bims-medebr 2026-04-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–04–19
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.
Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.
Peri-Microvascular Glycogen and Lactate Regulate Capillary Constrictions and Ischemia Outcome in Mice.
Role of brain glycogen and glucose regulation in migraine susceptibility.
Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.
Mitochondrial Calcium Signaling in the Brain: From Molecular Mechanisms to Behavioral Outcomes.
Protocol for metabolite extraction and sample preparation from primary astrocytes for mass spectrometry-based metabolomic analysis.
Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism.
Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.
Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
Long-term region-specific mitochondrial respiration impairment after perinatal asphyxia is prevented by the NAD⁺ donor nicotinamide riboside: A real-time organotypic metabolic profiling approach.
Time-resolved lipidomic profiling reveals alterations following 3-MCPDEs exposure in Sprague-Dawley rats.
Temporal and cell-specific changes to cellular iron sequestration and lipid peroxidation in a murine model of neonatal hypoxic-ischemic brain injury.
FABP7 controls radial glial scaffold stability during human cortical development.
Metabolic Symbiosis and Vulnerability in the CNS Axon-Myelin Unit.
Roles of Oxidative Phosphorylation and Fatty Acid Oxidation in Neuroinflammation Induced by Lipopolysaccharide in Hypothalamic Neuronal Cells.
MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.
Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.
Detecting early brain susceptibility changes before demyelination in cuprizone mouse model using quantitative susceptibility mapping (QSM).
Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.

NPJ Metab Health Dis. 2026 Apr 14. pii: 15. [Epub ahead of print]4(1):

Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.

Julian Avila Pacheco, Gleidia Sauli, Luis Fonseca-Ornelas, Haley Cirka, Deepa Kumari, Morgan Hazo, Sarah Jeanfavre, Pedro H Vendramini, Christina R Muratore, Clary B Clish, Dennis Selkoe, Saranna Fanning.

Despite the lipid-rich nature of the brain, defining the role of lipid metabolism in neurodegenerative disease and targeting lipid metabolic pathways for disease modification are in their infancy. In Parkinson's disease, Lewy body dementia, and other synucleinopathies, disease-associated forms of α-synuclein (αS) alter fatty acid (FA) metabolism, increasing monounsaturated FA-containing lipids. This disequilibrium in membrane fatty acyl composition results in aberrant αS:membrane interactions. We report treating PD patient neurons with myristic acid (C14:0) induces lipid metabolism modifications correcting abnormal PD-associated membrane composition and reversing PD-relevant phenotypes. C14:0 conditioning reduced Lewy-like αS inclusions; reduced abnormal pSer129 αS; corrected excess αS at membranes; and restored native αS tetramer:monomer homeostasis. Using nuclear magnetic resonance, we established C14:0 as correcting abnormal αS vesicle membranes dwell time in vitro, correlating with less pathogenic αS aggregation. Mechanistically, C14:0 rescued PD neuron phenotypes through remodeling the PD-associated lipidome, eliciting beneficial effects by increasing shorter, saturated fatty acyl-lipids.

DOI: https://doi.org/10.1038/s44324-026-00110-8
Nat Metab. 2026 Apr 14.

Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.

Romane Manceau, Celena M Cherian, Danie Majeur, Colin J Miller, Jasper D Fisher, Frédérick Boisjoly, J Beatrice Liston, Jennifer A Bako, Lianna W Wat, Charlotte F Chao, Audrey Labarre, Serena Hollman, Sanjana Prakash, Sébastien Audet, Lewis Depaauw-Holt, Benjamin Rogers, Anthony Bosson, Puja Biswas, Joyce J Y Xi, Catrina A S Callow, Niyoosha Yoosefi, Neele Schikora, Niki Shahraki, Yi Han Xia, Alisa Hui, Jared VanderZwaag, Khalil Bouyakdan, Demetra Rodaros, Pavel Kotchetkov, Caroline Daneault, Ghazal Fallahpour, Martine Tetreault, Marie-Ève Tremblay, Matthieu Ruiz, Baptiste Lacoste, J Alex Parker, Ciaran Murphy-Royal, Tao Huan, Stephanie Fulton, Elizabeth J Rideout, Thierry Alquier.

Lipids are essential for neuron development and physiology1-3. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear4. Here we show the presence and functional significance of neuronal lipid droplets (nLDs) in vivo using invertebrate and vertebrate models. We validate5 the presence of nLDs in vivo and demonstrate that triglyceride metabolism enzymes and LD-associated proteins control nLD formation through both canonical and recently discovered pathways6. Modulation of nLDs has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically in neurons that couple environmental cues with energy homeostasis. Mechanistically, nLD-derived lipids support neuron function by providing fatty acids and phospholipids to sustain mitochondrial and endoplasmic reticulum function and homeostasis. This identifies a conserved role for nLDs in coordinating lipid supply and demand in neurons, which has implications for maintenance of neuronal lipid homeostasis and function in health and disease.

DOI: https://doi.org/10.1038/s42255-026-01508-w
J Neurochem. 2026 Apr;170(4): e70430

Peri-Microvascular Glycogen and Lactate Regulate Capillary Constrictions and Ischemia Outcome in Mice.

Gokhan Uruk, Buket Donmez-Demir, Sinem Yilmaz-Ozcan, Canan Cakir-Aktas, Aslihan Taskiran-Sag, Gokce Gurler, Jordi Duran, Joan J Guinovart, Otto Baba, Tsuyoshi Morita, Hulya Karatas, Turgay Dalkara, Muge Yemisci.

  Ischemic stroke results in sudden blood flow cessation, thus unmet energy requirements. Glycogen stored around peri-microvascular astrocyte end-feet may mediate capillary contractility and cerebral blood flow alterations. Under glucose-deprived and hypoxic conditions, lactate derived from these glycogen stores may serve as an emergency fuel to sustain tissue perfusion during an acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, both 1,4-dideoxy-1,4-imino-d-arabinitol hydrochloride (DAB) administered to wild-type (WT) intracerebroventricularly (i.c.v.), and central nervous system and astrocyte-specific glycogen synthase-1 knock-out (GYS1Nestin-KO and GYS1Gfap-KO) mice were used. We assessed regional cerebral blood flow changes in vivo, pericyte-associated microvascular constrictions, semi-quantitative peri-microvascular glycogen levels, and lactate transporters ex vivo. Experiments revealed that both pharmacological and genetic manipulations of glycogen metabolism also resulted in severely compromised blood flow dynamics and higher infarct volumes after stroke. Disrupted cerebral glycogen utilization induced CD13-positive pericyte-associated microvascular constrictions, which were highly correlated with peri-microvascular periodic acid Schiff (PAS), IV58B6, and ESG1A9 intensity levels. Lastly, intravenous (i.v.) D/L-lactate and i.c.v. L-lactate administration reversed microvascular constrictions while glycogen phosphorylase inhibition potently reduced microvascular monocarboxylate transporter-1 (MCT1) coverage. In conclusion, disrupted glycogen utilization causes ischemic-like microvascular constrictions, increases susceptibility to brain ischemia, and is reversible with systemic lactate administration. Understanding the role of glycogen and lactate metabolism at the neurogliovascular level in the brain may provide novel insight into the pathophysiology and therapeutic opportunities of cerebrovascular disorders.

Keywords:  CD13‐positive pericyte; L‐lactate; glycogen; ischemic stroke; microcirculation

DOI:  https://doi.org/10.1111/jnc.70430
Neural Regen Res. 2026 Apr 14.

Role of brain glycogen and glucose regulation in migraine susceptibility.

Zeynep Kaya, Turgay Dalkara.

  Genetic disorders affecting glucose transport and fasting as a trigger suggest that disruptions in brain glucose metabolism may contribute to migraine susceptibility. The activation of the peripheral sympathetic nervous system plays a critical role in responding to declines in blood sugar. Beyond its role in glucose regulation, sympathetic activity driven by locus coeruleus also influences astrocytes, the glial cells responsible for supporting neuronal function. During periods of fasting, stress, and sleep deprivation, sustained sympathetic activation from locus coeruleus may contribute to reduced availability of glycosyl units derived from glycogen in peri-synaptic astrocyte processes. This is attributed to transcriptional shifts favoring glycogen synthesis over utilization, in contrast to the transient low-level locus coeruleus activity that typically promotes glycogen breakdown. The metabolism of glycogen within astrocyte processes is tightly coupled to excitatory synaptic activity, helping to meet the high energetic demands of synaptic transmission, as well as supporting the uptake of glutamate and potassium released during neuronal firing. Disruptions in glycogen metabolism, which impair these processes, may contribute to migraine pathophysiology by compromising the uptake of glutamate and potassium. This environment reduces the cortical spreading depolarization threshold and facilitates the activation of parenchymal inflammatory signaling, both of which increase susceptibility to migraine headaches. The locus coeruleus is closely connected to several hypothalamic nuclei, including the suprachiasmatic nucleus, which helps synchronize circadian rhythms. The hypothalamus can also be activated by nociceptive input as well as external triggers. These reciprocal interactions may give rise to loop activity that fluctuates throughout migraine attacks and interictal periods, potentially influencing glycogen and glucose metabolism in cortical astrocytes. In conclusion, disruptions in astrocyte energy supply to synaptic activity, which is modulated by the extensive projections of locus coeruleus, may contribute to the initiation and progress of certain migraine forms.

Keywords:  cortical spreading depolarization; glucose metabolism; glycogen; locus coeruleus; migraine; stress

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01610
PLoS One. 2026 ;21(4): e0347135

Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.

Shweta Tendulkar, Tong Wu, Amy Strickland, Amber R Hackett, Yurie Sato-Yamada, Xianrong Mao, Yo Sasaki, Jeffrey Milbrandt, A Joseph Bloom, Aaron DiAntonio.

Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. Schwann cell (SC)-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants- TDP43Q331K and Sod1D83G knock-in alleles-to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.

DOI: https://doi.org/10.1371/journal.pone.0347135
Neuroscientist. 2026 Apr 11. 10738584261425658

Mitochondrial Calcium Signaling in the Brain: From Molecular Mechanisms to Behavioral Outcomes.

Sandrine Pouvreau, Giovanni Marsicano, Julia Welte.

  Mitochondria are multifaceted organelles positioned at the intersection of multiple signaling pathways. Beyond serving as one of the main energy providers in the brain, they play crucial roles in shaping cytosolic calcium signals across both neuronal and glial cell populations, modulating synaptic transmission and plasticity, and regulating neuronal excitability and network activity. The involvement of mitochondrial calcium handling in brain cell physiology has been explored for many years. However, by enabling in vivo cell-specific manipulations, the molecular identification of mitochondrial calcium signaling protein complexes, over the past 2 decades, has tremendously improved our understanding of how mitochondria regulate brain function and behavior.This review synthesizes current knowledge of mitochondrial calcium handling mechanisms and protein complexes in the nervous system, as well as their involvement in brain function, from cellular physiology to behavioral consequences. We discuss pharmacological and genetic evidence for a role of mitochondrial calcium handling in synaptic transmission, neuronal excitability, astrocyte functions, and circuit activity. We underline experimental differences across approaches and models, as well as show how genetic tools have challenged or confirmed earlier pharmacological results. Finally, we examine how recent advances using transgenic models have revealed complex roles for mitochondrial calcium signaling in behavioral responses and opened new research avenues.

Keywords:  astrocytes; behavior; calcium signaling; mitochondria; neuronal activity; synaptic function

DOI:  https://doi.org/10.1177/10738584261425658
STAR Protoc. 2026 Apr 10. pii: S2666-1667(26)00144-9. [Epub ahead of print]7(2): 104491

Protocol for metabolite extraction and sample preparation from primary astrocytes for mass spectrometry-based metabolomic analysis.

Ya-Gin Chang, Gong-Min Lin, Chih-Yu Lin, Yijuang Chern.

  Astrocytes play essential roles in supporting neuronal function, particularly through the regulation of brain energy metabolism. In response to physiological and pathological stimuli, astrocytes dynamically adjust their metabolic pathways and energy output. Here, we present a protocol for metabolite extraction and sample preparation from primary astrocytes for mass spectrometry analysis. We describe steps for integrating astrocyte culture and liquid chromatography-mass spectrometry (LC-MS) metabolite analysis to enable reproducible profiling of astrocytic energy metabolism under different experimental conditions. For complete details on the use and execution of this protocol, please refer to Chang et al.1.

Keywords:  Cell culture; Metabolomics; Neuroscience; Protocols in Metabolomics and Lipidomics

DOI:  https://doi.org/10.1016/j.xpro.2026.104491
J Neurochem. 2026 Apr;170(4): e70434

Early Effects of Poly(I:C)-induced Neuroinflammation on Hippocampal Astrocyte Function and Glycolytic Metabolism.

Adriana Fernanda K Vizuete, João Pedro Montandon Garcez, Maria Cristina M Pellenz, Jordana Agliardi de Lima, Jéssica Taday, Jéssica Maria Souza, Marina Concli Leite, Carlos Alberto Gonçalves.

  Concern is growing about the role of neurotropic viruses, such as Zika virus, West Nile virus, herpes simplex virus, SARS-CoV-2, and human immunodeficiency virus, in central nervous system (CNS) infections, which trigger host immune responses, neuronal dysfunction and brain injury. Astrocytes function as immune system cells and, together with microglia, participate in the activation and maintenance of neuroinflammatory responses, a common pathophysiological event in neurodegenerative diseases. The reactive phenotype of glial cells leads to the synthesis and release of inflammatory mediators inducing a neurometabolic shift to nonoxidative glycolysis, a phenomenon similar to the Warburg effect. However, since viruses require energy from host cells to replicate, it is essential to understand the increase in glucose consumption during viral infections. For this purpose, we used an early polyinosinic:polycytidylic acid [Poly(I:C)] induced neuroinflammation model to investigate its effects on astrocyte function and neurometabolic responses in two approaches: acute hippocampal slices and in vivo intraperitoneal administration from male Wistar rats (PN30). We evaluated the effects of a dose-response curve of Poly(I:C), an immunostimulant agent that mimics double-stranded RNA virus infection, on the neuroinflammatory response, astrocyte reactivity, and glycolytic parameters. Poly(I:C) induced neuroinflammation and astrocyte reactivity in a dose-dependent manner. Both models of Poly(I:C)-induced early neuroinflammation and astrocyte reactivity which leads to neurometabolic reprogramming with enhanced several glycolytic parameters, such as glucose uptake and hexokinase activity, methylglyoxal (MG) synthesis and affect the glyoxalase-1 (GLO1) activity. Accordingly, inflammatory and glycolytic inhibitors reduced the glycolytic parameters induced by Poly(I:C). As expected, the inflammatory inhibitors downmodulated neuroinflammatory parameters, with arundic acid in particular reversing astrocyte reactivity. Moreover, the downregulation of the glycolytic pathway had a greater effect on the pronounced inflammatory process, and reversed the astrocyte reactivity induced by Poly(I:C) neuroinflammation. Our data are consistent with the hypothesis that a metabolic shift is required to maintain neuroinflammatory signaling, particularly in early Poly(I:C) induced neroinflammation, and highlight the glycolytic pathway as a potential target for controlling the neuroinflammatory response.

Keywords:  Poly(I:C); astrocytes; glycolysis; neuroinflammation

DOI:  https://doi.org/10.1111/jnc.70434
HGG Adv. 2026 Apr 13. pii: S2666-2477(26)00055-2. [Epub ahead of print] 100615

Biallelic variants in CHCHD4 are associated with combined OXPHOS defect leading to mitochondrial disease.

Matthieu Mantecon, Cerina Chhuon, Kevin Roger, Ida Chiara Guerrera, Christine Bole, Patrick Nitschke, Claire-Marie Dufeu-Bérat, Margaret Ashcroft, Robert W Taylor, Nathalie Boddaert, Agnès Rötig.

Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from variants in either mitochondrial- or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.

DOI: https://doi.org/10.1016/j.xhgg.2026.100615
Cells. 2026 Mar 28. pii: 603. [Epub ahead of print]15(7):

Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.

Bartosz Osuch, Patrycja Młotkowska, Elżbieta Marciniak, Tomasz Misztal.

  Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases.

Keywords:  AMPK–PGC-1α; BDNF; FNDC5; irisin; mitochondrial homeostasis; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells15070603
Pharmacol Res. 2026 Apr 13. pii: S1043-6618(26)00105-2. [Epub ahead of print]227 108190

Long-term region-specific mitochondrial respiration impairment after perinatal asphyxia is prevented by the NAD⁺ donor nicotinamide riboside: A real-time organotypic metabolic profiling approach.

Eugenio Díaz-Urbina, Cristopher Almarza, Harley Davidson, Alcán Cortés, Pedro Lobos, Eduardo Karahanian, Jose Inzunza, Fernando Ezquer, Paola Morales, Félix A Urra, Mario Herrera-Marschitz.

  Perinatal asphyxia (PA) is a primary cause of neonatal morbidity, with persistent neurological sequelae, associated with mitochondrial dysfunction and redox imbalance. The lack of experimental approaches for region-specific evaluation of mitochondrial bioenergetics in structurally preserved neural tissues has limited the identification of selective vulnerabilities and redox-based therapeutic targets. Here, we introduce a real-time metabolic profiling strategy that integrates Seahorse XFe96 respirometry with Cytation 5 image-based quality control to quantify mitochondrial respiration and glycolytic flux in organotypic cultures derived from distinct brain regions of neonatal rats exposed to global PA. Using this strategy, we demonstrate that PA induces a profound and region-selective impairment of mitochondrial function, characterized by reduced basal, ATP-linked, maximal, and spare respiratory capacity in the substantia nigra and neostriatum, while neocortical bioenergetics remain largely preserved. These alterations are accompanied by a shift toward glycolysis, reflected by increased extracellular acidification rates and reduced OCR/ECAR ratios. Notably, in vivo administration of the NAD⁺ precursor nicotinamide riboside (0.8 mmol·kg⁻¹, i.p., 1 h after birth) effectively prevented PA-induced mitochondrial respiration deficits, attenuated oxidative stress-induced cell death, and preserved regional neurochemical integrity, particularly within the nigrostriatal neurocircuitry. Together, these findings reveal a heterogeneous mitochondrial redox and bioenergetic vulnerability of the developing brain to perinatal hypoxia. This integrated organotypic-metabolic approach may offer novel opportunities to dissect out region-specific mitochondrial dysfunction and to explore NAD⁺-based therapeutic strategies targeting neonatal brain injury.

Keywords:  Basal ganglia; Brain plasticity; Development; Hypoxia; Mitochondria; Nicotinamide; Rat

DOI:  https://doi.org/10.1016/j.phrs.2026.108190
Food Chem Toxicol. 2026 Apr 12. pii: S0278-6915(26)00169-9. [Epub ahead of print]213 116095

Time-resolved lipidomic profiling reveals alterations following 3-MCPDEs exposure in Sprague-Dawley rats.

Wenhao Zheng.

  Lipidomic alterations were investigated in the plasma, liver, kidneys, and testes of Sprague-Dawley (SD) rats at 2, 6, 12, 24, and 48 h after oral administration of 3-MCPDEs (500 mg/kg BW). PLS-DA revealed a clear distinction between the 2 h plasma samples and controls, whereas the largest deviations in organs were observed at 12 h and 24 h post-exposure. Differential lipid analysis in plasma identified 62 putative discriminant lipids, including 34 glycerophospholipids, 13 glycerides, 5 sphingolipids, and 10 other lipid species. Pathway analysis further indicated that glycerophospholipid and sphingolipid metabolic pathways were significantly perturbed following 3-MCPDE exposure. In plasma, glycerophospholipid metabolism was predominantly affected, characterized by marked elevations of lysophospholipids and disrupted homeostasis of PC, PS, and PE species. In contrast, organs exhibited organ-dependent disturbances in sphingolipid metabolism, suggesting tissue-specific vulnerability that may be closely linked to 3-MCPDE-associated toxicity. Overall, these time-resolved lipidomic profiles delineate distinct systemic versus tissue lipid perturbation patterns after 3-MCPDE exposure and provide mechanistic clues for understanding its metabolic toxicity.

Keywords:  3-MCPD es; Biomarkers; Lipidomic; Phospholipid; Sphingolipid

DOI:  https://doi.org/10.1016/j.fct.2026.116095
Neurobiol Dis. 2026 Apr 09. pii: S0969-9961(26)00136-1. [Epub ahead of print]224 107391

Temporal and cell-specific changes to cellular iron sequestration and lipid peroxidation in a murine model of neonatal hypoxic-ischemic brain injury.

Joseph Vithayathil, Anjali Shankar, Sierra Foshe, Baoyi Lin, Ginger L Milne, Frances E Jensen, Delia M Talos, Joshua L Dunaief.

   BACKGROUND: Iron accumulation and lipid peroxidation are pathophysiologic mechanisms that contribute to neonatal hypoxic-ischemic (HI) brain injury. Characterization of spatiotemporal changes in these processes will help elucidate their role in ischemic neuronal injury as an initial step towards developing targeted interventions.
METHODS: HI was induced in post-natal day 9 mice using the modified-Vannucci model. Hippocampal tissue from ipsilateral HI exposed, contralateral hypoxia exposed and sham animals was collected at 6 h, 24 h, 72 h, 7d and 90d post-HI. Tissue was evaluated for cell death (TUNEL labeling), intracellular iron changes (flow cytometry, fluorescent mRNA/protein staining), and lipid peroxidation (mass spectrometry). Mass spectrometry measured isoprostanes (15-F2t-IsoP) and neuroprostanes (4-F4t-NP) as markers of arachidonic (ARA) and docosahexaenoic acid (DHA) peroxidation, respectively.
RESULTS: Compared to sham, the HI hippocampus showed increased intracellular labile iron levels that was maximal at 6 h post-HI with subsequent elevation in neuroprostanes and TUNEL labeling at 24 h post-HI. High throughput in situ mRNA labeling at 24 h post-HI showed changes in injured cells indicative of elevated labile iron and lipid peroxidation. At 72 h post-HI, labile iron levels, TUNEL labeling and lipid peroxidation declined corresponding with peak infiltration of ferritin positive microglia/macrophages and increased expression of glutathione peroxidase 4 (Gpx4) within surviving neurons.
CONCLUSIONS: These results characterize the relationship between intracellular labile iron, lipid peroxidation and cell death in neonatal HI. Injured cells display gene expression changes indicative of increased labile iron toxicity and lipid peroxidation. Microglial/macrophage iron sequestration and neuronal antioxidant responses may ameliorate further injury and represent targets for neuroprotective therapies.

Keywords:  Brain Iron dysregulation; Ferroptosis; GPX4; Isoprostanes; Lipid peroxidation; Neonatal hypoxic-ischemic brain injury; Neuroprostanes

DOI:  https://doi.org/10.1016/j.nbd.2026.107391
Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2523130123

FABP7 controls radial glial scaffold stability during human cortical development.

Yuanhao Wang, Xu Zhang, Ru Ba, Yimin Zhu, Hanwen Yu, Da Wang, Chu Chu, Xinyue Zhang, Yuan Hong, Shanshan Wu, Wanying Zhu, Min Xu, Qing Cheng, Chunjie Zhao, Xiao Han, Yan Liu.

  Radial glial (RG) cells serve as both neural progenitors and structural scaffolds for neuronal migration during cortical development. Although FABP7 has long been recognized as a marker of RG cells, its regulatory function has remained poorly defined. Using human fetal brain slices, embryonic mouse model, cerebral organoids, and assembloids, we demonstrate that FABP7 is essential for maintaining RG scaffold architecture and coordinating neuronal positioning. Single-cell analysis revealed that FABP7 deficiency induces transcriptional dysregulation, particularly affecting cytoskeletal organization, neural fate specification, and stress responses. Furthermore, transcriptomic features in FABP7 knockdown organoids exhibit convergence with neurodevelopmental disorders such as autism, alongside recapitulation of scaffold defects observed in idiopathic autism organoids. Mechanistically, FABP7 loss suppresses the mevalonate (MVA) pathway, resulting in impaired GTPase-mediated cytoskeletal organization and disruption of radial scaffold integrity. These findings identify FABP7 as a key regulator of cortical development and disease-relevant molecular programs, linking metabolic signaling to neurodevelopmental vulnerability.

Keywords:  FABP7; autism; brain organoids; mevalonate pathway; radial glial scaffold

DOI:  https://doi.org/10.1073/pnas.2523130123
Cell Mol Neurobiol. 2026 Apr 11.

Metabolic Symbiosis and Vulnerability in the CNS Axon-Myelin Unit.

Kun Miao, Meng Meng, Liangjing Liu, Meiyu Li, Yuanyuan Bai, Ying Guo, Guohui Zhang, Jiming Kong, Jiao Mu.

  Axonal degeneration and demyelination are common pathological phenotypes in central nervous system (CNS) injury and degenerative diseases. Axonal and myelin diseases have generally been considered distinct phenomena, although our knowledge of why the axon-myelin unit (AMU), as a highly interconnected structure, serves as a common point of vulnerability to damage remains inadequate. In this review, we first reaffirm that the tight biological interconnections between axons and myelin should be recognized as a "symbiotic" unit across development, metabolism, and disease progression. Second, we systematically delineate the fundamental structural architecture and metabolic coupling of AMU. Third, we analyze how the impairment of one component of AMU influences the survival and functional integrity of others. In conclusion, we present a unique conceptual framework indicating that therapeutic methods targeting bioenergetic support in the CNS should concentrate on the energy coupling pathways and damage-crossover mechanisms of the AMU.

Keywords:  Axon-myelin unit; Axonal degeneration; Demyelination.; Lactate shuttle; MCT1; Metabolic coupling

DOI:  https://doi.org/10.1007/s10571-026-01729-3
Int J Inflam. 2026 ;2026 6298730

Roles of Oxidative Phosphorylation and Fatty Acid Oxidation in Neuroinflammation Induced by Lipopolysaccharide in Hypothalamic Neuronal Cells.

Mohsine-Ali El-Hamri, Meriem Lahmouad, Jihane Zerrouk, Rafik El-Mernissi, Lhoussain Hajji, Khayelihle Brian Makhathini, Hanane Khalki, Oualid Abboussi.

  Neuroinflammation is intricately associated with impaired neuronal function and is a contributing factor in the development of neurodegenerative diseases. Significant alterations in cellular metabolism often accompany these inflammatory changes. Although considerable research has focused on understanding these metabolic shifts in astrocytes and microglia, the precise mechanisms linking neuroinflammation and cellular metabolism in neurons remain poorly understood. This study explores the connection between neuroinflammation and neuronal cell metabolism through a lipopolysaccharide (LPS)-induced neuroinflammation model utilizing GT1-7 hypothalamic neuron cultures. Our findings indicate that LPS-induced neuroinflammation in GT1-7 hypothalamic neurons is marked by reduced oxidative phosphorylation (OXPHOS) and decreased endogenous fatty acid oxidation (FAO). In contrast, exogenous FAO increases, leading to elevated ATP production, while glycolysis remains unchanged. These metabolic changes are associated with increased inflammatory markers (IL-6, TNF-α) and oxidative stress indicators (ROS, NO), as well as decreased synaptic plasticity (as indicated by synaptophysin) and impaired cellular function, as evidenced by reduced gonadotropin-releasing hormone (GnRH) release. Our study highlights the intricate interplay between neuroinflammation and neuronal cell metabolism. These findings emphasize the significance of metabolic changes in neuroinflammatory processes, offering potential insights for therapeutic interventions in neurodegenerative diseases.

Keywords:  gonadotropin-releasing hormone; neuroinflammation; neuronal cell metabolism; oxidative stress; synaptic plasticity

DOI:  https://doi.org/10.1155/ijin/6298730
Aging Dis. 2026 Apr 02.

MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.

Giacoma Galizzi.

Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca2+) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.

DOI: https://doi.org/10.14336/AD.2025.1342
Aging Dis. 2026 Apr 13.

Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD+/NADH Ratio.

Suman Rimal, Jae-Hyuk Lee, Yanzi He, Bingwei Lu.

Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer's disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.

DOI: https://doi.org/10.14336/AD.2026.0011
Neuroimage. 2026 Apr 11. pii: S1053-8119(26)00237-5. [Epub ahead of print]332 121922

Detecting early brain susceptibility changes before demyelination in cuprizone mouse model using quantitative susceptibility mapping (QSM).

Xinyue Han, Jie Chen, Zhuoheng Liu, Juan Liu, Mingquan Lin, Nian Wang.

  Multiple sclerosis (MS) is a neurological disease that affects the central nervous system through demyelination and inflammation. Animal model, including the cuprizone (CPZ) model, provides a robust platform for studying demyelination and remyelination in MS. While conventional MRI techniques are sensitive to myelin changes, quantitative susceptibility mapping (QSM) offers additional advantages by capturing both myelin- and iron-related pathology. In this study, we performed longitudinal whole-brain multimodal magnetic resonance imaging (MRI), including T2-weighted imaging, magnetization transfer imaging, and QSM, in CPZ-treated mice across multiple stages covering pre-demyelination, acute demyelination, chronic demyelination, and remyelination. Regional analyses focused on the corpus callosum (CC) and anterior commissure (AC), complemented by histological validation. All three MRI modalities detected demyelination, characterized by increased T2 signal, decreased magnetization transfer ratio (MTR), and increased susceptibility, with partial recovery during remyelination. QSM demonstrated unique sensitivity by identifying susceptibility decreases at week 2, before apparent demyelination, corresponding to early oligodendrocyte dysfunction. Regional heterogeneity was observed, with the CC showing rapid alterations during acute demyelination and the AC exhibiting steadier changes across acute and chronic phases. These results establish QSM as a sensitive imaging biomarker capable of detecting early MS pathology and tracking dynamic changes in oligodendrocytes. By complementing conventional MRI techniques, QSM enhances the characterization of white matter injury in the CPZ model and holds translational potential for monitoring disease progression and therapeutic response in MS.

Keywords:  Cuprizone; Demyelination; Longitudinal Study; Multiple sclerosis (MS); Oligodendrocyte; Quantitative susceptibility mapping (QSM); Remyelination

DOI:  https://doi.org/10.1016/j.neuroimage.2026.121922
Sci Rep. 2026 Apr 14.

Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.

Imen Belhaj, Ingrid Åmellem, Can H Tartanoglu, Hanne M Weidemann, Evan M Vallenari, Mingyi Yang, Farrukh A Chaudhry, Magnar Bjørås, Jon Storm-Mathisen, Linda Hildegard Bergersen.



Keywords:  5XFAD; Alzheimer’s disease; Glutamate receptors; Growth factors; Lactate; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-026-48154-6