bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–11–02
twenty papers selected by
Regina F. Fernández, Johns Hopkins University
  1. The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.
  2. Lactate oxidation for brain energy metabolism: To exercise or not, that is the question.
  3. Restoration of Enzymatic Activity of Energy-Related Proteins in Rats with Traumatic Brain Injury Following Administration of Gamma-Glutamylcysteine Ethyl Ester.
  4. A Neural-Glial Model of the ApoE-SORT1-FABP7 Axis Tied to Sleep Disruption and Alzheimer's Disease Pathophysiology.
  5. Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol.
  6. How Genes Meet Diet in LCHAD Deficiency: Nutrigenomics of Fatty Acid Oxidation Disorder.
  7. Serum lactate and LDH are related with theta and gamma activities in bipolar disorder: a band-specific metabolic coupling.
  8. The role and mechanism of fatty acid-binding protein 7 in spinal reactive astrocytes in prolonged postoperative pain induced by high-fat diet.
  9. Perioperative Anesthetic Considerations in HMG-CoA Lyase Deficiency: Case Report and Literature Review.
  10. Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury.
  11. Mass spectrometry-based profiling of phosphoinositide: advances, challenges, and future directions.
  12. A novel ABCA1 mutation in Tangier disease associated with severe premature and rapidly progressive neurodegenerative disorder.
  13. G6PD deficiency in brain induces schizophrenia-like behaviors and synaptic dysfunction.
  14. Brain Monoamine Deficits in the CD Mouse Model of Williams-Beuren Syndrome.
  15. Is Vitamin B6 a Precision Therapy for Neonatal Seizures?
  16. Intracellular lactate dynamics in Drosophila neurons.
  17. High-Throughput in vivo and in vitro screening of lipid nanoparticles for nucleic acid delivery to the brain.
  18. Phosphatidic acid at the crossroads of membrane dynamics: from molecular specificity to synthetic innovation.
  19. Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
  20. Metabolomics in stress-related disorders: a systematic review and bioinformatics analysis.
  1. Nat Metab. 2025 Oct 30.
    The neuron-astrocyte metabolic unit as a cornerstone of brain energy metabolism in health and disease.
    Juan P Bolaños, Pierre J Magistretti.
      Over the past years, substantial advances have deepened our understanding of the cellular and molecular drivers of brain energy metabolism. Enabled by transformative technologies offering cellular-level resolution, these insights have revealed a highly regulated and dynamic metabolic interplay among brain cell types, particularly between neurons and astrocytes. In this Review, we shed light on the intricate ways in which neurons and astrocytes operate as a metabolically coupled unit, optimized to sustain the energetic demands of neurotransmission while ensuring neuroprotection. We highlight intercellular cooperation as a key determinant of brain function and provide examples of how disruption of the neuron-astrocyte metabolic unit contributes to numerous diseases of the nervous system, underscoring the critical importance of continued fundamental research to dissect the regulatory principles and vulnerabilities of this intercellular metabolic axis and identify potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01404-9
  2. J Physiol. 2025 Oct 27.
    Lactate oxidation for brain energy metabolism: To exercise or not, that is the question.
    Fahmeed Hyder.
      
    Keywords:  acetate; astrocyte; fats; glycogen; glycolysis; ketones; neuron; oxygen; shuttle
    DOI:  https://doi.org/10.1113/JP290102
  3. Brain Sci. 2025 Sep 30. pii: 1067. [Epub ahead of print]15(10):
    Restoration of Enzymatic Activity of Energy-Related Proteins in Rats with Traumatic Brain Injury Following Administration of Gamma-Glutamylcysteine Ethyl Ester.
    Brittany Rice, Jonathan Overbay, Andrea Sebastian, Patrick G Sullivan, Tanea T Reed.
      Background/Objectives: Biochemical processes such as the glycolytic pathway and Kreb's cycle are important in producing ATP for the brain. Without a sufficient supply of glucose for energy metabolism, the brain cannot efficiently regulate or coordinate the actions and reactions of the body. It is well documented that traumatic brain injury (TBI) is associated with reduced energy metabolism through the production of reactive oxygen/nitrogen species. Antioxidants, such as glutathione (GSH), have been shown to combat the deleterious effects of oxidation by scavenging ROS/RNS, inhibiting propagation, and removing neurotoxic byproducts. Gamma-glutamylcysteine ethyl ester (GCEE), an ethyl ester moiety of gamma-glutamylcysteine, exhibits antioxidant activity by increasing GSH production. This therapeutic has protective effects against oxidative stress through the elevation of glutathione. Methods: This study investigates the enzymatic activities of several key energy-related proteins that have been identified as nitrated in treated Wistar rats with moderate TBI. To test the hypothesis that the elevation of GSH production upon administration of GCEE will normalize enzymatic activity post-TBI, adult male Wistar rats were equally divided into three groups: sham, saline, and GCEE. Rats were treated with 150 mg/kg saline or GCEE at 30 and 60 min post-TBI. Upon sacrifice, brains were harvested and enzymatic activity was measured spectrophotometrically. Results: An increase in enzymatic activity upon GSH elevation via GCEE administration in several key enzymes was observed. Conclusions: GCEE is a potential therapeutic strategy to restore energy-related proteins in the brain post-TBI via GSH elevation.
    Keywords:  bioenergetics; glutathione; oxidative stress; traumatic brain injury
    DOI:  https://doi.org/10.3390/brainsci15101067
  4. Biomolecules. 2025 Oct 10. pii: 1432. [Epub ahead of print]15(10):
    A Neural-Glial Model of the ApoE-SORT1-FABP7 Axis Tied to Sleep Disruption and Alzheimer's Disease Pathophysiology.
    Carlos C Flores, Yool Lee, Christopher J Davis, Patrick Solverson, Jason R Gerstner.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder where age, genetic factors and sleep disturbance significantly influence disease risk. Recent genome-wide association studies identified a C/T missense variant (rs141749679) in the sortilin (SORT1) gene linked to heightened AD risk, revealing SORT1's role as a key player in the disease's pathophysiology. This type I membrane glycoprotein is implicated in amyloid β (Aβ) accumulation and associated lipid dysregulation, particularly through its interaction with apolipoprotein E (ApoE). SORT1 facilitates the uptake of ApoE-bound polyunsaturated fatty acids (PUFAs), conversion to endocannabinoids (eCBs), and the regulation of anti-inflammatory pathways via peroxisome proliferator-activated receptors (PPARs). Notably, this neuroprotective signaling is contingent on the APOE allele, exhibiting functionality in presence of ApoE3 but disrupted with ApoE4. Additionally, the brain-type fatty acid binding protein, FABP7, mediates this signaling cascade, emphasizing its role in neuron-glia communication. FABP7 is known to regulate sleep across species and binds PUFAs and eCBs. Therefore, dysfunction of the ApoE-SORT1-FABP7 axis may underlie the neuroprotective loss observed in AD, linking sleep disruption and lipid homeostasis to disease progression. This perspective aims to elucidate the intricate neural-glial mechanisms governing the ApoE-SORT1-FABP7 interaction and their implications for targeting therapeutic interventions in Alzheimer's disease.
    Keywords:  astrocyte; circadian; excitability; metabolism; neurodegeneration
    DOI:  https://doi.org/10.3390/biom15101432
  5. Life (Basel). 2025 Sep 29. pii: 1530. [Epub ahead of print]15(10):
    Docosahexaenoic Acid Increases the Pro-Resolving Brain Lipid Mediators of Inflammation in Rat Pups Prenatally Exposed to Alcohol.
    Enrique M Ostrea, Deepak Yadav, Charlie T Cheng, Esther D Kisseih, Krishna R Maddipati, Ronald L Thomas.
      Fetal alcohol spectrum disorder (FASD/FAS) is a chronic inflammatory process of the fetal brain induced by alcohol and mediated by pro-inflammatory (PILM) and pro-resolving (PRLM) lipid mediators of inflammation. DHA (docosahexaenoic acid) is an essential precursor of PRLM. A study examining the response of lipid mediators of inflammation to alcohol insult and DHA supplementation can provide vital information on the pathogenesis of FASD/FAS and the potential ameliorative role of DHA. Four groups of timed pregnant rats were studied: control, low-dose (1.6 g/kg/day) and high-dose (2.4 g/kg/day) alcohol, and high-dose alcohol (2.4 g/kg/day) + DHA (1250 mg/kg/day). The pups were delivered on day 20, and their whole brain was examined for lipid mediators by liquid chromatography mass spectroscopy. The following biomarkers of brain lipid mediators were studied, namely, PILM (LTB4, PGE2, PGF2α, TXB2) and PRLM (LXA5, 4-HDoHE, 17-HDoHE, and MaR1n-3, DPA). The brain PILM and PRLM concentrations decreased significantly (p < 0.001) with high-dose alcohol. However, high-dose alcohol + DHA resulted in a significant (p < 0.001) increase in PRLM levels, viz., LXA5, MaR1n-3 DPA, 17-HDoHE, and a threefold increase in 4-HDoHE. We conclude that DHA supplementation in alcohol-exposed pregnant rats significantly increased levels of brain pro-resolving lipid mediators in the offspring, suggesting a potential role in modulating the inflammatory response.
    Keywords:  alcoholic pregnant rats; docosahexaenoic acid; inflammation; newborn rat pups; pro-inflammatory brain lipid mediator; pro-resolving brain lipid mediators
    DOI:  https://doi.org/10.3390/life15101530
  6. Int J Mol Sci. 2025 Oct 18. pii: 10140. [Epub ahead of print]26(20):
    How Genes Meet Diet in LCHAD Deficiency: Nutrigenomics of Fatty Acid Oxidation Disorder.
    Zdzislaw Kochan, Joanna Karbowska.
      Mitochondrial long-chain fatty acid β-oxidation supplies energy to the heart, liver, and skeletal muscle. Impairment of this process due to a block at the step catalyzed by long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) leads to bioenergetic failure, manifesting as hypoglycemia, recurrent rhabdomyolysis, cardiomyopathy, and hepatic dysfunction. Accumulation of toxic intermediates-long-chain 3-hydroxyacyl-CoAs and the corresponding 3-hydroxyacylcarnitines-contributes to pigmentary retinopathy and peripheral neuropathy. Early diagnosis and careful dietary management can reduce life-threatening decompensation in childhood and improve survival into adulthood. This review examines the genetics of human LCHAD deficiency, describes its multisystem complications, and outlines nutritional strategies used to bypass the enzymatic block. We also explore nutrigenomic signals elicited by dietary treatment in LCHAD deficiency.
    Keywords:  MCT; fatty acid oxidation; human; medium-chain fatty acids; mitochondrial diseases; nutritional regulation; nutritional therapy
    DOI:  https://doi.org/10.3390/ijms262010140
  7. Front Psychiatry. 2025 ;16 1695916
    Serum lactate and LDH are related with theta and gamma activities in bipolar disorder: a band-specific metabolic coupling.
    Sermin Kesebir, Rüştü Murat Demirer.
       Objective: Bipolar disorder includes features of a biphasic energy disregulation. Lactate and LDH have been suggested as biomarkers for mitochondrial dysfunction, which has a role in its etiology. This study aims to examine the correlation between electrophysiological brain dynamics, quantified by Entropy Doubling and Ruzsa Distance derived from EEG data, and peripheral lactate and lactate dehydrogenase (LDH) levels in patients with bipolar disorder in remission.
    Methods: In this study, 20 individuals diagnosed with Bipolar Disorder Type I following DSM-V criteria were consecutively assessed throughout their remission phase while attending our outpatient unit for routine evaluations. Metabolic syndrome and the usage of conventional antipsychotics serves as an exclusion criterion. We examined serum LDH and lactate levels and did EEGs. All EEG data is arranged with a sample rate of 125 Hz. The additive combinatorial entropy of the electrodes is what makes up the entropic Rusza Distance. The Hilbert-based Entropy Doubling approach was used to process the analytical signals for each EEG channel.
    Results: Energy dysregulation includes theta and gamma frequency bands, both in relation to lactate and LDH. Lactate and LDH levels in the F7 theta band were linearly correlated. A negative correlation was found between the levels of lactate and LDH levels in the O1, Fz, and Cz gamma bands.
    Conclusion: Our findings suggest that there is a unique relationship between electrophysiological brain dynamics and mitochondrial dysfunction mediated metabolic stress in bipolar disorder.
    Keywords:  EEG; LDH; bipolar disorder; lactate; metabolic syndrome; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fpsyt.2025.1695916
  8. Exp Cell Res. 2025 Oct 26. pii: S0014-4827(25)00401-X. [Epub ahead of print]453(2): 114801
    The role and mechanism of fatty acid-binding protein 7 in spinal reactive astrocytes in prolonged postoperative pain induced by high-fat diet.
    Han Zheng, Xiao Zhang, Mei Li, Yu Wang, Shufen Guo, Ming Jiang, Rui Xu, Yulin Huang, Zhengliang Ma.
      Obesity markedly exacerbates nociceptive sensitivity and substantially compromises the quality of life of affected people. Astrocytes orchestrate metabolic regulation and homeostatic maintenance in the central nervous system. Notably, fatty acid binding protein 7 (FABP7) is highly expressed in astrocytes that governs intracellular fatty acid uptake and transport. While systemic hyperlipidemia is pathognomonic of obesity, the mechanistic contribution of FABP7 in astrocytes to obesity-associated pain pathophysiology remains poorly characterized. The present study established a model of high-fat diet (HFD)-induced obesity combined with a standardized hind paw surgical incision paradigm, aiming to unveil the role of astrocytic FABP7 in HFD-induced chronic pain. Furthermore, an in vitro high-fat environment was induced by palmitic acid (PA),aiming to investigate the molecular mechanisms by which primary astrocytes were activated into the A1 phenotype to mediate neuroinflammation. FABP7 was overexpressed in the spinal dorsal of HFD mice. The activation of A1-type astrocytes and neuroinflammation cascades involving elevated iNOS eventually resulted in mechanical allodynia in HFD mice. Pharmacological inhibition of FABP7 via an intraperitoneal administration of SBFI-26 (20 mg/kg) significantly attenuated the paw withdrawal mechanical threshold and inhibited the A1-type astrocytes activation. PA-induced high-fat conditions promoted lipid droplet accumulation and upregulated FABP7 in astrocytes. Pharmacological inhibition of FABP7 using SBFI-26 (100 μmol/L) significantly suppressed the neurotoxic C3-positive A1 astrocyte phenotype, reduced intracellular lipid droplet accumulation, thereby inhibiting the activation of A1-type astrocytes and alleviating neuroinflammation. Overall, FABP7-mediated astrocytic reprogramming was a critical nexus bridging obesity with chronic pain. A1-astrocyte polarization initiated neuroinflammatory amplification, forming a feedforward loop perpetuating central sensitization. Our findings are expected to offer a viable target for metabolic pain management.
    Keywords:  Astrocytes; Fatty acid-binding protein 7; High-fat diet; Postoperative pain
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114801
  9. J Clin Med. 2025 Oct 17. pii: 7332. [Epub ahead of print]14(20):
    Perioperative Anesthetic Considerations in HMG-CoA Lyase Deficiency: Case Report and Literature Review.
    Vasileia Nyktari, Georgios Papastratigakis, Alexandra Koulousi, Chrysi Mandola, Foteini Chaniotaki, Ioannis Goniotakis, Stavroula Ilia, Alexandra Papaioannou.
      Background/Objectives: 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is an extremely rare autosomal recessive metabolic disorder caused by mutations in the HMGCL gene. HMGCLD disrupts ketogenesis and β-oxidation, leading to energy failure during fasting or stress, with clinical episodes characterized by hypoglycemia, hyperammonemia, lactic acidosis, and encephalopathy. Only 211 cases have been reported worldwide, with no prior reports on anesthetic management in these patients. Methods: We report a 14.5-year-old girl with known HMGCLD who was admitted with abdominal pain and nausea following a fatty meal. Imaging confirmed acute cholecystitis. Initial conservative management failed due to persistent vomiting and inability to tolerate feeding. Deviation from the metabolic protocol led to lactic acidosis and hypoglycemia, requiring intensive care with bicarbonate, carnitine, and glucose infusion. Once optimized, she underwent emergency laparoscopic cholecystectomy under sevoflurane-based anesthesia. Propofol was avoided, given the patient's compromised lipid metabolism. Intraoperative glucose and acid-base status were closely monitored, with balanced dextrose-based fluids. Results: The patient remained hemodynamically stable throughout and was discharged three days postoperatively. Conclusions: This case highlights the anesthetic challenges of HMGCLD, where system-level miscommunication can trigger severe metabolic decompensation. A review of the literature emphasizes fasting avoidance, continuous glucose supplementation, careful drug and fluid selection, and multidisciplinary coordination. This report provides the first anesthetic roadmap for HMGCLD, underscoring the need for individualized care and meticulous perioperative metabolic control.
    Keywords:  3-hydroxy-3-methylglutaryl CoA lyase deficiency; adolescent; anesthesia; case reports; emergency surgical procedures; fatty acid oxidation disorders; general; perioperative care
    DOI:  https://doi.org/10.3390/jcm14207332
  10. Biomolecules. 2025 Oct 02. pii: 1408. [Epub ahead of print]15(10):
    Upregulation of GLT-1 Expression Attenuates Neuronal Apoptosis and Cognitive Dysfunction via Inhibiting the CB1-CREB Signaling Pathway in Mice with Traumatic Brain Injury.
    Bin Bu, Ruiyao Ma, Chengyu Wang, Shukun Jiang, Xiaoming Xu.
       BACKGROUND: Glutamate transporter 1 (GLT-1) plays a vital role in maintaining glutamate homeostasis in the body. A decreased GLT-1 expression in astrocytes can heighten neuronal sensitivity to glutamate excitotoxicity after traumatic brain injury (TBI). Despite its significance, the mechanisms behind the reduced expression of GLT-1 following TBI remain poorly understood. After TBI, the endocannabinoid 2-arachidonoyl glycerol (2-AG) is elevated several times. 2-AG is known to inhibit key positive transcriptional regulators of GLT-1. This study aims to investigate the role of 2-AG in regulating GLT-1 expression and to uncover the underlying mechanisms involved.
    METHODS: A controlled cortical impact (CCI) model was used to establish a TBI model in C57BL/6J mice. The CB1 receptor antagonist (referred to as AM281) and the monoacylglycerol lipase (MAGL) inhibitor (referred to as JZL184) were administered to investigate the role and mechanism of 2-AG in regulating GLT-1 expression following TBI. Behavioral tests were conducted to assess neurological functions, including the open field, Y-maze, and novel object recognition tests. Apoptotic cells were identified using the TUNEL assay, while Western blot analysis and immunofluorescence were employed to determine protein expression levels.
    RESULTS: The expression of GLT-1 in the contused cortex and hippocampus following TBI showed an initial decrease, followed by a gradual recovery. It began to decrease within half an hour, reached its lowest level at 2 h, and then gradually increased, returning to normal levels by 7 days. The administration of AM281 alleviated neuronal death, improved cognitive function, and reversed the reduction of GLT-1 caused by TBI in vivo. Furthermore, 2-AG decreased GLT-1 expression in astrocytes through the CB1-CREB signaling pathway. Mechanistically, 2-AG activated CB1, which inhibited CREB phosphorylation in astrocytes. This decreased GLT-1 levels and ultimately increased neuronal sensitivity to glutamate excitotoxicity.
    CONCLUSIONS: Our research demonstrated that the upregulation of GLT-1 expression effectively mitigated neuronal apoptosis and cognitive dysfunction by inhibiting the CB1-CREB signaling pathway. This finding may offer a promising therapeutic strategy for TBI.
    Keywords:  2-AG; CREB; GLT-1; TBI; astrocyte
    DOI:  https://doi.org/10.3390/biom15101408
  11. Mol Omics. 2025 Oct 27.
    Mass spectrometry-based profiling of phosphoinositide: advances, challenges, and future directions.
    Yuki Ishino, Yuta Shimanaka, Junken Aoki, Nozomu Kono.
      Phosphoinositides (PIPs), the phosphorylated derivatives of phosphatidylinositol (PI), are low-abundance yet critical components of eukaryotic membranes. They play pivotal roles in a wide array of cellular processes, including signal transduction, membrane trafficking, and cell motility. The seven PIP subclasses, generated by phosphorylation at the 3-, 4-, and 5-positions of the inositol ring, are tightly regulated in both spatial and temporal contexts. Dysregulation of PIP metabolism is associated with a range of diseases, including cancer, myopathy, and neurodegenerative and developmental disorders. While the importance of phosphorylation of the inositol ring is well established, recent studies have clarified the role of the fatty acyl chain composition of PIPs. This has resulted in a growing interest in analytical techniques that can determine fatty acyl chain profiles of PIPs. Over the past three decades, substantial advances have been made in mass spectrometry-based techniques, enabling detailed characterization of PIP molecular species, including their phosphate regioisomers. This review provides an overview of the development of mass spectrometric methods for analyzing PIPs, with a particular focus on those enabling the separation of PIP regioisomers and the profiling of their acyl chain composition.
    DOI:  https://doi.org/10.1039/d5mo00115c
  12. J Clin Lipidol. 2025 Sep 05. pii: S1933-2874(25)00389-7. [Epub ahead of print]
    A novel ABCA1 mutation in Tangier disease associated with severe premature and rapidly progressive neurodegenerative disorder.
    Paolo Fornengo, Elisa Rinaudo, Serena Amato, Simone Mattivi, Silvia Deaglio.
      Tangier disease (TD) is a rare inherited disorder of lipoprotein metabolism, characterized by low levels of high-density lipoprotein-cholesterol (HDL-c) and accumulation of cholesterol esters in various tissues. It is caused by mutations in the ATP binding cassette transporter A1 (ABCA1). Clinical presentation is highly variable. Polyneuropathy is an encountered clinical presentation, whereas neurocognitive disorders are less frequently described. We present a case of a 68-year-old male with premature coronary heart disease, orange tonsils, thrombocytopenia, atypical neurodegenerative disease, and severe rapidly evolving neurocognitive disorder, until death. HDL-c levels were 6 mg/dL, apolipoprotein (Apo)AI was 2.8 mg/dL, and ApoE genotype was E2/E2. Genetic analysis revealed a homozygous c.1510-1 G>C variant in intron 12. This variant was considered of uncertain significance, because of the absence of reported clinical features. We suggest that this variant could be considered moderate/strong pathogenetic. We highlight the need to describe more clinical presentations related to genetic variants, given the limited data on genotype-phenotype correlations in TD.
    Keywords:  ABCA1; Dementia; HDL; Neurodegenerative disorders; Tangier disease
    DOI:  https://doi.org/10.1016/j.jacl.2025.09.001
  13. Transl Psychiatry. 2025 Oct 31. 15(1): 441
    G6PD deficiency in brain induces schizophrenia-like behaviors and synaptic dysfunction.
    Yu-Bing Wang, Pin-Xi Xie, Wan-Ying Mei, Yuan-Yuan Yong, Xinren Yu, Ling Hu, Jia-Yin Chen, Yu-Ling Sun, Xuan Zhao, Ning-Ning Song, Yu-Qiang Ding, Lei Zhang.
      Schizophrenia is a severe mental disorder characterized by aberrant brain development, influenced by genetic and environmental factors, with an incompletely understood etiology. Glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme in the pentose phosphate pathway (PPP), facilitates NADPH production for biosynthesis and redox homeostasis. Recent studies suggests that PPP inhibition and consequent oxidative stress contribute to schizophrenia pathogenesis. While clinical investigations have proposed a link between G6PD deficiency and schizophrenia, the underlying biological mechanisms remain unestablished. We here demonstrate that brain-specific G6PD knockout induces schizophrenia-like behaviors in mice, establishing a direct association between G6PD deficiency and schizophrenia. Proteomic analysis revealed aberrant synaptic protein expression in the knockout mice. These mice also exhibited synaptic impairments, including reduced presynaptic vesicles and diminished dendritic spines. Our findings suggest that G6PD deficiency disrupts synaptic homeostasis, contributing to schizophrenia-like behaviors. Our study provides novel insights into the molecular mechanisms of schizophrenia, identifying G6PD as an important regulator of synaptic function and a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41398-025-03631-w
  14. Biomolecules. 2025 Sep 28. pii: 1382. [Epub ahead of print]15(10):
    Brain Monoamine Deficits in the CD Mouse Model of Williams-Beuren Syndrome.
    Chloé Aman, Hélène Gréa, Alicia Rousseau, Anne-Emilie Allain, Susanna Pietropaolo, Philippe De Deurwaerdère, Valérie Lemaire.
      Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disease caused by a microdeletion on chromosome 7 (7q11.23) and associated with behavioral disorders such as hypersociability, impaired visuospatial memory, anxiety, and motor disorders. The precise underlying neurobiological bases remain unknown. The CD mouse is a genetic model that reproduces the deletion found in WBS patients on the equivalent mouse locus. Taking into account that monoaminergic systems are known to modulate behaviors that are altered in WBS, we hypothesized that CD mice could present quantitative and qualitative changes in brain noradrenaline, dopamine, and serotonin systems compared to wild-type (WT) littermates. We sampled 10 brain regions in female mice for quantifying monoamines and related compounds by high-performance liquid chromatography coupled to electrochemical detection. We found a decrease in dopamine in the nucleus accumbens and serotonin and its metabolites in the hypothalamus. Using correlative approaches of tissue content across the brain, we found that the relationships between neurotransmitters or their metabolic ratios (metabolite/neurotransmitter) changed in CD compared to WT. Notably, compared to WT, the ratios in CD mice showed striatal correlations for the serotonin/dopamine systems interaction, and cortical, thalamic, and hypothalamic correlations for the noradrenaline/dopamine systems interaction. The data suggest specific alterations of monoaminergic systems across the brain that could sustain the abnormal behavioral responses displayed by CD mice.
    Keywords:  connectivity; correlation; cortex; dopamine; hypothalamus; metabolism; neurochemistry; noradrenaline; nucleus accumbens; serotonin
    DOI:  https://doi.org/10.3390/biom15101382
  15. Neurol Int. 2025 Oct 01. pii: 157. [Epub ahead of print]17(10):
    Is Vitamin B6 a Precision Therapy for Neonatal Seizures?
    Raffaele Falsaperla, Vincenzo Sortino, Bruna Scalia, Marco Andrea Nicola Saporito.
      Background: Neonatal seizures are critical neurological events with long-term implications for brain development. Standard antiseizure medications, such as phenobarbital, often yield suboptimal seizure control and may be associated with neurotoxicity. This narrative review explores the role of vitamin B6 as a precision therapy in neonatal seizure syndromes, particularly in pyridoxine-responsive conditions. Methods: We conducted a narrative review of the biochemical functions of vitamin B6, focusing on its active form, pyridoxal 5'-phosphate (PLP), and its role as a coenzyme in neurotransmitter synthesis. We examined the genetic and metabolic disorders linked to vitamin B6 deficiency, such as mutations in pyridox(am)ine 5'-phosphate oxidase (PNPO), Aldehyde Dehydrogenase 7 Family Member A1 (ALDH7A1), alkaline locus phosphatase (ALPL), and cystathionine β-synthase (CBS), and discussed the clinical rationale for empirical administration in acute neonatal seizure settings. Results: Vitamin B6 is essential for the synthesis of gamma-aminobutyric acid (GABA), dopamine, and serotonin, with PLP-dependent enzymes such as glutamic acid decarboxylase and aromatic L-amino acid decarboxylase playing central roles. Deficiencies in PLP due to genetic mutations or metabolic disruptions can result in treatment-resistant neonatal seizures. Early supplementation, especially in suspected vitamin B6-dependent epilepsies, may provide both diagnostic clarity and seizure control, potentially reducing exposure to conventional antiseizure medications. Conclusions: Vitamin B6-responsive epilepsies highlight the clinical value of mechanism-based, individualized treatment approaches in neonatology. Incorporating genetic and metabolic screening into seizure management may improve outcomes and aligns with the principles of precision medicine.
    Keywords:  neonatal seizures; pyridoxine-dependent epilepsy; vitamin B6
    DOI:  https://doi.org/10.3390/neurolint17100157
  16. iScience. 2025 Oct 17. 28(10): 113462
    Intracellular lactate dynamics in Drosophila neurons.
    Matthew S Price, Elham Rastegari, Richa Gupta, Katie Vo, Travis I Moore, Kartik Venkatachalam.
      Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigated the effects of nutrient deprivation on lactate dynamics in Drosophila neurons by leveraging the limiting effects of the unstirred layer, a diffusion barrier that forms around cells in culture. We found that neurons constitutively consume lactate when the availability of trehalose, a glucose disaccharide preferred by insects, is limited by the unstirred layer. Acute mechanical disruption of the unstirred layer reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates under unstirred layer conditions correlate inversely with the cells' mitochondrial density. Furthermore, neuronal lactate levels exhibited temporal correlations that allowed postperturbation lactate dynamics to be predicted by preperturbation values. Collectively, our findings reveal the influence of naturally forming diffusion barriers on neuronal metabolic preferences and demonstrate the existence of temporal correlations between lactate dynamics under conditions of nutrient deprivation and those evoked by the subsequent restoration of nutrient availability.
    Keywords:  cell biology; molecular biology; molecular neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.113462
  17. Int J Pharm. 2025 Oct 23. pii: S0378-5173(25)01115-9. [Epub ahead of print]686 126278
    High-Throughput in vivo and in vitro screening of lipid nanoparticles for nucleic acid delivery to the brain.
    Marco Túllio Rodrigues Alves, Sérgio Ricardo Aluotto Scalzo Júnior, Walison Nunes da Silva, Raquel Alves de Almeida Costa, Pedro Henrique Dias Moura Prazeres, Rayssa Brianis de Oliveira Costa, Lays Cordeiro Guimarães, Leonardo de Oliveira Guarnieri, Maria Marta Figueiredo, Fabricio de Araujo Moreira, Vinicius de Toledo Ribas, André Ricardo Massensini, Pedro Pires Goulart Guimarães.
      Gene therapy is a promising approach for correcting acquired or inherited brain diseases, nevertheless, faces a challenge in effectively delivering nucleic acids to the brain. Ionizable lipid nanoparticles (LNPs) are commonly used as delivery systems, however they are often screened in in vitro settings which poorly replicates in vivo biological barriers. Here, we used a high-throughput in vivo and in vitro screening methods to assess a library of LNPs for nucleic acid delivery to neurons and brain tissue. LNPs were formulated via microfluidic mixing with different helper lipid and molar ratios, each containing a unique barcode DNA (b-DNA). LNPs were characterized and pooled for intravenous injection in C57BL/6 mice, and their biodistribution was assessed via next-generation sequencing. The top-performing LNPs, which exhibited higher b-DNA delivery to the brain, were further assessed for transfection efficiency in primary neurons using pDNA and mRNA. We established concentration-response curves, monitored protein expression overtime, and performed cell viability assays. Our results showed that DOPE-based LNPs outperformed other formulations in brain delivery and neuronal transfection. Additionally, altering the ionizable lipid in our top formulation to FDA-approved options did not improve neuronal transfection efficiency. Finally, our identified top performing LNP4 was able to induce luciferase expression in brain after intravenous administration. No signs of neurological damage, inflammation or behavioral impairments were observed. Our results demonstrate that our LNPs efficiently deliver nucleic acids to neurons and the brain, while our screening strategy accelerates the design of LNPs for brain gene therapy.
    Keywords:  Brain delivery; DNA barcodes; Lipid nanoparticles, ionizable lipids; Neuron transfection; Nucleic acid delivery
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.126278
  18. Adv Biol Regul. 2025 Oct 25. pii: S2212-4926(25)00050-8. [Epub ahead of print] 101123
    Phosphatidic acid at the crossroads of membrane dynamics: from molecular specificity to synthetic innovation.
    Alexander Wolf, Emeline Tanguy, Stéphane Gasman, Nicolas Vitale.
      Phosphatidic acid (PA) has emerged as a central regulator of membrane dynamics, vesicle trafficking, exocytosis, and intracellular signaling. Building on recent advances, including subspecies-specific functions of PA in neuroendocrine exocytosis, the primacy of PLD1-derived PA in vivo, and the development of natural-mimetic PA analogues, this review integrates biochemical, biophysical, and systems-level insights across eukaryotes. We contextualize the role of PA in vesicular trafficking, delineate how acyl-chain composition encodes molecular specificity, summarize enzymatic sources and sinks sculpting spatiotemporal control of PA pools within cells, and examine emerging tools used for measuring and disturbing PA in living cells to unravel its function. Given the pleiotropic roles of PA among numerous experimental contexts such as the nervous, endocrine, immune, and metabolic systems, mapping mechanistic connections to disease through mTOR and RAF/MEK/ERK signaling, autophagy, and organelle contact-site biology. Finally, we outline future directions spanning single-cell lipidomics, imaging mass spectrometry, and therapeutic lipid engineering. Together, available evidence positions PA as a conserved, tunable molecular switch that coordinates membrane mechanics with signal transduction to enable realisation of a wide range of function within cells.
    Keywords:  Chemical biology; Endocytosis; Exocytosis; Lipidomics; Phosphatidic acid
    DOI:  https://doi.org/10.1016/j.jbior.2025.101123
  19. Nat Aging. 2025 Oct 29.
    Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
    Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang.
      Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer's disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD.
    DOI:  https://doi.org/10.1038/s43587-025-00976-1
  20. Naunyn Schmiedebergs Arch Pharmacol. 2025 Oct 31.
    Metabolomics in stress-related disorders: a systematic review and bioinformatics analysis.
    Giovana Mezzomo, Tainá Schons, Pedro Henrique Rosa, Paola Rampelotto Ziani, Luisa Soares Pedroso, Gabriel Rocha, Pietra Paiva Alves, Rianne Remus Pulcinelli, Adriane R Rosa.
      Stress-related disorders, including major depressive disorder (MDD), bipolar disorder (BD), and post-traumatic stress disorder (PTSD), share complex biological mechanisms and overlapping symptoms, posing challenges for diagnosis and treatment. This in silico study aimed to identify metabolomic patterns and explore dysfunctional metabolic pathways that are common and specific within a transdiagnostic psychiatric sample. A systematic review was conducted to identify metabolomic studies using mass spectrometry on blood samples from patients with MDD, BD, and PTSD. Study screening was performed using Rayyan, and metabolite codes were retrieved from the HMDB and ChEBI databases. Identified metabolites were classified using the R software, and metabolic pathway enrichment analysis was conducted in MetaboAnalyst. Thirteen eligible studies were identified, reporting 583 metabolites. Among these, four metabolites-arginine, inosine, 5-oxoproline (5-OP), and pyruvic acid-were consistently altered across disorders. Bioinformatics analysis revealed key metabolic pathways primarily related to amino acid, energy, carbohydrate, and lipid metabolism, suggesting shared biological mechanisms. These findings reinforce the transdiagnostic nature of metabolic dysfunction in psychiatric disorders and may contribute to the development of personalized therapeutic strategies and biomarker panels for improved diagnosis and treatment.
    Keywords:  Bioinformatic; Mass spectrometry; Metabolic pathways; Mood disorders; Omics; PTSD; Transdiagnostic psychiatry
    DOI:  https://doi.org/10.1007/s00210-025-04542-9
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