Eckle, Petros Andrikopoulos, Dmitri A. Rusakov, Sergey Kasparov & Alexander V. Gourine

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. The data identifies the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.

Nature. July 2024

Perioperative stroke deteriorates white matter integrity by enhancing cytotoxic CD8 + T‐cell activation

Yuxi Zhou, Xin Wang, Wen Yin, Yan Li, Yunlu Guo, Chen Chen, Johannes Boltze, Arthur Liesz, Tim Sparwasser, Daxiang Wen, Weifeng Yu, and Peiying Li

Here we explore the regulatory mechanisms of microglia‐mediated cytotoxic CD8+ T‐cell infiltration in the white matter injury of perioperative stroke (PIS). We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8+ T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8+ T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor‐interacting protein kinase 1 (RIPK1) activity could alleviate CD8+ T‐cell infiltration and demyelination in PIS mice. Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8+ T cells and microglia necroptosis, suggesting that modulating interactions of CD8+ T cells and microglia could be a novel therapeutic target of long‐term neurological deficits of PIS.. CNS Neuroscience and Therapeutics. July 2024

The association between air pollutant exposure and cerebral small vessel disease imaging markers with modifying effects of PRS-defined genetic susceptibility

Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40–69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5–10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles.. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.

Toxicology and Environmental Safety. June 2024

Deborah H. Brotherton, Sarbjit Nijjar, Christos G. Savva, Nicholas Dale, Alexander D. Cameron

Connexins allow intercellular communication by forming gap junction channels (GJCs) between juxtaposed cells. Connexin26 (Cx26) can be regulated directly by CO2. This is proposed to be mediated through carbamylation of K125. We show that mutating K125 to glutamate, mimicking the negative charge of carbamylation, causes Cx26 GJCs to be constitutively closed. Through cryo-EM we observe that the K125E mutation pushes a conformational equilibrium towards the channel having a constricted pore entrance, similar to effects seen on raising the partial pressure of CO2. In previous structures of connexins, the cytoplasmic loop, important in regulation and where K125 is located, is disordered. Through further cryo-EM studies we trap distinct states of Cx26 and observe density for the cytoplasmic loop. The interplay between the position of this loop, the conformations of the transmembrane helices and the position of the N-terminal helix, which controls the aperture to the pore, provides a mechanism for regulation.

eLife. June 2023

Andriko von Kügelgen, C. Keith Cassidy, Sofie van Dorst, Lennart L. Pagani, Christopher Batters, Zephyr Ford, Jan Löwe, Vikram Alva, Phillip J. Stansfeld & Tanmay A. M. Bharat

Nitrosopumilus maritimus is an ammonia-oxidizing archaeon that is crucial to the global nitrogen cycle. A critical step for nitrogen oxidation is the entrapment of ammonium ions from a dilute marine environment at the cell surface and their subsequent channelling to the cell membrane of N. maritimus. Here we elucidate the structure of the molecular machinery responsible for this process, comprising the surface layer (S-layer), using electron cryotomography and subtomogram averaging from cells. We supplemented our in situ structure of the ammonium-binding S-layer array with a single-particle electron cryomicroscopy structure, revealing detailed features of this immunoglobulin-rich and glycan-decorated S-layer. This in situ structural study illuminates the biogeochemically essential process of ammonium binding and channelling, common to many marine microorganisms that are fundamental to the nitrogen cycle.

Nature. May 2024

Amol Bhandare, Maisy Haley, Vanessa Torrico Anderson, Luana B. Domingos, Marcia Lopes, Sonia A. L. Corrêa, Mark J. Wall

Pathological forms of neural activity, such as epileptic seizures, modify the expression pattern of multiple proteins, leading to persistent changes in brain function. One such protein is activity-regulated cytoskeleton-associated protein (Arc), which is critically involved in protein-synthesis–dependent synaptic plasticity underlying learning and memory. In the present study, we have investigated how the expression of ArcKR, a form of Arc in which the ubiquitination sites have been mutated, resulting in slowed Arc degradation, modifies group I metabotropic glutamate receptor–mediated long-term depression (G1-mGluR-LTD) following seizures. We have shown that expression of ArcKR, a form of Arc in which degradation is reduced, significantly modulates the magnitude of G1-mGluR-LTD following epileptic seizures. However, the effect of ArcKR on LTD depends on the epileptic model used, with enhancement of LTD in an in vitro model and a reduction in the kainate mouse model.

Epilepsia. May 2024

Ulyana Lalo, Yuriy Pankratov

Intracellular Ca2+-signaling in astrocytes is instrumental for their brain “housekeeping” role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca2+ level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca2+-sensitive ryanodine receptors (RyRs). We explored the role for ryanodine receptors in the modulation of cytosolic Ca2+-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data demonstrate that ryanodine receptors are essential for astrocytic Ca2+-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.

Frontiers in Cellular Neuroscience. May 2024