bims-medebr 2026-02-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–02–22
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.
APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.
Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.
Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
From lipid function to dysfunction: Very long-chain fatty acids as emerging regulators of neuroinflammatory pathways.
Cellular mechanisms of brain lipid metabolism in health and disease.
Mass spectrometry-based lipid analysis in NPC1 disease: Methods for phosphoinositide quantification, lipid imaging, and myelin lipid profiling.
Dysregulated Lipid Metabolism and Neurovascular Unit Dysfunction: Novel Mechanisms Linking Alzheimer's Disease and Vascular Dementia.
The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.
Acceleration of Lactate Uptake and Utilization Contributes to Neuroprotective Action of FGF21 Involved in Naturally Aging Mice.
New horizons: disrupted brain energy metabolism as a driver of delirium.
Rewiring Brain Recovery: Astrocyte-Neuron Metabolic Cooperation in Stroke.
Histology-guided spatial lipidomics and proteomics of the trisynaptic circuit in the human hippocampus.
Cetoleic acid and other long-chain unsaturated fatty acids as neuroprotective nutraceuticals.
The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.
Transient neonatal hypoglycemia and the developing brain: Associations, mechanisms, and clinical implications.
Volumetric differences in the brain in children with hypoxic-ischemic encephalopathy after therapeutic hypothermia: a review of MRI findings.
Acetyl-CoA Homeostasis via Mitochondrial Pyruvate Oxidation Governs Survival, Transcriptional Fidelity and Neural Specification in Primed Human Embryonic Stem Cells.
Metabolic labeling of glycerophospholipids.

Front Neurosci. 2026 ;20 1731771

Metabolic interactions in the brain: the crucial roles of neurons, astrocytes, and microglia in health and disease.

Yonghui Pang, Jiachen Yang, Jingjing Liu, Zhengyi Xie, Jin Wang.

  This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain's resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.

Keywords:  astrocytes; disease; homeostasis; metabolism; microglia; neurons

DOI:  https://doi.org/10.3389/fnins.2026.1731771
Neurochem Int. 2026 Feb 13. pii: S0197-0186(26)00016-1. [Epub ahead of print]194 106125

APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.

Nashanthea J Roland, Johnny W Zigmond, Jane E Manganaro, L Daniel Estrella, Kelly L Stauch.

  Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD.

Keywords:  Alzheimer's disease; Apolipoprotein E; Cholesterol; Synapse; Synaptic mitochondria

DOI:  https://doi.org/10.1016/j.neuint.2026.106125
J Lipid Res. 2026 Feb 13. pii: S0022-2275(26)00026-X. [Epub ahead of print] 101000

Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.

Michael R Strickland, Zhen Wang, Lesley R Golden, Hu Wang, Ping Lu, Yingxue Ren, G Travis Tabor, Na Zhao, Jason D Ulrich, Xianlin Han, Junmin Peng, David M Holtzman.

  Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the central nervous system (CNS) and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late onset Alzheimer's disease (AD) and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of Alzheimer's disease. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and ApoE isoform. Lipidomics revealed microglia-derived ApoE lipoproteins were enriched in cholesterol esters whereas astrocyte ApoE lipoproteins were enriched in sphingomyelin. Proteomics revealed astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in C1q and Lpl compared to ApoE2 and ApoE3 microglial lipoproteins which were enriched in Ankk1 and ApoC1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis.

Keywords:  Alzheimer’s disease; ApoE; Apolipoproteins; apolipoprotein E; astrocytes; brain lipids; lipidomics; microglia; proteomics

DOI:  https://doi.org/10.1016/j.jlr.2026.101000
Front Aging Neurosci. 2026 ;18 1689139

Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.

Leah E Jamerson, Tara D Bradshaw, Patrick C Bradshaw.

  Changes in brain [NADPH]/[NADP+] and [NAD+]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD+]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP+]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+] and mitochondrial [NAD+]/[NADH]. The reductive shift in the cytoplasmic [NAD+]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD+]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP+]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.

Keywords:  NAD+; NADPH; aging; astrocyte; brain; dietary restriction; fasting; redox

DOI:  https://doi.org/10.3389/fnagi.2026.1689139
iScience. 2026 Feb 20. 29(2): 114724

From lipid function to dysfunction: Very long-chain fatty acids as emerging regulators of neuroinflammatory pathways.

Ranjan Kumar Sahu, Yunseon Yang, Hyung-Lok Chung.

  Lipids are key structural and functional components of the brain, essential for cellular integrity and homeostasis. They regulate signaling pathways driving neuroinflammation, a key factor in many neurological disorders. We review the interplay between lipid metabolism and neuroinflammation, with a focus on very long-chain fatty acids, that are crucial for membrane integrity and of myelin formation. Insights from human genetic disorders highlight how lipid metabolic dysfunction triggers neuroinflammatory cascade. Studies in Drosophila now complement these findings by enabling rapid dissection of conserved pathways and testing of therapeutic strategies, including enzyme modulators, dietary interventions, and gene therapies. By bridging patient-derived insights with powerful in vivo modeling, Drosophila research is uncovering actionable mechanisms linking lipid dysregulation to neurodevelopmental and neurodegenerative disease.

Keywords:  biochemistry; biological sciences; natural sciences

DOI:  https://doi.org/10.1016/j.isci.2026.114724
Nat Cell Biol. 2026 Feb 20.

Cellular mechanisms of brain lipid metabolism in health and disease.

Francesco Petrelli, Carlotta Gilardi, Carla Marie Igelbüscher, Diana Panfilova, Alicia Rey, Rosa Chiara Paolicelli, Marlen Knobloch.

Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.

DOI: https://doi.org/10.1038/s41556-026-01880-5
Methods Enzymol. 2026 ;pii: S0076-6879(25)00484-7. [Epub ahead of print]726 333-355

Mass spectrometry-based lipid analysis in NPC1 disease: Methods for phosphoinositide quantification, lipid imaging, and myelin lipid profiling.

Koralege C Pathmasiri, Stephanie M Cologna.

  Loss of NPC cholesterol transporter 1 protein function results in severe lipid dysregulation in multiple vital organs, including the brain, in Niemann-Pick Type C1 (NPC1) disease. Investigation of lipid changes and lipid metabolism disruptions in NPC1 is critical to elucidating the disease mechanisms driving the pathophysiology, identifying potential biomarkers, and guiding therapeutic strategies. One such example is phosphoinositides, which are key lipids involved in multiple signaling pathways relevant to NPC1 that are challenging to study due to their low abundance and detection difficulty. In this chapter, we present a detailed phosphoinositide analysis protocol using mass spectrometry. When studying lipids, spatial information is also important because it reveals distribution within the tissue, which can provide insights into functional roles and disease-related alterations. MALDI-MS lipid imaging is a powerful tool for investigating the spatial distribution of lipids. Herein, we also discuss a protocol for lipid imaging using MALDI-MSI, along with key precautions and troubleshooting tips. Finally, we present a myelin isolation protocol integrated with LC-MS lipidomics to investigate the myelin lipidome in tissues such as the brain, as myelin lipid composition is crucial for maintaining neuronal function and is often disrupted in neurodegenerative diseases like NPC1, including the investigation of phosphoinositides.

Keywords:  Chromatography; Imaging; Lipidomics; Mass spectrometry; Niemann-Pick Type C

DOI:  https://doi.org/10.1016/bs.mie.2025.11.003
Aging Dis. 2026 Feb 13.

Dysregulated Lipid Metabolism and Neurovascular Unit Dysfunction: Novel Mechanisms Linking Alzheimer's Disease and Vascular Dementia.

MengGe Li, HuiYue Wang, ZhenYan Tang, ShuSheng Yang, Li Lin.

The neurovascular unit (NVU) represents a multicellular functional ensemble pivotal to the preservation of cerebral homeostasis, encompassing endothelial cells, pericytes, glial cells (astrocytes, microglia, oligodendrocytes), and neurons. This complex orchestrates the regulation of blood-brain barrier (BBB) integrity, cerebral blood flow (CBF), and the metabolic microenvironment requisite for neuronal viability and functional competence. Accumulating lines of evidence have underscored that NVU dysfunction constitutes a critical early pathological event in neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VaD). The present review summarizes the structural composition and core physiological functionalities of the NVU, with particular emphasis on the emerging role of lipid metabolism dysregulation in mediating NVU impairment-an aberrant process encompassing lipid droplets, apolipoprotein E (APOE), ATPase phospholipid transporting 11B (ATP11B), triggering receptor expressed on myeloid cells 2 (TREM2), and ATP-binding cassette (ABC) transporters. We further delineate the mechanisms by which disrupted lipid homeostasis elicits neuroinflammation, amplifies oxidative stress, impairs amyloid-β (Aβ) clearance, and precipitates BBB breakdown, ultimately culminating in cognitive decline. Simultaneously, this review examines controversies within the field, such as the specific role of apolipoprotein E ε4 allele (APOE4) in disease and highlights the significant pathophysiological differences between preclinical animal models and human diseases. Therapeutic strategies targeting lipid metabolism or the blood-brain barrier still face considerable challenges in clinical translation. Meanwhile, emerging tools such as lipidomics contribute to systematically analyzing the associated dysregulated lipid networks, thereby aiding in the identification of novel therapeutic targets.

DOI: https://doi.org/10.14336/AD.2025.1464
iScience. 2026 Feb 20. 29(2): 114717

The succinate prodrug NV354 prevents brain lesions and late-stage motor dysfunction in mitochondrial complex I deficiency.

Meagan J McManus, Yi Zhu, Cesar Alves, Neha Kohli, Patricia Prada-Dacasa, Laura Sanchez-Benito, Elisenda Sanz, Irene Yee, Lozen Robinson, Malkah Sheldon, Walter J McHugh, Abhay Ranganathan, Jennie Meng, Nina Duncan, Alvar Grönberg, Douglas C Wallace, Sarah Piel, Michael Karlsson, Steven J Moss, Lee Webster, Magnus J Hansson, Eskil Elmér, Johannes K Ehinger, Albert Quintana, Todd J Kilbaugh.

  Leigh syndrome is a fatal pediatric neurodegenerative disease caused by mitochondrial dysfunction, which can be modeled in the Ndufs4 KO mouse with mitochondrial respiratory chain complex I (CI) deficiency. This study explores NV354, a prodrug of succinate with enhanced oral bioavailability and brain uptake, as a potential therapy to counteract this devastating condition. NV354 modulated whole-body respiration and metabolic flexibility, prevented late-stage motor dysfunction, delayed clinical ataxia scores, and improved body weight development, but had otherwise minimal effect on neurobehavior and lifespan of the animals. The succinate prodrug prevented development of the brain stem lesions pathognomonic for Leigh syndrome, attenuated neuronal loss in the brainstem, diminished activation of astrocytes, blocked hypertrophic microglial accumulation, and reduced reactive oxygen species (ROS) levels in the brain. NV354 also partially alleviated motor symptoms and metabolic decompensation in a rat model of Parkinson disease induced by the CI inhibitor rotenone. In conclusion, the succinate prodrug NV354 shows promise as a potential treatment of mitochondrial CI-related neurodegeneration.

Keywords:  biochemistry; biological sciences; natural sciences; neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.114717
Aging Cell. 2026 Mar;25(3): e70423

Acceleration of Lactate Uptake and Utilization Contributes to Neuroprotective Action of FGF21 Involved in Naturally Aging Mice.

Keru Ji, Hongde Wei, Ruguang Wang, Yutong Wu, Chen Li, Hongchang Gao, Liangcai Zhao.

  Brain aging is characterized by neuroinflammation and lactate metabolic changes. However, the functional role of FGF21 in the aging brain and its influence on lactate homeostasis remains unclear until now. In the study, male C57BL/6 mice were divided into 2-month-old (control), 20-month (aging), and FGF21-treated aging mice (FGF21). We also examined the MAPK signals and astrocyte-neuron lactate shuttle (ANLS) proteins in wild-type and hydroxycarboxylic acid receptor 1-knockout (HCA1-KO) mice with aging or long-term L-lactate infusion. In a mouse model of aging, neuronal FGF21 expression and ANLS rate were upregulated in hippocampal and cortical regions. Administration of exogenous FGF21 (1 mg/kg) to aging or lactate-infused mice can significantly improve learning and memory performance and the lactate metabolic microenvironment in an MCT2-dependent manner. Besides, HCA1-KO can significantly abolish both the CREB and MAPK signaling activation in lactate-infused mice, which differs from the scenario of aging mice. Furthermore, in vitro aging model further confirmed that p38-mediated FGF21 production and PI3K-mTOR-dependent MCT2 protein translation process, respectively. The increase in levels of FGF21 protein as the brain ages might help neurons cope with age-related neuroinflammation and lactate accumulation in mice. Our findings indicated that the shuttle rate of lactate and its microenvironment are related to neuronal function, which may be one therapeutic target for aging-related cognitive dysfunction.

Keywords:  ANLS; FGF21; HCA1; MCT2; aging; lactate homeostasis

DOI:  https://doi.org/10.1111/acel.70423
Age Ageing. 2026 Feb 01. pii: afag024. [Epub ahead of print]55(2):

New horizons: disrupted brain energy metabolism as a driver of delirium.

Meher Sabharwal, Gordon Boyd, Colm Cunningham.

  Delirium is a highly prevalent neuropsychiatric syndrome characterised by acute inattention, altered arousal and impaired cognition. Cerebral energy insufficiency is hypothesised to drive delirium and both hypoglycaemia and hypoxia can directly precipitate functional deficits and EEG slowing. Here we review the evidence that disrupted energy metabolism may play a causative role in delirium across multiple settings. Neuromonitoring methods including near infrared resonance spectroscopy and Transcranial Doppler suggest an association between altered cerebral perfusion and delirium, albeit with a minority of studies demonstrating associations with hyperoxia or low brain oxygen extraction. Hyperglycaemia, hypoglycaemia, relative hypoglycaemia and large fluctuations in glucose show associations with delirium, dependent on the setting. Functional neuroimaging methodologies such as functional MRI and fluorodeoxyglucose-positron emission tomography, demonstrate regional rather than global changes in functional hyperaemia and hypometabolism and the networks across which these changes occur may be key drivers of the delirium phenotype. Whether those changes reflect regulated changes in activity, the development of insulin resistance or an impairment of neurovascular coupling in those circuits requires further research. Availability of glucose, the ability to take it up and use it are all important in maintaining normal brain function and the disruption of any or all of these could impair energy metabolism in the brain during acute illness and delirium. Optimising brain glucose utilisation is a rational goal towards reducing delirium. Clinical trials with intranasal insulin offer tentative indication that this might be tractable and alternative fuels also might mitigate delirium. Systematic experiments and clinical trials are necessary to assess whether restoring normal metabolism can protect against delirium in different clinical environments.

Keywords:  delirium; encephalopathy; energy metabolism; glucose; insulin resistance functional imaging; older people; oxygen; perfusion

DOI:  https://doi.org/10.1093/ageing/afag024
Antioxid Redox Signal. 2026 Feb;44(7-9): 410-435

Rewiring Brain Recovery: Astrocyte-Neuron Metabolic Cooperation in Stroke.

Weizhuo Lu, Zenghong Jiang, Jiyue Wen.

   SIGNIFICANCE: The high level of metabolism in the central nervous system (CNS) induces the production of large amounts of free radicals following stroke, thereby resulting in oxidative stress. The brain is particularly vulnerable to oxidative stress-induced damage due to its high oxygen consumption. Astrocytes, as key regulators of CNS homeostasis, play a critical role in modulating oxidative stress and maintaining CNS function.
RECENT ADVANCES: Accumulating evidence has shown that astrocytes undergo polarization into two distinct states: A1 (neurotoxic and pro-inflammatory) and A2 (neuroprotective and anti-inflammatory) phenotypes following ischemic stroke, which, respectively, exhibit harmful and beneficial roles in oxidative stress-induced brain injury. In addition, metabolic crosstalk between astrocytes and neurons during the acute phase of ischemic stroke, involving lactate, amino acids, healthy mitochondria, and fatty acids, is crucial in maintaining neuronal morphology and function.
CRITICAL ISSUES: A2 astrocytes possess significant antioxidative capabilities by expressing high levels of antioxidative stress genes. Notably, the polarization of astrocytes toward the A2 subtype appears to enhance their beneficial and supportive role in metabolic crosstalk with neurons. A deeper understanding of astrocytic roles, particularly those of A2 astrocytes, in redox regulation and astrocyte-neuron metabolic crosstalk may provide novel therapeutic strategies for ischemic stroke. Therefore, in this review, we mainly discuss the roles of astrocytes, particularly A2 astrocytic polarization, in redox regulation and metabolic crosstalk with neurons following ischemic stroke.
FUTURE DIRECTION: Elucidating the molecular mechanisms underlying astrocytic polarization toward the A2 subtype during the pathological process of ischemic stroke represents a promising avenue for future research. Antioxid. Redox Signal. 44, 410-435.

Keywords:  astrocyte polarization; ischemic stroke; metabolic crosstalk; oxidative stress

DOI:  https://doi.org/10.1177/15230864251411183
Anal Chim Acta. 2026 Mar 22. pii: S0003-2670(26)00060-7. [Epub ahead of print]1392 345110

Histology-guided spatial lipidomics and proteomics of the trisynaptic circuit in the human hippocampus.

Caitlin M Tressler, Lauren DeVine, Rahul Bharadwaj, Dalton R Brown, Daniel Weinberger, Kristine Glunde, Robert N Cole.

  The human hippocampal trisynaptic circuit activity is essential for learning and memory. This canonical circuit has spatially distinct populations of neurons, but their unique contributions to neurodevelopment, as well as to dysfunction in neurodegenerative disorders, are missed when analyzing bulk tissue homogenates. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to guide laser capture microdissection (LCMD) of regions of interest for spatial multimodal analyses is a relatively new approach to study topographically distinct neuronal cell populations in heterogenous tissues. However, MALDI-MSI may not identify region-defining molecular mass-to-charge ions. Here, we apply a multimodal approach of MALDI-MSI-LCMD-lipidomic and proteomic analysis to the trisynaptic circuit. Our MALDI-MSI of the hippocampus revealed that the of mass-to-charge ions of the cornu ammonis 1 (CA1) and cornu ammonis 3 (CA3) did not segment from the surrounding tissue. Thus, we developed a novel histology-guided MALDI-MS imaging-LCMD-spatial lipidomic/proteomic pipeline with four steps which does not rely on segmentation analysis to determine and co-register regions of interest in tissue sections. Our pipeline allows MALDI imaging, LCMD, lipidomic and proteomic analysis from the same tissue section and does not require co-registration across serial sections. In addition, poly-l-lysine coating for improving tissue/cell adherence on indium-tin-oxide microscopy slides did not impact MALDI-MSI or spatial proteomics. We show that the human trisynaptic circuit proteomes of CA1 and CA3 pyramidal neurons are more similar to each other than those of the dentate gyrus (DG), which is consistent with previously reported transcriptomics studies. The spatial distributions of several phospholipids and proteins, however, were significantly different in cell bodies from the CA1, CA3 and DG regions, and these lipids correlated with some lipid metabolizing enzymes in those regions. As little is known about lipid metabolism in the hippocampus, our pipeline provides an initial step in studying the combined and differential spatial regulation of the lipids and proteins within the trisynaptic circuit that will provide insights into the development and disease-related molecular changes in these important hippocampal regions.

Keywords:  Hippocampus; Human; Lipidomic; Lipids; Mass spectrometry; Proteins; Proteomic; Single cell type; Trisynaptic circuit

DOI:  https://doi.org/10.1016/j.aca.2026.345110
Lipids Health Dis. 2026 Feb 16.

Cetoleic acid and other long-chain unsaturated fatty acids as neuroprotective nutraceuticals.

Patrik Anthony Tang, Maria José Ruiz-Pastor, Aurélia E Lewis, Kari Espolin Fladmark, Asgeir Kobro-Flatmoen, Øyvind Halskau, Pradeep Lal.

  Long-chain monounsaturated fatty acids such as erucic acid, cetoleic acid and gondoic acid, are 20-22-carbon fatty acids with a double bond in their ω-9, ω-11 and ω-9 positions, respectively. Recent experimental research suggests that these lipids may provide benefits related to cardiovascular, but also brain health. Research on cetoleic acid using cell lines suggests that this fatty acid may positively affect neurological health. Also, in limited doses, erucic acid and gondoic acid have been reported to have a neuroprotective effect through action on peroxisome proliferator-activated receptors, and monounsaturated fatty acids generally are able to influence these receptors. Herein, we review the current state of knowledge of monounsaturated fatty acids effect on health, with an emphasis on erucic acid and cetoleic acid and their possible neuroprotective effects. Research has not progressed far regarding the direct neuroprotective effects of cetoleic acid, and mechanisms underlying such effects. However, both erucic and cetoleic acid influence the availabilities of docosahexaenoic and eicosapentaenoic acids, that do confer several health benefits, including neuroprotective effects. We highlight knowledge gaps related to metabolism, putative neuroprotective mechanisms, and briefly review animal model systems suitable for investigating these gaps.

Keywords:  Alzheimer's disease; Cetoleic acid; Erucic acid; Lipid metabolism; Neurodegenerative disease; Zebrafish

DOI:  https://doi.org/10.1186/s12944-026-02876-8
Aging Dis. 2026 Feb 10.

The Effects of Aging and Anti-Aging Dietary Restriction on Brain Glutathione and Thioredoxin Redox Systems.

Leah E Jamerson, Patrick C Bradshaw.

Glutathione (GSH) is a cofactor for several enzymes including glutathione peroxidases (GPXs) that detoxify H2O2 and for glutaredoxins that catalyze protein cysteine deglutathionylation. Aging results in a decreased rate of brain GSH synthesis and an oxidation of brain GSH to glutathione disulfide (GSSG), which increases oxidative damage, but is delayed or reversed by anti-aging dietary restriction (DR). Fasting increases the hepatic synthesis and release of GSH, which is catabolized to its amino acids, possibly increasing their transport to the brain for the re-synthesis of GSH. Brain GSH synthesis is limited by cysteine availability. Some astrocytes may increase GSH synthesis during fasting and DR by increasing metabolic flux through the cysteine and H2S-synthesizing transsulfuration pathway. In contrast to the cytoplasm where the GPX1-GSH pathway for H2O2 detoxification is highly active, the mitochondrial matrix relies largely on peroxiredoxin 3 (PRDX3), which functions together with thioredoxin 2 and thioredoxin reductase 2. In contrast to the cytoplasmic and mitochondrial GSH/GSSG, the ER GSH/GSSG is more oxidized in young organisms and becomes reduced with aging and plays a more fundamental role in buffering protein disulfide bond isomerization than for providing GSH to ER GPXs. Studies addressing the aging and DR-induced redox changes in the cytoplasm, mitochondria, and ER in different neural cell types and brain regions are needed to establish effective therapies for aging-related disorders. This review further covers the brain cell-type and brain region-specific gene expression changes that occur with aging and DR for the major enzymes that maintain the cellular redox state.

DOI: https://doi.org/10.14336/AD.2025.1505
J Neonatal Perinatal Med. 2026 Feb 16. 19345798261424796

Transient neonatal hypoglycemia and the developing brain: Associations, mechanisms, and clinical implications.

Maria F Martinez-Alcala, Blanca V Velez-Rangel, Cristian F Lozano-Vazquez, Raul A Miranda-Ojeda.

  BackgroundTransient neonatal hypoglycemia (TNH) has long been viewed as a benign, self-limited phenomenon. For this review, TNH refers mainly to hypoglycemia in late preterm and term infants during the first 48-72 h of life, usually at glucose levels below 47 mg/dL (2.6 mmol/L). Emerging data suggest that specific patterns of early low glucose (especially when recurrent, severe, or occurring in high-risk) infants may be linked to later neurodevelopmental difficulties.ObjectiveTo synthesize contemporary clinical, epidemiological, and mechanistic evidence on the impact of TNH on long-term brain development, with emphasis on domain-specific outcomes.MethodsWe conducted a structured narrative review of human studies on TNH, continuous glucose monitoring, and neurodevelopmental outcomes, integrating population-based cohorts, clinical studies, and systematic reviews with key mechanistic data.ResultsAcross heterogeneous cohorts, TNH is associated with an increased risk of selective neurodevelopmental differences (particularly in executive function, visuomotor integration, fine motor skills, and early literacy) while global cognitive scores are often preserved. Prospective cohorts and registry studies indicate that recurrent or prolonged episodes, especially in infants who are small for gestational age or born to mothers with diabetes, more often precede later difficulties, although many exposed infants develop typically. Population-based analyses also report associations between neonatal hypoglycemia and later learning, attention, or autism spectrum diagnoses, but these findings remain confounded and non-causal.ConclusionsTNH appears to be a marker of increased neurodevelopmental vulnerability in specific subgroups rather than uniformly benign or inevitably harmful. Careful identification and physiologically informed treatment of at-risk neonates, together with structured long-term follow-up, are warranted.

Keywords:  genetic vulnerability; glucose; metabolic health; neurodevelopmental conditions; neurodiversity; perinatal; transient neonatal hypoglycemia

DOI:  https://doi.org/10.1177/19345798261424796
Pol J Radiol. 2026 ;91 e37-e44

Volumetric differences in the brain in children with hypoxic-ischemic encephalopathy after therapeutic hypothermia: a review of MRI findings.

Bartłomiej Syzdoł, Kamila Ćwik, Magdalena Woźniak.

  Hypoxic-ischemic encephalopathy (HIE) remains a leading cause of neonatal brain injury, often resulting in long-term neurodevelopmental impairment. Therapeutic hypothermia (TH) is currently the only evidence-based treatment for HIE. This review summarizes volumetric magnetic resonance imaging (MRI) findings in children with HIE treated with TH. Across multiple studies, the hippocampus, thalamus, cerebellum, and basal ganglia consistently exhibit reduced volumes compared to healthy controls, though the statistical significance of these differences varies. Hippocampal volume reductions are observed in the neonatal period and later childhood, and are associated with poorer memory and cognitive outcomes. Thalamic and basal ganglia volumes are lower from the neonatal period through later childhood. Reduced thalamic volume is associated with impairments in cognitive and motor function. Cerebellar volume findings are inconsistent. Interpretation of volumetric differences remains challenging due to methodological heterogeneity across studies. Future studies are needed to validate volumetric biomarkers and establish normative data, facilitating the integration of volumetric MRI into early diagnostic and therapeutic strategies for children with HIE.

Keywords:  brain volume; hypoxic-ischemic encephalopathy; magnetic resonance imaging; neurodevelopmental outcomes; pediatrics; therapeutic hypothermia

DOI:  https://doi.org/10.5114/pjr/211222
J Cell Physiol. 2026 Feb;241(2): e70153

Acetyl-CoA Homeostasis via Mitochondrial Pyruvate Oxidation Governs Survival, Transcriptional Fidelity and Neural Specification in Primed Human Embryonic Stem Cells.

Ning Zhong, Yujie Liu, Min Shao, Hanzhi Zhao, Yongqiang Wang, Junjie Gu, Qinwen Chen, Huiyong Yin, Ying Jin, Bing Liao.

  Human embryonic stem cells (hESCs) hold immense promises for regenerative medicine and exhibit two distinct pluripotency states: primed and naïve. However, metabolic regulation underlying these states remains incompletely understood. In particular, mitochondrial pyruvate oxidation in pluripotency regulation has not been documented. Here, we combined an inducible dihydrolipoamide S-acetyltransferase (DLAT) knockout model and pharmacological inhibition of mitochondrial pyruvate uptake (via the mitochondrial pyruvate carrier inhibitor UK5099) to dissect the state-specific effects of mitochondrial pyruvate oxidation in isogenic naïve and primed hESCs. Primed hESCs lacking DLAT or treated with UK5099 displayed pronounced cell death, reduced global protein acetylation levels, and transcriptional dysregulation. These defects were partially rescued by sodium acetate supplementation, implicating a reduction in acetyl-CoA abundance as a key mechanism. Notably, a set of neural lineage genes was specifically downregulated by disrupted mitochondrial pyruvate oxidation in primed hESCs, revealing the importance of mitochondrial pyruvate oxidation-mediated acetyl-CoA production in priming neural differentiation. In line with this, disruption of mitochondrial pyruvate oxidation impaired the differentiation process of primed hESCs towards neuroectoderm. In contrast, DLAT depletion in naïve hESCs did not affect cell growth and the naïve pluripotency state, highlighting the pluripotency state-dependent function of mitochondrial pyruvate oxidation. Our study uncovers the pivotal roles of mitochondrial pyruvate oxidation-mediated acetyl-CoA production for sustaining survival and transcriptional fidelity as well as facilitating neural differentiation in primed hESCs. Moreover, we emphasize that the function of mitochondrial pyruvate oxidation in hESCs is pluripotency state-dependent. These findings provide new cues for optimizing hESC maintenance and differentiation through targeted metabolic manipulation.

Keywords:  DLAT; acetyl‐CoA; histone acetylation; human embryonic stem cells; human naïve pluripotency; human primed pluripotency; mitochondrial pyruvate oxidation

DOI:  https://doi.org/10.1002/jcp.70153
Methods Enzymol. 2026 ;pii: S0076-6879(25)00491-4. [Epub ahead of print]726 289-319

Metabolic labeling of glycerophospholipids.

Robert J Maraski, Christelle F Ancajas, Jinchao Lou, Michael D Best.

  The approach of metabolic labeling provides an invaluable tool for elucidating previously unknown and poorly understood metabolic processes within cells. By introducing clickable versions of substrates into cells, the products of these biomolecule mimics can be conveniently tracked via post-derivatization of the clickable tag with a variety of reporter groups. Here, we will describe lipid metabolic labeling as an invaluable approach for interrogating lipid metabolic pathways, which can yield crucial information regarding complex lipid biosynthesis and trafficking networks that can open new therapeutic targets involving downstream natural products. In this chapter, we present detailed experimental procedures for the development of clickable serine probes for the labeling of phosphatidylserine (PS) and other lipids, including probe design and synthesis as well as analysis of biological incorporation via confocal microscopy, thin-layer chromatography (TLC), and liquid chromatography mass spectrometry (LCMS). This strategy provides a powerful approach for interrogating lipid biosynthetic pathways centered around PS.

Keywords:  Click chemistry; Fluorescence microscopy; Lipids; Membranes; Metabolic labeling; Phosphatidylserine; Phospholipids

DOI:  https://doi.org/10.1016/bs.mie.2025.11.010