bims-medebr 2026-05-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–05–03
thirty papers selected by
Regina F. Fernández, Johns Hopkins University

Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain.
Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.
CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.
Therapeutic potential of regulating microglial Glut1 in modulating brain glucose metabolism and neuroinflammation in postoperative delirium.
Oleic acid improves pathological changes in Aβ1-42-induced astrocytes and Alzheimer's disease mouse models through PKA/ACACB/CPT1A.
Glycolysis as a central pathological axis in neurodegenerative diseases.
Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.
Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
Apolipoprotein E4 and Synaptic Dysfunction in Alzheimer's Disease: Mechanisms and Therapeutic Implications.
Profiling of fatty acids and lipids in animal and human tissues yields new leads for disease progression biomarkers of X-linked adrenoleukodystrophy.
Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.
SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.
Energy metabolism, adenosine, and glutamate signaling reprogramming by decanoic acid in Glut1 disorder syndrome.
Fat on Fire: Disrupted Microglial Lipid Metabolism as a Driver of Anesthetic Neurotoxicity.
Association of serum biomarkers for lipid and amino acid metabolism with cognition in adolescents.
From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.
Mechanistic Insights into Glufosinate-ammonium (GLA)-Induced Brain Injury Revealed by LC-MS/MS-Based Metabolomics.
PHGDH-mediated serine synthesis reduces oligodendrocyte death by sustaining GSH and NADPH levels after brain ischemia.
Stable Isotopes for the Study of Energy Nutrient Metabolic Pathways in Relation to Health and Disease.
Selected Brain Metabolites and Mitochondrial DNA Copy Number as Potential Markers of Ongoing Neurodegeneration in Patients with Wolfram Syndrome.
Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.
Efficacy of Treating Post-Traumatic Epilepsy in Children With Ketogenic Diet.
Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.
Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.
Short-, medium-, versus long-chain fatty acids: mechanisms of immunomodulation and disease pathogenesis.
Reprogramming lipid metabolism in pediatric cancers.
Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.
Cellular expression and subcellular localization of autotaxin, a lysophosphatidic acid-generating enzyme, in the adult and developing mouse brain.
Evaluation of c26:0-Lyso-Phosphatidylcholine Levels in X-Linked Adrenoleukodystrophy: Diagnosis and Biochemical Monitoring.
Mitochondrial dysfunction in cerebrovascular diseases.

J Biol Chem. 2026 Apr 27. pii: S0021-9258(26)01970-8. [Epub ahead of print] 113098

Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain.

Alejandro Lopez-Ramirez, Andrew J Worth, Ziyi Lindsay Wang, Saliha Yilmaz, Sebastian Hayes, Hsin-Yao Tang, Joseph Farris, Md Suhail Alam, Prasad Padmanabhan, Kasturi Haldar.

Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, non-ketotic hyperglycinemia (NKH), with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency but the consequences for energy mechanisms remain unknown. We find that brains of young-attenuated mutant mice show a 1.5-fold increase in glycine and no change in folate responsiveness. They are, however, reduced > 5-fold in GLDC, indicate decrease in the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase (PDH) complex as well as rise in signatures of astrocyte mitochondrial β-oxidation of fatty acids proportionate to mutation severity and activation of PDH. Together these data reveal a novel GLDC mechanism that regulates catabolic mitochondrial energy processes in both attenuated and severe brain disease and suggest new targets in energy metabolism to treat NKH.

DOI: https://doi.org/10.1016/j.jbc.2026.113098
J Integr Neurosci. 2026 Apr 21. 25(4): 48436

Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.

Jeyakumar Balakrishnan, Suganya Kannan, Kathiresan Shanmugam, Dhavamani Sugasini.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.

Keywords:  Alzheimer’s disease; apolipoprotein E; lipid metabolism; lipidomics; mitochondria; neuroinflammation; precision medicine

DOI:  https://doi.org/10.31083/JIN48436
Biomed Pharmacother. 2026 Apr 30. pii: S0753-3322(26)00506-8. [Epub ahead of print]199 119470

CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.

Natalia Mast, Ilya Bederman, Nicole El-Darzi, Irina A Pikuleva.

  CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders.

Keywords:  Acetyl-CoA; Metabolic flexibility; Myelination; Phosphatidylcholine; Sphingomyelin; Vascular deficits

DOI:  https://doi.org/10.1016/j.biopha.2026.119470
Exp Neurol. 2026 Apr 25. pii: S0014-4886(26)00158-5. [Epub ahead of print]402 115794

Therapeutic potential of regulating microglial Glut1 in modulating brain glucose metabolism and neuroinflammation in postoperative delirium.

Huikai Yang, Qingzu Liu, Chongyang Liu, Min Liu, Danyang Geng, Mengyao Qu, Yanan He, Yanhong Liu, Miao Sun, Yulong Ma, Weidong Mi.

   BACKGROUND: Postoperative delirium (POD) is a common and serious complication of surgery, driven in part by neuroinflammation mediated by microglial activation. However, the molecular mechanisms underlying this process remain poorly defined. This study investigates the role of glucose transporter 1 (Glut1) in microglial activation and the pathogenesis of POD.
METHODS: A mouse model of POD-like behaviour was established via partial hepatectomy. Microglia were depleted using PLX3397 and isolated to confirm their role, and that of Glut1, in POD pathogenesis. Glut1 function was inhibited pharmacologically with BAY-876, and its expression in microglia was modulated using microglia-specific adeno-associated viruses (AAV-mir-Glut1+/+ and AAV-mir-Glut1-/-). In vitro, BV2 microglial cells and BV2-HT22 neuron co-cultures were stimulated with lipopolysaccharide (LPS) to assess how inflammatory activation alters glucose metabolism and affects neuronal glucose uptake. Regulatory effects of microglial Glut1 were evaluated using PET-CT imaging, biodistribution analysis, histology, and biochemical assays.
RESULTS: An increase in brain glucose metabolism was observed during POD-like behaviour, corresponding with microglial activation following anesthesia and surgery. Inhibition of Glut1 with BAY-876 reduced cerebral glucose uptake, suppressed microglial activation, and improved cognitive performance. Critically, microglia-specific modulation of Glut1 expression attenuated neuroinflammation, corrected metabolic abnormalities, and mitigated POD-like behaviour.
CONCLUSIONS: Glut1-mediated glucose hypermetabolism in microglia contributes to POD through a metabolic-inflammatory cascade. These findings reveal a key role for microglial Glut1 in linking energy metabolism to neuroinflammation and suggest that targeting this pathway may offer a novel strategy for the prevention and treatment of POD and related perioperative neurocognitive disorders.

Keywords:  Glucose metabolism; Glucose transporter 1; Microglia; Neuroinflammation; Postoperative delirium

DOI:  https://doi.org/10.1016/j.expneurol.2026.115794
Front Neurosci. 2026 ;20 1771310

Oleic acid improves pathological changes in Aβ1-42-induced astrocytes and Alzheimer's disease mouse models through PKA/ACACB/CPT1A.

YiBo Xie, Jianan Tian, Hui Li, Yahui Peng, Mingjie Li, Yun Wu.

   Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence indicates that fatty acid oxidation is impaired in both patients with AD and AD animal models. In the brain, fatty acid metabolism occurs predominantly in astrocytes. Diets enriched in monounsaturated fatty acids (MUFAs) are often recommended for individuals with AD. Oleic acid (OA), a common dietary MUFA, has been shown to reduce amyloid plaque accumulation in transgenic mouse models of AD. Moreover, OA decreases the expression of acetyl-CoA carboxylase beta (ACACB/ACC2), a key regulator of fatty acid β-oxidation. However, the precise mechanism by which OA may alleviate amyloid plaque deposition through modulation of brain fatty acid metabolism remains unclear.
Objective: To determine whether dietary OA supplementation partially restores astrocytic fatty acid metabolism by suppressing ACACB and enhancing fatty acid β-oxidation, thereby attenuating AD-related pathology.
Methods: Using NHANES 2011-2014 data, we applied survey-weighted multivariable logistic regression to examine the association between energy-adjusted MUFA intake and low cognitive function, with adjustment for multiple testing. We then screened GEO datasets to identify AD-associated genes involved in fatty acid metabolic dysregulation, identifying ACACB as a candidate target. The expression of ACACB and its downstream effector carnitine palmitoyltransferase 1A (CPT1A) were validated in mouse and cell models. APP/PS1 mice received dietary OA supplementation, followed by behavioral testing and brain histopathological analyses. In parallel, an Aβ1-42-induced astrocyte injury model was used to assess lipid droplet accumulation, mitochondrial function, and cellular energy metabolism. ACACB knockdown/overexpression and CPT1A overexpression were used to test pathway-specific effects of OA.
Results: Higher MUFA intake was associated with better cognitive function. ACACB as a key fatty acid metabolism-related gene in AD. In APP/PS1 mice, OA improved cognitive performance and reduced Aβ plaque deposition, accompanied by decreased ACACB and increased CPT1A expression in brain tissue. In vitro, OA modulated ACC2 activity through protein kinase A (PKA) signaling, increased fatty acid β-oxidation, reduced lipid droplet accumulation, restored mitochondrial membrane potential and ATP production, and enhanced astrocyte-mediated support of neuronal synaptic growth.
Conclusion: OA ameliorates AD-related pathology and cognitive impairment by restoring astrocytic fatty acid β-oxidation through the PKA/ACACB/CPT1A pathway.

Keywords:  ACACB; Alzheimer’s disease; astrocyte; fatty acid; oleic acid

DOI:  https://doi.org/10.3389/fnins.2026.1771310
Rev Neurosci. 2026 Apr 23.

Glycolysis as a central pathological axis in neurodegenerative diseases.

Ting Cheng, Mingwei Li, Yulong Yang, Zhihong Rao, Wenming Yang.

  Glycolysis is increasingly recognized as a pathological backbone in neurodegenerative diseases rather than merely an accompanying epiphenomenon. This article first delineates the division of metabolic labor among neurons, astrocytes, microglia, and oligodendrocytes in the brain, with particular emphasis on cell type-specific glycolytic flux, lactate shuttling, and an integrated brain-periphery framework of energy metabolism. It then systematically compares alterations in glucose uptake, glycolytic intermediates, and lactate metabolism across Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Wilson disease (WD), Huntington's disease (HD), and multiple sclerosis (MS), highlighting pronounced heterogeneity across cell types, disease stages, and brain regions. These metabolic disturbances encompass not only global cerebral hypometabolism and an energy crisis, but also compensatory hyperglycolysis and inflammation-associated metabolic reprogramming in astrocytes and microglia, and extend further to systemic metabolic phenotypes involving peripheral blood cells, muscle, and liver. The article summarizes recent methodological advances for characterizing glycolytic reprogramming, including fluorodeoxyglucose positron emission tomography (FDG-PET), hyperpolarized carbon-13 magnetic resonance spectroscopy(ˆ13C-MRS), metabolomics, single-cell and spatial transcriptomics, genetically encoded metabolic sensors, and Seahorse assays. In addition, potential therapeutic strategies are discussed, focusing on targets such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3), the astrocyte-neuron lactate shuttle (ANLS), microglial glycolysis and lactylation, as well as systemic metabolic modulation and nanodelivery approaches. Finally, key challenges are highlighted, including unclear causal relationships, biphasic and cell type-specific effects, insufficient brain-periphery integration, and the lack of standardized metrics, underscoring the need for longitudinal, multimodal, and stage-specific strategies to reposition glycolysis as a targetable therapeutic dimension in neurodegenerative diseases.

Keywords:  glial cells; glycolysis; lactate; neurodegenerative diseases; neurons

DOI:  https://doi.org/10.1515/revneuro-2026-0037
Front Aging Neurosci. 2026 ;18 1710075

Dysregulated glucose metabolism in the visual cortex of human subjects with mild cognitive impairment and Alzheimer's disease.

Ulrik N Mjaaseth, Ming-Fo Hsu, Joseph Arballo, Fawaz G Haj, Viharkumar Patel.

   Introduction: Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired glucose metabolism. While most studies focus on heavily affected brain regions such as the hippocampus and prefrontal cortex, the visual cortex remains relatively preserved in early AD and provides an opportunity to examine metabolic alterations that precede widespread pathology.
Methods: Postmortem human visual cortex samples were obtained from control, mild cognitive impairment (MCI), and AD subjects without non-AD neuropathologic conditions. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry, and expression of key metabolic, inflammatory, and AD-related genes was measured by quantitative PCR. Data analysis was conducted using MetaboAnalyst and R.
Results: Metabolomic profiling revealed progressive disruptions in glucose metabolism, and mitochondrial function across MCI and AD subjects. Gene expression analyses showed reduced levels of glycolytic enzymes (HK1, PFKM, PKM1), mitochondrial regulators (PDHA1, NDUFC1), and the neuronal glucose transporter SLC2A3. Insulin signaling was altered, with decreased IDE and increased INSR and PTPN1 gene expression. Inflammatory markers including TNF, IL1B, and GFAP were elevated in AD. Sex-stratified analyses revealed both shared and distinct metabolic signatures, particularly within glucose and mitochondrial pathways. Several metabolic gene changes correlated negatively with Braak stage, highlighting a progressive decline in energy metabolism alongside tau pathology.
Discussion: These findings demonstrate early and progressive metabolic dysfunction in the visual cortex of MCI and AD subjects. Even in a region with limited structural pathology, profound alterations in energy metabolism were observed, underscoring its central role in AD pathogenesis and highlighting improving neuronal metabolic function as a promising target for therapeutic intervention.

Keywords:  Alzheimer’s disease; Braak staging; glucose metabolism; insulin signaling; mild cognitive impairment; mitochondrial function; neurodegeneration; visual cortex

DOI:  https://doi.org/10.3389/fnagi.2026.1710075
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718012. [Epub ahead of print]

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.

Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.

Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

DOI: https://doi.org/10.64898/2026.04.14.718012
Ageing Res Rev. 2026 Apr 28. pii: S1568-1637(26)00145-5. [Epub ahead of print] 103153

Apolipoprotein E4 and Synaptic Dysfunction in Alzheimer's Disease: Mechanisms and Therapeutic Implications.

Zhiying Yao, Ivan Steve Godje Godje, Bin Jiao, Lu Shen, Shi-Lin Luo.

  Alzheimer's disease (AD) is characterized by progressive cognitive decline, with synaptic dysfunction as the strongest correlate of clinical symptoms. The apolipoprotein E ε4 (ApoE4) allele is the most potent genetic risk factor for late-onset AD. Beyond its roles in amyloid-β aggregation and tau hyperphosphorylation, ApoE4 disrupts synaptic integrity by perturbing lipid metabolism, neuroimmune regulation, mitochondrial dynamics, and activity-dependent plasticity. These ApoE4-driven mechanisms impair presynaptic vesicle trafficking, destabilize postsynaptic receptor and scaffolding networks (including PSD-95, SynGAP, and Shank3), and accelerate complement- and microglia-mediated synaptic pruning. Collectively, these processes converge to destabilize neuronal circuits and drive early cognitive decline. In this review, we synthesize current evidence on the molecular mechanisms by which ApoE4 compromises synaptic function, with particular emphasis on lipid microdomain instability, mitochondrial failure, and the collapse of postsynaptic density proteins. We also discuss therapeutic strategies to enhance synaptic resilience, including modulation of glutamatergic transmission, restoration of lipid homeostasis, augmentation of neurotrophic signaling, and regulation of microglial activity. Targeting synaptic preservation in APOE ε4 carriers holds promise as a disease-modifying approach to mitigate cognitive decline in AD.

Keywords:  Alzheimer’s disease; ApoE4; Synaptic dysfunction; lipid metabolism; therapeutic strategies

DOI:  https://doi.org/10.1016/j.arr.2026.103153
J Biol Chem. 2026 Apr 24. pii: S0021-9258(26)01073-2. [Epub ahead of print] 112201

Profiling of fatty acids and lipids in animal and human tissues yields new leads for disease progression biomarkers of X-linked adrenoleukodystrophy.

Alla Kloss, Laura Parisi, Donghui Wang, Martin Hanus, Rachelle Golden, Kelly Keefe, Ruby Chiang, Yihang Li, Alex Brezzani, Paul Lang, Can Kayatekin, Tatiana Gladysheva.

X-ALD is a rare disorder caused by impaired b-oxidation of very long chain fatty acids, their accumulation and incorporation in lipids and resulting in pathology, severely impacting central nervous system. Thorough comparative profiling of fatty acids and lipids in different human tissues and biological fluids described in this manuscript has revealed significant differences in composition which explained why blood lipids successfully used as diagnostics biomarkers for X-ALD do not correlate with disease progression and cannot inform on decision making regarding medical intervention. Our data yielded insights in understanding why the metabolic disorder resulting in elevated levels of VLCFAs in all tissues in X-ALD patients causes severe pathology limited to the central nervous system. We then conducted global lipid profiling of cerebrospinal fluid from pediatric patients and using data filtering based on disease progression trend identified new leads for lipid markers with strong disease progression correlations. Data suggests that few associated proteins should be evaluated as potential biomarkers which may be detectable in blood. We also present data from lipids and fatty acids profiling of tissues from X-ALD mouse model and WT mice, and comparison with the profiling data obtained for human tissues. This analysis yielded clues to understanding why the ABCD1 KO mouse model which has the relevant biochemical phenotype, develops only a subtle pathology, while in humans disease manifestation is severe. In the ABCD1 KO mouse longitudinal study reported in this manuscript, we have identified trending lipids which may serve as sensitive biomarkers of fatty acids metabolism modulations.

DOI: https://doi.org/10.1016/j.jbc.2026.112201
Neuropsychopharmacology. 2026 Apr 30.

Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.

Simone Astori, Olivia Zanoletti, Jocelyn Grosse, Carmen Sandi.

Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-and how such adaptations shape behavior-remains poorly understood. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, which led us to hypothesize that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. To test this hypothesis, we examined how acute mitochondrial inhibition alters MSN function using mouse brain slices. Inhibition of mitochondrial complex I with the selective inhibitor rotenone reduced MSN intrinsic excitability, an effect that was counteracted by intracellular ATP replenishment. We next asked whether ATP-sensitive potassium (K-ATP) channels, canonical regulators of membrane excitability under metabolic stress, contribute to these responses. Histological analyses revealed specific expression of Kir6.2 subunits in both D1- and D2-MSNs, as compared to non-MSNs, and electrophysiological recordings showed that K-ATP channel activation blockade prevented rotenone-induced reductions in MSN excitability. In behavioral assays, complex I inhibition impaired effort-related performance, an effect that was rescued by K-ATP channel blockade. These findings identify K-ATP channels in MSNs as key mediators that sense acute changes in neuronal energy state and translate them into rapid adjustments in NAc excitability and behavior.

DOI: https://doi.org/10.1038/s41386-026-02429-8
Cell Prolif. 2026 Apr 30. e70221

SCD2 Alleviates Diabetes-Associated Cognitive Dysfunction by Improving Microglial Lipid Metabolism.

Yang Yang, Juan He, Jing Zheng, Bing Shao, Lixin Shi, Miao Zhang.

  The mechanisms underlying diabetes-associated cognitive dysfunction (DACD) are not fully understood, and microglial metabolic dysfunction is emerging as a key contributor. This study investigates whether stearoyl-CoA desaturase 2 (SCD2) alleviates cognitive impairment by modulating microglial lipid metabolism and function. Bioinformatics analysis of a single-cell RNA-seq dataset (GSE201644) identified SCD2 downregulation in diabetic (db/db) microglia. A T2D mouse model underwent hippocampal overexpression of SCD2 via AAV injection. In vitro, high glucose (HG)-treated BV2 microglia-like cells were subjected to SCD2 overexpression or oleic acid (OA) supplementation. Mitochondrial function (OCR, ATP, ETC complexes), lipid droplet accumulation (BODIPY, PLIN2), and inflammation (TNF-α, IL-6) were assessed. Cognitive behaviour (MWM, NOR) and neurophysiology (synaptic markers, neuronal survival) were evaluated. Diabetic microglia exhibited reduced SCD2 expression, impaired oxidative phosphorylation and lipid droplet accumulation (LDAM). SCD2 overexpression or OA rescued mitochondrial function, mitigated lipid droplet accumulation and attenuated inflammation. In vivo, hippocampal SCD2 overexpression attenuated neuroinflammation, preserved synaptic integrity and improved cognition in diabetic mice. SCD2 is essential for maintaining microglial lipid and mitochondrial homeostasis in diabetes. Restoring SCD2 function alleviates neuroinflammation and synaptic deficits, thereby rescuing cognitive impairment, highlighting its therapeutic potential for DACD.

Keywords:  SCD2; diabetes‐associated cognitive dysfunction; lipid droplet accumulation; microglia; neuroinflammation; oxidative phosphorylation

DOI:  https://doi.org/10.1111/cpr.70221
Epilepsia Open. 2026 Apr 28.

Energy metabolism, adenosine, and glutamate signaling reprogramming by decanoic acid in Glut1 disorder syndrome.

Erwann Pain, Yatra Kapatel, Pankaj K Singh, Katie Lloyd Jones, Jamuna Selvakumaran, Alberto Malerba, Walter Lucchesi, Tricia Rutherford, Christina A Gurnett, Matthew C Walker, Robin S B Williams.

  Glut1 deficiency syndrome (Glut1DS) leads to neurological and cognitive symptoms and is primarily treated using carbohydrate-restricted ketogenic diets. However, a recent clinical trial of a less restrictive, non-ketogenic, medium chain triglyceride (MCT) diet with a high decanoic acid content suggests efficacy in Glut1DS treatment. Here, we employ human Glut1DS-derived iPSCs to investigate a role for these medium chain fatty acids in the regulation of gene expression as a proxy for metabolic reprogramming. We show that the new high decanoic blend reproduces many therapeutic changes in energy metabolism-related gene expression seen during glucose-restricted ketogenic diets, including enhanced expression of β-oxidation, TCA cycle, and oxidative phosphorylation-related genes, but under high glucose conditions. These treatments also unexpectedly regulate transcription of adenosine signaling and synaptic transmission-related genes. This study thus identifies potential molecular mechanisms of decanoic acid that may underlie its clinical benefit in Glut1DS and expands its role to other genetic epilepsies. PLAIN LANGUAGE SUMMARY: Ketogenic diets provide the first-choice treatment for glucose transporter type 1 deficiency syndrome (Glut1DS), where reduced carbohydrate intake triggers the production of ketones as the therapeutic mechanism. Alternatively, a new, flexible medium chain triglyceride diet has been developed that does not involve reduced carbohydrate restriction nor ketone production. This study investigates the metabolic mechanisms underlying this diet in Glut1DS patient-derived stem cells. Interestingly, the diet mimicked the beneficial effects of ketogenic diets to improve energy metabolism, and surprisingly indicated new ways that the diet may provide therapeutic benefit in Glut1DS treatment.

Keywords:  Glut1 deficiency syndrome; adenosine signaling; glucose transporter 1 (SCL2A1); glutamate receptors; ketogenic diets; transcriptional regulation

DOI:  https://doi.org/10.1002/epi4.70263
Neurosci Bull. 2026 Apr 28.

Fat on Fire: Disrupted Microglial Lipid Metabolism as a Driver of Anesthetic Neurotoxicity.

Yu-Jie Mou, Hai-Yue Tu, Yi-Chan Wang, Shao-Yong Song, Hua-Yue Liu, Dong Wang, Jun-Chao Wu, Xiao-Wen Meng, Zheng-Hong Qin, Fu-Hai Ji.

  Anesthetics are indispensable in clinical practice, yet growing evidence indicates that they can disrupt brain function beyond their intended effects. While research on anesthetic neurotoxicity has largely focused on neurons, microglia are now recognized as central players in determining perioperative outcomes. Lipid metabolism in microglia has emerged as a key regulator of immune responses, synaptic maintenance, and neuroinflammation. Anesthetic exposure disturbs this metabolic balance, leading to lipid droplet accumulation, defective fatty acid oxidation, and pro-inflammatory activation that contribute to cognitive impairment. However, knowledge in this field remains fragmented and has not been systematically synthesized. In this review, we integrate current evidence on how anesthetics perturb microglial lipid metabolism and delineate the mechanistic pathways involved, with the goal of identifying potential therapeutic targets related to microglial lipid metabolism to alleviate anesthesia neurotoxicity.

Keywords:  Anesthetic neurotoxicity; Cognitive dysfunction; Lipid metabolism; Lipid-targeted therapy; Microglia

DOI:  https://doi.org/10.1007/s12264-026-01623-4
Pediatr Res. 2026 Apr 30.

Association of serum biomarkers for lipid and amino acid metabolism with cognition in adolescents.

Aleksi Rautauoma, Aino-Maija Eloranta, Timo A Lakka, Eero A Haapala.

BACKGROUND: We investigated the associations of serum biomarkers for lipid and amino acid metabolism with cognition in adolescents.
METHODS: Altogether 276 adolescents aged 15-16 years were studied. Serum biomarkers for lipid and amino acid metabolism were analyzed using nuclear magnetic resonance spectroscopy. Cognition was assessed using the CogState tests measuring psychomotor function, attention, short-term memory, working memory, and visual learning and memory. The composite cognition score (COMP) including all cognitive measures was calculated.
RESULTS: Higher total cholesterol, phosphoglycerides, cholines, sphingomyelins, VLDL- and LDL cholesterol, apolipoprotein B, omega-3 and omega-6 fatty acids, polyunsaturated and monounsaturated fatty acids, and saturated fatty acids were associated with poorer psychomotor function. Higher sphingomyelins, HDL cholesterol, apolipoprotein A1, and glutamine were associated with worse visual learning and memory. Higher LDL cholesterol diameter and higher omega 3 to total fatty acid ratio were associated with better working memory accuracy. Higher serum histidine was associated with better attention and phenylalanine with faster psychomotor function under working memory demand.
CONCLUSION: Serum biomarkers for lipid metabolism, such as higher total cholesterol and saturated fatty acids, were associated with poorer cognition, particularly psychomotor function, among adolescents.
IMPACT: Serum metabolites, such as saturated fatty acids and branched-chain amino acids, have been associated with impaired cognition in the elderly. However, there are few studies on the associations of biomarkers of serum lipid and amino acid metabolism with cognition in youth. We found that serum biomarkers for lipid metabolism, such as higher serum concentrations of total cholesterol, phosphoglycerides, and saturated fatty acids, were associated with poorer cognition, particularly psychomotor function, among adolescents. Our findings suggest that biomarkers of lipid metabolism that are harmful for cardiometabolic health can also impair cognitive development in adolescents.

DOI: https://doi.org/10.1038/s41390-026-05040-1
Cells. 2026 Apr 10. pii: 672. [Epub ahead of print]15(8):

From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease.

Romina María Uranga, Shailaja Kesaraju Allani.

  The increasing prevalence of obesity and Alzheimer's disease (AD) in the aging population underscores an urgent need to understand the common cellular and metabolic mechanisms they share. Accumulated evidence suggests that overlapping metabolic disturbances contribute to the pathogenesis of these two conditions. In this review, we highlight key underlying interconnecting metabolic pathways: (1) adipose-brain crosstalk mediated by adipokines and adipose tissue-derived extracellular vesicles that can modulate neuronal function and amyloid pathology, (2) dysregulated lipid metabolism affecting cholesterol, sphingolipids, and phospholipids and thereby promoting inflammation, amyloid precursor protein processing, and tau hyperphosphorylation, (3) impaired glycolysis and insulin resistance, which accelerate both obesity and neurodegenerative processes, (4) mitochondrial dysfunction marked by disrupted tricarboxylic acid cycle enzymes and electron transport chain complexes, leading to elevated reactive oxygen species and driving both obesity and AD pathology, and (5) gut microbiota dysbiosis, which can trigger inflammation as well as amyloid and tau aggregation. Together, these mechanisms show that metabolic alterations appear early, preceding clinical disease, and that understanding these underlying connections can provide strategies to protect metabolic health and prevent disease progression.

Keywords:  Alzheimer’s disease; TCA cycle; adipokines; adipose tissue; electron transport chain; glycolysis; gut–brain axis; insulin resistance; lipids; microbiota; mitochondrial dysfunction; obesity

DOI:  https://doi.org/10.3390/cells15080672
Chem Biol Interact. 2026 Apr 29. pii: S0009-2797(26)00226-7. [Epub ahead of print] 112118

Mechanistic Insights into Glufosinate-ammonium (GLA)-Induced Brain Injury Revealed by LC-MS/MS-Based Metabolomics.

Huan-le Ye, Xin-Xin Zheng, Mian-Mian Li, Zhi-Qiang Zhang, Liu-Xu Chen, Wen-Jing Zhang, Ren Cheng-Han Fan, Guo-Xin He, An-Cong Xu.

   AIMS: This study aimed to elucidate the biochemical and metabolic mechanisms underlying glufosinate-ammonium-induced neurotoxicity, with a focus on brain metabolic disturbances.
METHODS: Male Sprague-Dawley rats were administered glufosinate-ammonium by intragastric gavage, with saline-treated animals serving as controls. Neuropathological changes and cognitive performance were assessed at 2 and 6 days post-exposure. Oxidative stress and energy metabolism were evaluated by measuring plasma antioxidant indices, and brain levels of superoxide dismutase (SOD), glutathione (GSH/GSSG), total antioxidant capacity (T-AOC), and adenosine triphosphate (ATP). In addition, untargeted LC-MS/MS-based metabolomics of brain tissue was conducted to characterize exposure-related metabolic perturbations.
RESULTS: Histopathological examination revealed marked brain injury on day 2 post-exposure, characterized by neuronal necrosis, apoptosis, and severe mitochondrial disruption. Although pathological severity was attenuated by day 6, residual cellular damage remained evident. Behavioral testing revealed significant impairments in spatial learning and memory in the glufosinate-ammonium-exposed group. Biochemical analyses revealed disrupted oxidative stress and energy metabolism, reflected by altered levels of superoxide dismutase (SOD), glutathione (GSH/GSSG), total antioxidant capacity (T-AOC), and adenosine triphosphate (ATP) in brain tissue. Metabolomic analysis revealed pronounced alterations in brain metabolic profiles, involving pathways related to oxidative stress, energy metabolism, and amino acid metabolism. Early-stage disturbances were dominated by alterations in glutamate and tricarboxylic acid (TCA) cycle-related metabolites, whereas later-stage changes primarily involved taurine and hypotaurine metabolism.
CONCLUSION: Following glufosinate-ammonium exposure, rats exhibited neurological dysfunction and cognitive impairment, accompanied by metabolic disturbances in brain tissue, particularly in oxidative stress, energy metabolism, and amino acid metabolism. These findings provide mechanistic insight into glufosinate-ammonium-induced neurotoxicity and highlight the critical role of metabolic dysregulation.

Keywords:  Brain injury; Glufosinate-ammonium; Metabolomics; Neurotoxicity

DOI:  https://doi.org/10.1016/j.cbi.2026.112118
Front Pharmacol. 2026 ;17 1735477

PHGDH-mediated serine synthesis reduces oligodendrocyte death by sustaining GSH and NADPH levels after brain ischemia.

Zhaolong Zhang, Jinhua Tan, Mengfei Lv, Zhongying Duan, Congxiao Wang, Mingchen Gao, Yu Cui, Yugong Feng.

   Introduction: White matter is vulnerable to early ischemic injury. The susceptibility of oligodendrocytes to ischemic damage can lead to demyelination, axonal degeneration, and neurological deficits, making them a key focus for understanding and developing therapies for stroke-related brain injury. In this study, we aimed to investigate how cell metabolism contributes to oligodendrocyte survival and white matter integrity maintenance following ischemia.
Methods: NCT-503 was injected after inducing transient middle cerebral artery occlusion. After reperfusion, brain infarct volume and neurobehavioral deficits and behaviour performance were assessed. Immunofluorescence staining was performed to evaluate oligodendrocytes death. Cell viability was measured using the CCK8 assay. Flow cytometry analysis was conducted to examine reactive oxygen species (ROS) levels.
Results: De novo serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH) was hardly expressed in neurons, microglia and oligodendrocyte precursor cells (OPCs) but selectively expressed in mature oligodendrocytes and astrocytes. Brain ischemic injury specifically enhanced the expression of PHGDH in oligodendrocytes. PHGDH inhibition with NCT-503 did not affect acute neuronal injury but worsened sensorimotor and cognitive functional outcomes after ischemic stroke. Moreover, white matter integrity and oligodendrocyte survival were specifically reduced after PHGDH inhibition and serine supplementation facilitated oligodendrocyte survival and enhanced white matter integrity, and consequently improved neurological functions. Mechanistically, PHGDH-mediated serine synthesis protected oligodendrocytes from oxidative stress-induced death by promoting glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) production through the one-carbon metabolism pathway.
Conclusion: This study reveals the role of PHGDH-mediated de novo serine synthesis in reducing oligodendrocyte death which may provide a potential target for improving neurological function after ischemic stroke.

Keywords:  OGD/R; PHGDH; ischemic stroke; oligodendrocytes; serine; white matter

DOI:  https://doi.org/10.3389/fphar.2026.1735477
Metabolites. 2026 Mar 31. pii: 231. [Epub ahead of print]16(4):

Stable Isotopes for the Study of Energy Nutrient Metabolic Pathways in Relation to Health and Disease.

Dalila Azzout-Marniche, Daniel Tomé.

  Background: Stable isotope-based analytical methods have brought about a significant transformation in the study of energy nutrient metabolism, enabling precise in vivo measurement of metabolic fluxes at systemic, tissue, and organ-specific levels in both healthy and diseased states. The regulation of these metabolic fluxes is governed by dynamic interactions between proteins, lipids, carbohydrates, and their precursors-such as glucose, fatty acids, and amino acids-as well as final metabolic products. Discussion: Advanced analytical technologies, including nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), which can offer enhanced precision, have been developed for investigating nutrient metabolism and fluxes in humans, providing precise information on metabolic pathways. These techniques have primarily utilized stable isotopes, such as 2H, 13C, 15N, and 18O, which have largely replaced radioactive isotopes and are now central to metabolic research. These isotopes have been used to label glucose, fatty acids, or amino acids-the main biomolecular precursors-enabling detailed investigation at systemic, tissue, and organ-specific levels of carbohydrate, lipid, and protein metabolism, and revealing pathway alterations associated with diseases conditions, such as diabetes, non-alcoholic fatty liver disease, cardiovascular disorders, and cancer. The use of deuterium oxide (D2O) has allowed for long-term metabolic studies, providing a cost-effective and less invasive means to monitor metabolic changes over days to months. Total daily energy expenditure can be measured in free living conditions by the doubly stable isotopes 2H- and 18O-labeled water method. Stable isotope tracing, combined with advanced imaging and modeling, has also been instrumental in assessing body composition, energy expenditure, and nutrient bioavailability. Collectively, these methods have expanded our understanding of human physiology and disease, supporting the development of novel diagnostic tools, the identification of new biomarkers, and the tailoring of nutritional and therapeutic interventions. Conclusions: This review aimed to provide an overview of the applications of stable isotopes for the study of energy nutrient metabolic pathways. The ongoing integration of stable isotope approaches with artificial intelligence, omics technologies, and miniaturized detection techniques could promise to further refine our understanding of human metabolism and drive advances in personalized medicine.

Keywords:  amino acid; fatty acid; glucose; nutrient metabolism; protein; stable isotopes

DOI:  https://doi.org/10.3390/metabo16040231
Metabolites. 2026 Apr 20. pii: 281. [Epub ahead of print]16(4):

Selected Brain Metabolites and Mitochondrial DNA Copy Number as Potential Markers of Ongoing Neurodegeneration in Patients with Wolfram Syndrome.

Ewa Zmysłowska-Polakowska, Tomasz Płoszaj, Sebastian Skoczylas, Julia Grzybowska-Adamowicz, Dobromiła Barańska, Katarzyna Matera, Aleksandra Palatyńska-Ulatowska, Wojciech Młynarski, Agnieszka Zmysłowska, Michal Ciborowski.

  Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by central nervous system atrophy. Methods: The aim of the study was to analyse magnetic resonance images (MRI) of the brain in combination with single-voxel magnetic resonance spectroscopy (MRS) and to assess the copy number of mitochondrial DNA (mtDNA-CN) in 10 patients with WFS compared with a control group of 17 healthy individuals. Results: A significant decrease in the amount of selected metabolites was observed in WFS patients compared to controls in all assessed brain regions (pons, cerebellum, white matter, thalamus, and hippocampus). For three metabolites, Glutamate (Glu), Glutamate + Glutamine (Glx) and total N-acetylaspartate (TNAA), significant differences in concentrations were found between the study groups in almost all matrices evaluating specific areas of the brain (p < 0.011), with the exception of a trend toward reduced TNAA in the hippocampus (p = 0.065). In addition, patients with WFS had a significant decrease in the mitochondrial-to-nuclear DNA ratio compared to controls (p < 0.0003). Some metabolites, such as N-acetylaspartate and total N-acetylaspartate, showed strong correlations with specific regions of the visual pathway on MRI scans in patients with WFS. Conclusions: Selected brain metabolites and mtDNA-CN may become potential markers of WFS, and the results of this study may be used to define indicators for future therapeutic strategies.

Keywords:  MRS; Wolfram syndrome; markers; mtDNA copy number; neurodegeneration

DOI:  https://doi.org/10.3390/metabo16040281
Nat Neurosci. 2026 Apr 30.

Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation.

Sami Sauma, Stephanie Stransky, Ipek Selcen, Simone Sidoli, Rinat Abzalimov, Ye He, Patrizia Casaccia.

How it is determined whether postnatal oligodendrocyte progenitor cells (OPCs) will survive, proliferate or differentiate remains unclear. Here we suggest that temporal and brain regional fluctuations of glucose, concomitant with changes in vascularization, modulate OPC population dynamics. We found that regions with high glucose levels exhibited greater OPC proliferation and histone acetylation than regions with low glucose and that this was mediated by the enzyme ATP-citrate lyase (ACLY), which converts glucose-derived citrate to acetyl-CoA. Mice with Acly deletion in OPCs showed a transient hypomyelination phenotype resulting from decreased OPC numbers, whereas their differentiation into oligodendrocytes (OLs) proceeded due to compensatory upregulation of enzymes responsible for extranuclear generation of acetyl-CoA from alternative metabolic substrates. Therefore, OPCs rely on ACLY-dependent nuclear acetyl-CoA from glucose-derived citrate, to regulate proliferation, whereas OLs rely on extranuclear acetyl-CoA from other sources for myelin formation. This suggests a metabolic regulation of OL lineage cell population dynamics.

DOI: https://doi.org/10.1038/s41593-026-02263-7
J Child Neurol. 2026 Apr 25. 8830738261439221

Efficacy of Treating Post-Traumatic Epilepsy in Children With Ketogenic Diet.

Hyoung Won Choi, Sonam Bhalla, Philip Holt, Meredith Johnson.

  ObjectiveTo investigate the efficacy of ketogenic diet for seizure control in a cohort of children with post-traumatic epilepsy.MethodsWe performed a retrospective chart review of patients who sustained traumatic brain injury (TBI) and were subsequently evaluated at the Children's Hospital of Atlanta ketogenic program for the treatment of post-traumatic epilepsy (PTE) from January 2010 to December 2024.ResultsIn this study, we analysed 13 children with PTE who were maintained on a ketogenic diet for at least 3 months. Ten of the participants were male. The mean age at diet initiation was 5 years 1 month (range 2 years 1 month to 12 years 9 months). The median duration of seizure occurrence before ketogenic diet initiation was 2 years (range 1-8 years). Many patients hadd non-accidental trauma with severe TBI (11/13). The rate of response to ketogenic diet treatment for PTE was 69% (9/13).ConclusionThis study provides class IV evidence that ketogenic diet is an effective treatment strategy to reduce seizure burden in children with PTE.

Keywords:  ketogenic diet; post-traumatic epilepsy

DOI:  https://doi.org/10.1177/08830738261439221
Curr Nutr Rep. 2026 Apr 27. pii: 40. [Epub ahead of print]15(1):

Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.

Meenakshi Umar, Karson Franjieh, Amanda Louise White, Elisse Ward-Dones, Saifudeen Ismael, Rose C Roskey, Jacques Courseault, Gregory Jaye Bix.



Keywords:  Alzheimer's disease; Folate; Parkinson’s disease; neurodegenerative diseases; one-carbon metabolism

DOI:  https://doi.org/10.1007/s13668-026-00761-5
Neurosci Lett. 2026 Apr 28. pii: S0304-3940(26)00115-1. [Epub ahead of print] 138616

Brain creatine, estradiol and neurocognitive complaints in perimenopausal women: an exploratory cross-sectional study.

Sergej M Ostojic, Jelena Ostojic.

   BACKGROUND: Menopause and the perimenopausal transition involve profound hormonal and metabolic changes that may impair brain function. Beyond structural alterations, reduced cerebral bioenergetics could underlie the cognitive complaints often reported during this period. Because creatine serves as a key neuronal energy buffer and is influenced by estrogen, this study examined brain creatine concentrations in perimenopausal women and their associations with neurocognitive symptoms and serum estradiol.
METHODS: Twelve healthy perimenopausal women (mean age 49.8 ± 5.4 years) experiencing irregular cycles and at least one perimenopausal symptom underwent multi-voxel 1H-magnetic resonance spectroscopy to quantify total brain creatine across bilateral frontal, precentral, and parietal gray- and white-matter regions and the thalamus. Serum estradiol was measured by ELISA, and symptom severity was rated on visual analog scales. Associations were assessed using Kendall's τ.
RESULTS: Mean whole-brain creatine concentration (6.31 ± 0.98 mM) was significantly lower than reference values in younger adults (Z = -1.65, P = 0.049). Lower creatine levels in the thalamus, right precentral, and right parietal white matter correlated with greater concentration difficulties (τ = -0.38 to -0.51, P ≤ 0.049), while right frontal white-matter creatine positively correlated with headache severity (τ = 0.41, P = 0.034). Serum estradiol averaged 119.5 ± 109.5 pg/mL and was inversely associated with right parietal gray-matter creatine (τ = -0.37, P = 0.049).
CONCLUSIONS: Perimenopausal women exhibited lower cerebral creatine than younger adults, with region-specific reductions linked to concentration difficulties and estradiol levels. These findings suggest that estrogen-related changes in brain bioenergetics may contribute to cognitive symptoms during the menopausal transition.

Keywords:  Bioenergetics; Creatine; Estradiol; MRS; Neurocognitive; Perimenopause

DOI:  https://doi.org/10.1016/j.neulet.2026.138616
Cell Mol Immunol. 2026 Apr 30.

Short-, medium-, versus long-chain fatty acids: mechanisms of immunomodulation and disease pathogenesis.

Chang H Kim.

  Fatty acids, such as short-chain fatty acids, medium-chain fatty acids and long-chain fatty acids, exist in different chain lengths and with various modifications, which determine their physical, metabolic and biological properties. They serve as important nutrients in energy production via mitochondrial beta-oxidation in various cell types including immune cells. At optimal levels in the body, fatty acids support normal differentiation and function of immune cells. However, at excessive levels, they can cause dysregulation of immune cells and inflammation. The three types of fatty acids regulate cells, in part, via the activation of G protein-coupled receptors, such as GPR41, GPR43, GPR109A, and Olfr78 for short-chain, GPR40 and GPR120 for both medium- and long-chain fatty acids, and GPR84 for medium-chain fatty acids. Activation of these receptors by fatty acids regulates cell proliferation and cell-specific functions. Importantly, fatty acids induce the production of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide through activation of G-protein coupled receptors. Short-chain fatty acids additionally control epigenetic regulators such as histone deacetylases and histone acetyltransferases. Saturated long-chain fatty acids and omega-6 polyunsaturated fatty acids are implicated in metabolic diseases and inflammatory conditions, whereas short-chain fatty acids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids are generally associated with functional immunity with anti-inflammatory effects. This article explores how fatty acids regulate the immune system, focusing on their common and unique roles, as well as their opposing functions.

Keywords:  Immune regulation; Medium-chain fatty acids; Polyunsaturated fatty acids; Saturated fatty acids; Short-chain fatty acids

DOI:  https://doi.org/10.1038/s41423-026-01412-z
Oncogenesis. 2026 Apr 30.

Reprogramming lipid metabolism in pediatric cancers.

Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher.

Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.

DOI: https://doi.org/10.1038/s41389-026-00617-1
J Neuroinflammation. 2026 Apr 25.

Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.

Clair C Ashley, Nicholas J Constantino, Ryan J Pettit-Mee, J Andy Snipes, Kai Saito, Riley E Irmen, Rui Zhang, Evan M Neary, Matthew J Lanning, Celeste M Karch, Lance A Johnson, Josh M Morganti, Shannon L Macauley.



Keywords:  Amyloid plaques; Lactate; Metabolism; Microglia

DOI:  https://doi.org/10.1186/s12974-026-03825-z
Neurosci Res. 2026 Apr 27. pii: S0168-0102(26)00049-0. [Epub ahead of print] 105062

Cellular expression and subcellular localization of autotaxin, a lysophosphatidic acid-generating enzyme, in the adult and developing mouse brain.

Masanori Tachikawa, Masahiro Fukaya, Eriko Miura, Zhengyu Zhang, Shinichi Okudaira, Chihiro Takasaki, Ken-Ichi Hosoya, Junken Aoki, Masahiko Watanabe.

  Autotaxin (ATX) is a lysophosphatidic acid-producing enzyme. In this study, we describe the cellular expression and subcellular localization of ATX in the mouse brain, thereby providing a fundamental framework for understanding lysophosphatidic acid signaling in vivo. High expression levels of ATX in the choroid plexus were observed in both developing and adult brains. ATX was localized predominantly at the cerebrospinal fluid (CSF)-facing apical side of choroid plexus epithelial cells, suggesting preferential secretion of ATX towards the CSF. High ATX expression was detected in oligodendrocytes and low-to-moderate levels were detected in neurons and astrocytes. ATX was preferentially localized in vesicle- and endoplasmic reticulum-rich regions of the cytoplasm. In the embryonic and early postnatal brain, ATX immunolabeling was intensely detected in neuronal perikarya and processes, whereas it was faint in the radial glia/astrocyte lineage. A marked upregulation of ATX in oligodendrocytes was observed during the active myelination stage that persisted into adulthood. The highly regulated, cell type-dependent expression of ATX suggests that ATX is a key regulatory factor for lysophosphatidic acid signaling in brain development and function.

Keywords:  antibody; cerebrospinal fluid; choroid plexus; immunoelectron microscopy; immunohistochemistry; lysophospholipase D; neural development; proteomics

DOI:  https://doi.org/10.1016/j.neures.2026.105062
Int J Dev Neurosci. 2026 May;86(3): e70136

Evaluation of c26:0-Lyso-Phosphatidylcholine Levels in X-Linked Adrenoleukodystrophy: Diagnosis and Biochemical Monitoring.

Gilian Guerreiro, Marion Deon, Graziela Becker, Luísa Tedesco, Carmen Regla Vargas.

   INTRODUCTION: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by ABCD1 mutations that impair very long-chain fatty acid (VLCFA) degradation, leading to progressive neurological damage and adrenal insufficiency. C26:0-Lysophosphatidylcholine (C26:0-Lyso-PC) has emerged as a robust biomarker for X-ALD and a candidate for newborn screening programs.
OBJECTIVES: The objective of this study is to standardize and validate C26:0-Lyso-PC quantification by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and evaluate its diagnostic accuracy in high-risk populations.
DESIGN AND METHODS: Reference values were established from 25 healthy controls and compared with five confirmed X-ALD cases (one cerebral childhood form, three heterozygous women and one asymptomatic male). Additionally, 64 DBS samples from individuals at high risk for inborn errors of metabolism (IEM) were tested. Plasma VLCFA were quantified by gas chromatography-mass spectrometry (GC/MS).
RESULTS: Control C26:0-Lyso-PC values ranged from 0.13 to 0.25 μg/mL (mean = 0.19 μg/mL). All X-ALD patients exhibited elevated concentrations (0.377-0.787 μg/mL). Among samples from patients at high risk for disease, four were abnormal-two consistent with X-ALD and two with other peroxisomal disorders. Strong correlations were observed between C26:0-Lyso-PC and plasma C26:0 (r = 0.952, p < 0.001) and the C26:0/C22:0 ratio (r = 0.801, p < 0.05). The method demonstrated high reproducibility (intra-assay CV = 8.6% and interassay CV = 12.8%).
CONCLUSIONS: C26:0-Lyso-PC measurement in DBS by LC-MS/MS is a rapid, sensitive and reproducible alternative to plasma VLCFA analysis, enabling reliable discrimination of X-ALD and other peroxisomal disorders. These findings support its integration into targeted and population-based screening to allow presymptomatic diagnosis, early intervention and genetic counselling.

Keywords:  C26:0‐Lyso‐PC; X‐ALD; diagnosis; neonatal screening; tandem mass spectrometry

DOI:  https://doi.org/10.1002/jdn.70136
Trends Mol Med. 2026 Apr 30. pii: S1471-4914(26)00084-5. [Epub ahead of print]

Mitochondrial dysfunction in cerebrovascular diseases.

Fabio Marcheggiani, Ilaria Nunzi, Loredana Rao, Nada Dhaouadi, Salvatore Nesci, Paolo Pinton, Saverio Marchi.

  Mitochondria are central regulators of cerebrovascular health through their control of energy metabolism, Ca2+ homeostasis, and redox signaling, and their dysfunction represents a convergent pathogenic mechanism across cerebrovascular diseases. In ischemic stroke, mitochondrial failure exacerbates neuronal injury via permeability transition pore opening, oxidative stress, and bioenergetic collapse, while altered mitochondrial dynamics and the release of mitochondrial damage-associated molecular patterns amplify neuroinflammation during reperfusion. Beyond stroke, mitochondrial dysfunction contributes to intracranial aneurysms, atherosclerotic stenosis, and vascular malformations, where oxidative stress, mitochondrial DNA instability, and cell type-specific metabolic reprogramming drive vascular remodeling and lesion progression. In this review, we integrate recent evidence highlighting context- and stage-dependent roles of mitochondria in cerebrovascular pathology and discuss implications for biomarker discovery, therapeutic targeting, and translational strategies.

Keywords:  cerebral malformations; inflammation; mitochondria; mitochondrial calcium uniporter; permeability transition pore; stroke

DOI:  https://doi.org/10.1016/j.molmed.2026.04.002