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Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health 1 , it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease 2 , 3 . Resident microglia in the central nervous system are identified as the specific macrophage population that regulates myelin growth and integrity.

Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss‐of‐function mutations in any of Ccm1 , Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial‐to‐mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFβ/BMP‐dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3‐MEK5‐ERK5‐MEF2 signaling axis that induces a strong increase in Kruppel‐like factor 4 (KLF4) in ECs in vivo . KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1‐null ECs. KLF4 promotes TGFβ/BMP signaling through the production of BMP6. Importantly, in endothelial‐specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM. Synopsis Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target. KLF4 is strongly upregulated in endothelial cells in the absence of any of the three CCM genes. The endothelial‐to‐mesenchymal transition observed in endothelial cells null for CCM1 is induced by KLF4. KLF4 activates TGFβ/BMP signaling by increasing Bmp6 expression in endothelial cells in the absence of CCM1. The development and progression of cavernomas is strongly reduced upon genetic Klf4 inactivation. KLF4 is a strong candidate as a novel target for the pharmacological treatment of CCM, since its inactivation reduces mouse mortality associated to this disease by 75%. Graphical Abstract Current therapy for cerebral cavernous malformation (CCM) therapy is limited to neurosurgery. Transcription factor KLF4 is found to be a crucial determinant for the development of cavernomas and thus a future therapeutic target.

Increasing evidence supports the role of appetite-regulating pathways, including ghrelin and leptin, in alcoholism. This study tested the hypothesis that intravenous exogenous ghrelin administration acutely decreases endogenous serum leptin levels, and that changes in leptin levels negatively correlate with alcohol craving. This was a double-blind, placebo-controlled human laboratory study. Non-treatment-seeking, alcohol-dependent, heavy drinkers ( n =45) were randomized to receive intravenous ghrelin or placebo, followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol trial cues. There was a main effect for intravenous ghrelin administration, compared with placebo, in reducing serum leptin levels ( P <0.01). Post hoc analysis showed significant differences in serum leptin levels at the alcohol trial ( P <0.05) that persisted at the end of the experiment ( P <0.05). By contrast, there were no significant differences in serum leptin levels at the juice trial ( P =not significant (NS)). The change of serum leptin level at the alcohol trial correlated with the increase in alcohol urge ( P <0.05), whereas urge to drink juice was not correlated with the leptin change at the juice trial ( P =NS). These findings provide preliminary evidence of ghrelin–leptin cross-talk in alcoholic individuals and suggest that their relationship may have a role in alcohol craving.

Annexins, a group of Ca2+-dependent phospholipid-binding proteins, exert diverse roles in neuronal development, normal central nervous system (CNS) functioning, neurological disorders, and CNS tumors. This paper reviews the roles of individual annexins (A1-A13) in these contexts. Annexins possess unique structural and functional features, such as Ca2+-dependent binding to phospholipids, participating in membrane organization, and modulating cell signaling. They are implicated in various CNS processes, including endocytosis, exocytosis, and stabilization of plasma membranes. Annexins exhibit dynamic roles in neuronal development, influencing differentiation, proliferation, and synaptic formation in CNS tissues. Notably, annexins such as ANXA1 and ANXA2 play roles in apoptosis and blood-brain barrier (BBB) integrity. Neurological disorders, including Alzheimer’s disease, multiple sclerosis, and depression, involve annexin dysregulation, influencing neuroinflammation, blood-brain barrier integrity, and stress responses. Moreover, annexins contribute to the pathogenesis of CNS tumors, either promoting or suppressing tumor growth, angiogenesis, and invasion. Annexin expression patterns vary across different CNS tumor types, providing potential prognostic markers and therapeutic targets. This review underscores the multifaceted roles of annexins in the CNS, highlighting their importance in normal functioning, disease progression, and potential therapeutic interventions.

All forms of life are equipped with intricate molecular mechanisms that tune their cellular responses to external and internal cues. These mechanisms are key to cells’ survival in natural environments and important for the performance of bioprocesses, which are characterized by variable environments (e.g., nutrient availability). One of these molecular mechanisms, protein allostery, enables rapid fine-tuning of the rate of cellular processes by modulating protein activity in response to metabolites in vivo . Using the industrial yeast and model eukaryote Saccharomyces cerevisiae as a paradigm, the present work reveals that, in the major route for sugar utilization known as glycolysis, three distinct allosteric regulations are critical to yeast cell survival when transitioning between carbon sources. These three regulations, while not required for pathway operation per se , allow efficient and balanced pathway operation under dynamic conditions. These findings, therefore, reveal a new aspect of yeast glycolysis, one of the best-studied metabolic pathways.

The vast increase in Alzheimer disease (AD) worldwide has grave implications for individuals, family support systems and the health-care systems that will attempt to cope with the disease. Early markers of the disease are essential for efficient selection of clinical trial participants for drug development and for timely treatment once an intervention becomes available. There is avid interest in noninvasive, inexpensive markers that have the potential to identify prodromal AD. This Review considers sensory impairments that have the potential to serve as early indicators of AD, with a focus on olfaction, hearing and vision. Current evidence regarding the potential markers of AD in each modality is examined, with a particular emphasis on olfaction and current findings that olfactory function is associated with prodromal AD. Research suggests that olfactory impairment is associated with other markers that signal the emergence of prodromal AD. Auditory impairment is associated with dementia in epidemiological studies and visual system deficits have been reported in AD; however, the emergence of these deficits in prodromal AD is unclear. Further research is necessary to address the relative sensitivity and specificity of olfactory, auditory and visual measures for the detection of prodromal AD.

Key Points Auditory neuropathy impairs speech comprehension severely, beyond the extent that would be expected on the basis of increased threshold of audibility Auditory neuropathy encompasses a range of disease mechanisms that typically disrupt the synaptic encoding and/or neural transmission of auditory information in the cochlea and auditory nerve Auditory synaptopathy, impaired sound encoding at the synapses between inner hair cells and spiral ganglion neurons, results from genetic defects or insults such as exposure to loud noise Advanced physiological and psychophysical testing combined with molecular genetic analysis facilitate diagnostics of auditory synaptopathy and neuropathy Although traditional hearing aids often do not provide substantial benefit for patients with auditory synaptopathy or neuropathy, cochlear implants can provide effective hearing rehabilitation depending on the site(s) of disorder In auditory neuropathy, sensory transduction and amplification is preserved, but abnormal neural encoding of sound stimuli impairs speech comprehension severely, beyond what would be expected on the basis of increased threshold of audibility. Here, Moser and Starr provide an overview of the mechanisms of auditory neuropathy, including auditory synaptopathy. Moreover, the authors provide a brief guide to physiological and psychophysical tests for the clinical diagnosis of the disorders, discuss the strategies for hearing rehabilitation, and provide an outlook on future therapies. Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they “can hear but cannot understand”. This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function — resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca 2+ influx, or synaptic vesicle exocytosis — leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Aquaporin-4 (AQP4) is the main water channel protein expressed in the central nervous system (CNS). AQP4 is densely expressed in astrocyte end-feet, and is an important factor in CNS water and potassium homeostasis. Changes in AQP4 activity and expression have been implicated in several CNS disorders, including (but not limited to) epilepsy, edema, stroke, and glioblastoma. For this reason, many studies have been done to understand the various ways in which AQP4 is regulated endogenously, and could be regulated pharmaceutically. In particular, four regulatory methods have been thoroughly studied; regulation of gene expression via microRNAs, regulation of AQP4 channel gating/trafficking via phosphorylation, regulation of water permeability using heavy metal ions, and regulation of water permeability using small molecule inhibitors. A major challenge when studying AQP4 regulation is inter-method variability. A compound or phosphorylation which shows an inhibitory effect in vitro may show no effect in a different in vitro method, or even show an increase in AQP4 expression in vivo. Although a large amount of variability exists between in vitro methods, some microRNAs, heavy metal ions, and two small molecule inhibitors, acetazolamide and TGN-020, have shown promise in the field of AQP4 regulation.

The combined actions of immune cells, vascular cells and neurons mediate a 'neuroinflammatory' response to pathogens, trauma and degeneration in the CNS. Here, Xanthos and Sandkühler show that similar responses can be evoked by neural activity and describe the physiological and pathological roles of this 'neurogenic neuroinflammation'. The CNS is endowed with an elaborated response repertoire termed 'neuroinflammation', which enables it to cope with pathogens, toxins, traumata and degeneration. On the basis of recent publications, we deduce that orchestrated actions of immune cells, vascular cells and neurons that constitute neuroinflammation are not only provoked by pathological conditions but can also be induced by increased neuronal activity. We suggest that the technical term 'neurogenic neuroinflammation' should be used for inflammatory reactions in the CNS in response to neuronal activity. We believe that neurogenic neuro-inflammation maintains homeostasis to enable the CNS to cope with enhanced metabolic demands and increases the computational power and plasticity of CNS neuronal networks. However, neurogenic neuroinflammation may also become maladaptive and aggravate the outcomes of pain, stress and epilepsy.

ABSTRACT At the junction between the glycolysis and the tricarboxylic acid cycle—as well as various other metabolic pathways—lies the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node (PPO-node). These three metabolites form the core of a network involving at least eleven different types of enzymes, each with numerous subtypes. Obviously, no single organism maintains each of these eleven enzymes; instead, different organisms possess different subsets in their PPO-node, which results in a remarkable degree of variation, despite connecting such deeply conserved metabolic pathways as the glycolysis and the tricarboxylic acid cycle. The PPO-node enzymes play a crucial role in cellular energetics, with most of them involved in (de)phosphorylation of nucleotide phosphates, while those responsible for malate conversion are important redox enzymes. Variations in PPO-node therefore reflect the different energetic niches that organisms can occupy. In this review, we give an overview of the biochemistry of these eleven PPO-node enzymes. We attempt to highlight the variation that exists, both in PPO-node compositions, as well as in the roles that the enzymes can have within those different settings, through various recent discoveries in both bacteria and archaea that reveal deviations from canonical functions. Three metabolites, phosphoenolpyruvate, pyruvate and oxaloacetate together form the PPO-node, and are interconnected by a subset of 11 different enzymes; the current knowledge regarding these enzymes at the heart of metabolism is presented.