bims-medebr 2026-03-15 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–03–15
27 papers selected by
Regina F. Fernández, Johns Hopkins University

Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice.
Longitudinal analysis of lipid changes in the sciatic nerve caused by overexpression of PMP22 in murine models of CMT1A.
Dysregulated Cholesterol Clearance via CYP46A1 Contributes to Cerebellar Sterol Imbalance in Mecp2-Null Mice.
Comprehensive lipidomics of Drosophila melanogaster reveal Rotenone exposure induces redox-driven lipid droplet accumulation, systemic lipidome perturbation and differential metabolic prioritization linked to Parkinson's disease.
LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models.
Resolving sn-Positional Isomers of Docosahexaenoic Acid-Bound Phospholipids in the Mouse Brain by Cyclic Ion Mobility Mass Spectrometry Imaging.
Selective Mitochondrial Damage and Dysfunction in Cholesterol-Exposed Neuronal Cells: Role of Mitochondrial Lipid Peroxidation.
Lactate potentiates NMDA receptor currents via an intracellular redox mechanism targeting GluN2B subunits: implications for synaptic plasticity.
Effect of addiction on brain glucose metabolism assessed by PET/CT molecular imaging: a systematic review and meta-analysis.
Microglia Mitochondria Support Neuronal Maturation via Metabolic and Transcriptional Reprogramming in Human 3D In Vitro Brain Model.
Brain lipidomics identifies mitochondrial redox dysfunction and metabolic trade-offs associated with Parkinson's disease-like pathology induced by Nanoplastics exposure.
Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability.
Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.
Metabolic Dysfunction in Alzheimer's Disease: Brain Glucose Hypometabolism as an Early Precursor to Amyloid and Tau Pathology.
Elevation of Stearoyl-Coenzyme A Desaturase and Monounsaturated Fatty Acids in Parkinson's Disease Serum.
The impact of dendritic mitochondrial heterogeneity on synapse function.
Traumatic brain injury and alcohol: A narrative review of the role of mitochondrial dysfunction and ferroptosis in neurocognitive outcomes.
Polyunsaturated Fatty Acid Balance Modulates Microglial State in a Murine Model of Oxygen-Induced Neovascularization.
Ultra-high field 31P functional magnetic resonance spectroscopy reveals NAD+ dynamics in brain energy metabolism during visual stimulation.
Short-term docosahexaenoic acid rich diet prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice.
APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.
Sex and age differences in brain metabolism and cognition in adolescents.
Endogenous progesterone deficiency impairs neonatal brain development via microglial dysregulation under chronic hypoxia.
Lipid Messengers: Mechanisms and Clinical Applications of Exosomal Lipids in Neurodegenerative Diseases.
β-hydroxybutyrate Modulates Neuroinflammatory Responses and Astrocyte Reactivity in an In Vitro Model of Traumatic Brain Injury.
Oligodendrocyte Dysfunction in Alzheimer's Disease: Integrating Spatial Epigenomics and Metabolic Circuitry in Demyelination - A Critical Review.
Are neurodegenerative diseases late-onset neurodevelopmental disorders? Tracing the developmental origins of neuronal vulnerability.

Front Mol Neurosci. 2026 ;19 1636268

Dysregulated lipid metabolism and hypomyelination in postnatal peroxisome-deficient Pex2 knockout Zellweger mice.

Tanja Eberhart, Khanichi N Charles, Brenda Salumbides-Torres, Nia Price, Steven J Fliesler, Phyllis L Faust, Werner J Kovacs.

  Peroxisomes are dynamic organelles that play a crucial role in cellular metabolism, particularly in fatty acid degradation, cholesterol homeostasis and reactive oxygen species metabolism. Their dysfunction is associated with severe neurological disorders, including Zellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD). In this study, we investigated the relationship between cholesterol homeostasis and myelination in postnatal peroxisome-deficient Pex2 knockout mice. We dissected the central nervous system (CNS) of 10-day-old (P10) control and Pex2 -/- mice into five regions: spinal cord, brainstem, cerebellum, diencephalon and cerebral cortex. Catalase activity, a marker enzyme of peroxisomes, was significantly increased in CNS regions of Pex2 -/- mice, indicating an oxidative imbalance. Proteomic analysis revealed significant alterations in peroxisomal proteins and pathways related to neurodegenerative diseases, cholesterol and fatty acid metabolism and mRNA processing. Cholesterol biosynthesis was particularly dysregulated: enzyme activities, mRNA, and protein levels were reduced in white matter regions but increased in the cerebral cortex. The elevated desmosterol levels in the brain of Pex2 -/- mice indicate impaired cholesterol synthesis. Sphingolipid metabolism was also altered in the peroxisome-deficient CNS, as the protein levels of enzymes dihydroceramide desaturase 1, ceramide synthase 2, fatty acid 2-hydroxylase, and UDP-glycosyltransferase 8 were significantly decreased. Myelination was significantly reduced throughout the CNS, as evidenced by decreased activities of the myelin marker 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and decreased mRNA and protein levels of myelin-associated proteins. The consistent decrease in ribosomal protein S6 phosphorylation in the CNS of Pex2 -/- mice suggests that decreased mechanistic target of rapamycin complex 1 (mTORC1) activity contributes to hypomyelination. Gene expression analysis revealed an upregulation of pro-inflammatory cytokines and altered expression of some homeostatic and disease-associated microglial (DAM) genes. However, full DAM activation was not yet observed in Pex2 -/- mice at P10. In conclusion, this study shows that systemic peroxisome deficiency leads to severe hypomyelination and dysregulation of cholesterol and fatty acid metabolism in the CNS, providing new insights into the pathophysiology of peroxisomal disorders.

Keywords:  Zellweger syndrome; brain; central nervous system; cholesterol; fatty acids; myelination; peroxisomes; proteomics

DOI:  https://doi.org/10.3389/fnmol.2026.1636268
J Lipid Res. 2026 Mar 11. pii: S0022-2275(26)00044-1. [Epub ahead of print] 101018

Longitudinal analysis of lipid changes in the sciatic nerve caused by overexpression of PMP22 in murine models of CMT1A.

Tom P Hellings, Naima Lamzira-Arichi, Jeroen P Vreijling, Hailiang Mei, Davy Cats, Tom B Kuipers, Rico J E Derks, Marieke Heijink, Niek Blomberg, Iulia Sidorov, Martin Giera, Frank Baas, Kees Fluiter.

  Charcot-Marie-Tooth type 1A (CMT1A), a prevalent progressive demyelinating peripheral neuropathy is caused by a duplication of the peripheral myelin protein (PMP22) gene. PMP22 is crucial for formation of compact myelin, but the mechanism by which PMP22 overexpression results in CMT1A pathogenesis remains elusive. Emerging evidence points to a role of PMP22 in lipid metabolism as a key modulator of disease progression. Here we show that C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, have PMP22 dose-dependent lipidomic and transcriptomic alterations. Both models show a decrease in membrane-associated lipids (e.g. phospholipids, sphingolipids) and an increase in neutral lipids (e.g. cholesteryl esters) from three weeks of age. Notably, while cholesteryl ester concentrations are elevated, particularly in C22 mice, total cholesterol levels were significantly reduced, accompanied by the downregulation of key genes involved in cholesterol biosynthesis. Significant decreases were also observed in phospholipids and sphingolipids, including ceramide and sphingomyelin, with a proportional shift towards shorter fatty acid chains in sphingomyelin due to altered ceramide synthase expression. Plasmalogen concentrations were decreased with shifts in the proportion of specific plasmalogen species, aligning with impaired synthesis. These lipidomic changes, impacting myelin-associated lipids and fatty acid compositions, underscore their critical role in the dysmyelination observed in CMT1A. Our findings suggest potential avenues for dietary interventions, such as specific fatty acid and plasmalogen supplementation, to improve myelination in CMT1A.

Keywords:  Cholesterol/Cell and tissue; Genomics; Lipidomics; Plasmalogens and Sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2026.101018
Int J Mol Sci. 2026 Mar 03. pii: 2348. [Epub ahead of print]27(5):

Dysregulated Cholesterol Clearance via CYP46A1 Contributes to Cerebellar Sterol Imbalance in Mecp2-Null Mice.

Pablo J Tapia, Bastian I Rivera, C Sofía Espinoza, Francisca Stolzenbach, María J Yáñez, Bredford Kerr.

  Rett syndrome (RTT) is a neurodevelopmental disorder characterized by motor deficits, partly attributed to cerebellar dysfunction. RTT is primarily caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MECP2), which has been implicated in cholesterol homeostasis by mechanisms that remain poorly understood. Given that brain cholesterol is primarily synthesized de novo and that disrupted cholesterol homeostasis is linked to various neurological disorders, we aimed to investigate cholesterol regulation in the cerebellum of Mecp2-null mice, a well-established RTT model. We measured total cholesterol levels in cerebellar tissue and cerebellar synaptosomes and assessed the expression of genes involved in cholesterol biosynthesis and intracellular transport. Our results show significantly elevated total cholesterol in both cerebellar tissue and synaptosomes. Furthermore, we identified a marked reduction in CYP46A1 expression, which is essential for the elimination of encephalon sterols. In contrast, key cholesterol biosynthetic regulators (Srebp2, Hmgcs1, Sqle) showed no significant changes in expression, suggesting an impaired cerebellar cholesterol turnover-driven by defective clearance-rather than enhanced synthesis may underlie the metabolic imbalance observed in the cerebellum of the RTT mouse model. Altogether, these findings provide a mechanistic insight into how MeCP2 deficiency disrupts cerebellar cholesterol homeostasis and highlight cholesterol clearance pathways as potential contributors to RTT pathology and a factor to consider for further RTT therapeutic approaches.

Keywords:  CYP46A1; MeCP2; Rett syndrome; cerebellum; cholesterol

DOI:  https://doi.org/10.3390/ijms27052348
Neurotoxicology. 2026 Mar 08. pii: S0161-813X(26)00046-X. [Epub ahead of print] 103425

Comprehensive lipidomics of Drosophila melanogaster reveal Rotenone exposure induces redox-driven lipid droplet accumulation, systemic lipidome perturbation and differential metabolic prioritization linked to Parkinson's disease.

Ashutosh K Tiwari, Priya Rathor, Rajendra Patel, Pawan Kumar Jha, Nick Birse, Ratnasekhar Ch.

  With the global increase in pesticide use and an aging population, concerns about neurodegenerative disease risk and brain health are intensifying, particularly as environmental toxicants like rotenone emerge as significant hazards. Despite the brain's unique vulnerability as a lipid-rich organ, the metabolic impact of chronic rotenone exposure-especially on lipid homeostasis-remains poorly defined. Here, we employed Drosophila melanogaster as an established environmental toxicology model to systematically profile lipidomic alterations induced by rotenone. Using high-resolution, untargeted Orbitrap HRAMS lipidomics, we uncovered extensive disruption of mitochondrial lipids, including cardiolipins (CL) and phosphatidylethanolamines (PE), alongside major shifts in glycerolipid classes such as diglycerides (DG) and triglycerides (TG). Notably, our findings reveal previously uncharacterized, tissue-specific remodeling of PE and ether-linked PE (PE-O) species, pointing to impaired metabolic crosstalk between mitochondria and peroxisomes-a process essential for cellular redox balance. We also observed a distinct rise in monounsaturated fatty acids and lipid droplet accumulation, accompanied by disrupted coordination of lipid and fatty acid metabolism between brain and peripheral tissues, establishing a novel biomarker axis of environmental lipidome disruption. Targeted intervention with NAC and L-DOPA restored lipid homeostasis and mitochondrial function, highlighting both the systemic risks associated with chronic pesticide exposure and new avenues for therapeutic intervention.

Keywords:  Drosophila melanogaster; lipidomics; mitochondrial-peroxisome cross-talk; neurotoxicity, brain lipid metabolism, redox homeostasis; system-wide lipidomics

DOI:  https://doi.org/10.1016/j.neuro.2026.103425
J Neurochem. 2026 Mar;170(3): e70403

LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models.

Gabriela Joras Baumart, Matheus Scarpatto Rodrigues, Juliete Nathali Sholl, Arieli Cruz de Sousa, Augusto Ferreira Weber, Lílian Corrêa Costa-Beber, Hémelin Resende Farias, Mariana Viana Costa, Ariadni Mesquita Peres, Pedro Rocha de Camargo, Fernanda Telles Fróes, Rachel Krolow Bast, Andreza Fabro de Bem, Fabrício Figueiró, Fátima T C R Guma, Jade de Oliveira.

  Astrocytes are the primary antioxidant defense cells of the brain, protecting the central nervous system (CNS) through a controlled inflammatory response and acting as metabolic suppliers to neurons. These cells exhibit morphological, functional, and molecular changes in pathological conditions, such as neurodegenerative diseases. Previous studies have demonstrated a link between hypercholesterolemia, especially elevated levels of low-density lipoprotein (LDL) cholesterol, and brain disorders, including hippocampal astrogliosis. In this context, this study aimed to investigate how LDL cholesterol modulates astrocyte biology. In vitro, high-passage rat C6 astroglial cells were exposed to human LDL cholesterol (50 or 300 μg/mL) for 24 or 48 h. We evaluated lipid accumulation, cholesterol metabolism-related gene expression, astrocyte-related gene expression, reactive species production, antioxidant activity, redox-related gene expression, fatty acid and glucose uptake, cell proliferation, and metabolic activity - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. LDL exposure increased intracellular lipid content and downregulated LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and sterol regulatory element-binding transcription factor 1 (SREBF1) gene expression. LDL exposure altered astrocytic marker expression, as evidenced by increased glial fibrillary acid protein (GFAP) messenger RNA (mRNA) levels at 24 h with 300 μg/mL LDL and at 48 h with 50 μg/mL LDL. LDL cholesterol decreased long-chain fatty acids (LCFA) uptake and superoxide dismutase (SOD) activity at 24 h and increased cluster of differentiation 36 (CD36), also known as fatty acid translocase levels, at 48 h. Nuclear factor erythroid 2-related factor 2 (NRF2) expression was significantly increased after 48 h of incubation with 300 μg/mL LDL. The MTT reduction assay did not indicate decreased cell viability; instead, it revealed increased metabolic activity after 24 h of incubation with 300 μg/mL LDL, with no changes observed in glucose uptake. In vivo, hippocampal astrocytes from young (3-month-old) and middle-aged (14-month-old) LDL receptor knockout (LDLr-/-) and wild-type C57BL/6 mice were analyzed by immunofluorescence and quantitative reverse transcription polymerase chain reaction (RT-qPCR). In the hippocampal Cornu Ammonis 3 (CA3) region, 14-month-old LDLr-/- mice showed an increase in the number of processes compared to 3-month-old wild-type C57BL/6 mice. Aging and genotype influenced astrocyte morphology and expression of genes such as S100 calcium-binding protein B (S100B) and aquaporin-4 (AQP4). Our findings demonstrate that LDL cholesterol induces morphological, metabolic, and molecular changes in astrocytes, both in vitro and in vivo, suggesting that astroglial cells are sensitive to lipid imbalance and may play a role in the brain consequences of hypercholesterolemia.

Keywords:  LDL cholesterol; LDLr−/− mice; astrocytes; hypercholesterolemia; lipid droplets; metabolism

DOI:  https://doi.org/10.1111/jnc.70403
Anal Chem. 2026 Mar 09.

Resolving sn-Positional Isomers of Docosahexaenoic Acid-Bound Phospholipids in the Mouse Brain by Cyclic Ion Mobility Mass Spectrometry Imaging.

Seiya Tanaka, Emi Sasaki, Taiji Kawase, Thanai Paxton, Kenji Hirose, Aya Yoshinaga-Kiriake, Kazuaki Yoshinaga, Yugo Iwasaki, Naohiro Gotoh, Katsuyoshi Masuda.

Phospholipids containing docosahexaenoic acid (DHA, 22:6) are crucial for brain function and are abundant in the brain. While 22:6 predominantly associates with the sn-2 position of phosphatidylcholine (PC) in the plasma and liver, the brain contains a characteristic PC in which 22:6 is bound to the sn-1 position. However, the precise relationship between the 22:6-binding site and its distribution in the brain remains unclear. Ion mobility mass spectrometry imaging can visualize phospholipid molecular species in the brain. However, the distribution of structurally similar phospholipids, such as PC sn-positional isomers, has not been fully elucidated. Here, we used cyclic ion mobility coupled mass spectrometry imaging to distinguish PC isomers, specifically PC(22:6/16:0) and PC(16:0/22:6), after 30 passes of cyclic ion mobility, and revealed their differential distribution in the mouse brain using a stable isotope-labeled 22:6. We observed significant differences between the brain distribution of the isomers in mice orally administered 22:6-incorporated PCs. The reliability of the results was further supported by quantitative data obtained using liquid chromatography-tandem mass spectrometry. This study demonstrates for the first time that cyclic ion mobility mass spectrometry imaging can effectively distinguish and visualize structurally similar isomers, such as phospholipid sn-positional isomers with different distributions.

DOI: https://doi.org/10.1021/acs.analchem.5c06621
Arch Biochem Biophys. 2026 Mar 11. pii: S0003-9861(26)00061-5. [Epub ahead of print] 110790

Selective Mitochondrial Damage and Dysfunction in Cholesterol-Exposed Neuronal Cells: Role of Mitochondrial Lipid Peroxidation.

Jing Li, Xiangyu Hao, Tian Hao Xiao, Bao Ting Zhu.

  Studies have revealed an association between elevated neuronal cholesterol and neuronal dysfunction, in particular, mitochondrial impairment. However, the mechanism by which cholesterol disrupts neuronal mitochondrial function remains unclear, which prompts our current investigation. Using cultured HT22 mouse hippocampal neuronal cells as an in-vitro model, we found that the unmetabolized cholesterol, rather than its ester derivatives, can alter the MTT activity in cultured neuronal cells in a concentration-dependent manner, with an apparent IC50 ≤1 μM. At low micromolar concentrations (≤10 μM), cholesterol selectively disrupts mitochondrial function without causing overt cell death or reducing cell density. Functional and structural analyses revealed increased mitochondrial lipid peroxidation, loss of mitochondrial membrane potential, opening of the mitochondrial permeability transition pore, disruption of mitochondrial membrane integrity and ultrastructure, reduced mitochondrial density, and decreased cellular ATP levels. Seahorse-based bioenergetic profiling further demonstrated marked reductions in basal respiration, maximal respiratory capacity, and ATP-linked respiration, indicating a broad impairment of mitochondrial oxidative metabolism. In contrast, higher cholesterol concentrations (100 μM) induced overt cytotoxicity. Furthermore, genes involved in cholesterol biosynthesis (e.g., HMGCR, HMGCS1) and transport (e.g., STARD4, ABCA1), as well as mitochondrial energy metabolism pathways, are altered in cholesterol-treated neuronal cells. These results suggest that free cholesterol at very low concentrations can induce selective mitochondrial toxicity in cultured neurons and impairs mitochondrial ATP production. These findings shed lights on the crucial role of dysregulated cholesterol homeostasis in the pathogenesis of neurodegenerative diseases and also form the basis for therapeutic interventions.

Keywords:  ATP Synthesis; Cholesterol; Cholesterol Biosynthesis; Mitochondrial Dysfunction; Mitochondrial Impairment

DOI:  https://doi.org/10.1016/j.abb.2026.110790
J Physiol. 2026 Mar 11.

Lactate potentiates NMDA receptor currents via an intracellular redox mechanism targeting GluN2B subunits: implications for synaptic plasticity.

Hubert Fiumelli, Gabriel Herrera-López, Fouad Lemtiri-Chlieh, Lorène Mottier, John Girgis, Carine Ben-Adiba, Pascal Jourdain, Nicolò Carrano, Hanan Mahmood, Amanda Ooi, Stefan T Arold, Monica Di Luca, Fabrizio Gardoni, Pierre J Magistretti.

  Astrocyte-derived lactate, through the astrocyte-neuron lactate shuttle, fuels neuronal energy demands and acts as a signalling molecule promoting synaptic plasticity and memory consolidation. Lactate regulates neuronal excitability and expression of genes related to synaptic plasticity and neuroprotection, but the molecular mechanisms remain unclear. Using patch-clamp recordings in cultured cortical neurons we found that lactate enhances NMDA receptor currents (INMDAR), increasing their amplitude and decay time constant. Not reproduced by HCAR1 agonists, this modulation depends on monocarboxylate transporters and lactate dehydrogenase, requiring lactate entry, metabolic conversion to pyruvate and NADH formation within neurons. Disruption of intracellular calcium dynamics or inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) diminishes lactate's effects on INMDAR. Two redox-sensitive cysteine-containing sequences in the intracellular C-terminal domain of GluN2B subunit play a crucial role in the potentiation of NMDAR by lactate. Experiments in HEK cells demonstrate that functional CaMKII and GluN2B-containing NMDARs are necessary for lactate's effects. Mutations in GluN2B, that disrupt either CaMKII binding or cysteine-mediated redox regulation, abolish lactate's modulatory action. Immunoprecipitation experiments in neurons show that lactate promotes CaMKII-GluN2B association, which is critical for increasing INMDAR amplitude. Proximity ligation assays between GluN2B and PSD-95 reveal that lactate induces GluN2B accumulation in dendritic spines, an effect a CaMKII inhibitor prevents. These findings elucidate a pathway whereby lactate enhances NMDAR function through metabolic conversion and redox-sensitive interactions requiring CaMKII, linking astrocyte energy metabolism to synaptic modulation. KEY POINTS: Astrocytes produce lactate, traditionally seen as an energy source, which also acts as a signalling molecule in the brain, influencing memory and synaptic plasticity by modulating NMDA receptor (NMDAR) function. Lactate enhances NMDAR responses specifically by increasing current amplitude through changes in cellular redox balance, which requires the entry of lactate into neurons and its conversion to pyruvate, producing NADH. Lactate-induced potentiation of NMDARs depends on calcium signalling involving Ca2 +/calmodulin-dependent protein kinase II (CaMKII), which interacts directly with the GluN2B subunit of the receptor. Lactate strengthens the interaction between CaMKII and GluN2B through redox-sensitive cysteine residues in GluN2B, facilitating synaptic localization of this complex and enhancing synaptic responses. These findings reveal a molecular pathway by which lactate, produced by astrocytes, can significantly influence neuronal activity and synaptic function, linking brain metabolism with learning and memory processes.

Keywords:  GluN2B subunits; NMDA receptors (NMDARs); calcium/calmodulin‐dependent protein kinase II (CaMKII); lactate; redox state; signalling; synaptic plasticity

DOI:  https://doi.org/10.1113/JP288960
Brain Imaging Behav. 2026 Mar 14. pii: 48. [Epub ahead of print]20(2):

Effect of addiction on brain glucose metabolism assessed by PET/CT molecular imaging: a systematic review and meta-analysis.

Qariemah Azahar, Syahir Mansor.



Keywords:   18F-FDG PET; Addiction; CMRglc ; Glucose metabolism; PET/CT; cerebral metabolic rate of glucose

DOI:  https://doi.org/10.1007/s11682-026-01132-y
Adv Sci (Weinh). 2026 Mar 13. e08815

Microglia Mitochondria Support Neuronal Maturation via Metabolic and Transcriptional Reprogramming in Human 3D In Vitro Brain Model.

Sydney P Sterben, Charitha C Anamala, Sahan B S Kansakar, Vaishnavi Koduri, Volha Liaudanskaya.

  Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by disrupted neuronal circuit maturation. Emerging evidence implicates microglial function and mitochondrial regulation as contributors to ASD-associated biology, yet the mechanisms linking these processes to neuronal development remain poorly defined. Neuronal maturation requires tightly coordinated metabolic and transcriptional remodeling, in which mitochondria play a central role in regulating the developmental tempo and metabolic identity, while microglia modulate neuronal synaptic network maturation; however, whether microglia influence neuronal development through direct mitochondrial contributions remains unknown. Here, using a 3D human in vitro brain model, it is shown that microglial mitochondria can act as transferable cues that promote metabolic, mitochondria-dynamic, and transcriptional aspects of neuronal maturation. Neurons treated with microglial mitochondria exhibited enhanced oxidative metabolism, improved mitochondrial dynamics, and activation of gene programs associated with nervous system development and neurogenesis. These effects are accompanied by increased expression of dendritic maturation markers, supporting the view that transferred mitochondria can contribute to the regulation of neuronal state. However, full structural and synaptic maturation required the combined action of microglia-derived mitochondria and secreted signaling factors. Together, this study identified microglial mitochondrial transfer as a contributor to neuronal maturation with potential relevance to developmental trajectories disrupted in ASD.

Keywords:  autism spectrum disorder; microglia; mitochondria; neurodevelopment; transcriptional reprogramming

DOI:  https://doi.org/10.1002/advs.202508815
Free Radic Biol Med. 2026 Mar 09. pii: S0891-5849(26)00214-5. [Epub ahead of print]

Brain lipidomics identifies mitochondrial redox dysfunction and metabolic trade-offs associated with Parkinson's disease-like pathology induced by Nanoplastics exposure.

Priya Rathor, Ashutosh K Tiwari, Rajendra P Patel, Anoop Verma, Sheelendra Pratap Singh, Ratnasekhar Ch.

  Growing nanoplastics exposure raises concern for neurotoxicity, particularly given recent evidence of plastic accumulation within human brain tissue a highly lipid enriched organ, yet effects on brain lipid metabolism remain poorly understood. Here, we employed high-resolution untargeted lipidomics to map brain lipid perturbations in Drosophila melanogaster chronically exposed to environmentally relevant levels of polystyrene nanoplastics (PS- NPs). PS-NPs accumulated in fly brains and induced dose-dependent remodeling of mitochondrial membrane lipids, notably cardiolipins and phosphatidylethanolamines, accompanied by increased diacylglycerols/triacylglycerols and monounsaturated fatty acids and by lipid droplet expansion. Guided by these lipidomic signatures, targeted biochemical assays demonstrated depolarized mitochondrial membrane potential, elevated mitochondrial reactive-oxygen species, inhibition of respiratory-chain complexes I and IV, and a shift in NAD(H) and NADP(H) redox couples toward a reduced state and increasing lipid peroxidation. This redox imbalance was accompanied by decreased tyrosine-hydroxylase expression, dopamine depletion, and impaired locomotor behavior, hallmarks of Parkinson's disease (PD)-like neurodegeneration. Dopaminergic neurochemistry was impaired (tyrosine hydroxylase and dopamine decreased), with concomitant reduction of GABA, and locomotor and circadian deficits emerged. Remarkably, co-treatment with the antioxidant N-acetylcysteine (NAC) restored mitochondrial membrane potential, reduced mitochondrial ROS and lipid peroxidation, normalized neutral lipid and MUFA accumulation, and rescued neurotransmitter levels and behavior. Stable-isotope tracing confirmed disrupted TCA cycle flux after NPs exposure that was rescued by NAC. Collectively, these findings reveal lipidomic remodeling as a critical link between environmental NPs exposure and PD-like pathology, highlighting mitochondrial redox-lipid interactions as early determinants and support redox-directed interventions to mitigate risk.

Keywords:  brain metabolism; global lipidomics; mitochondrial dysfunction; nanoplastics; neurotoxicity

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.023
J Neurochem. 2026 Mar;170(3): e70394

Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability.

Paweł Hanus, Dorota Frydecka, Michał Ślęzak.

  Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasingly recognized as an important factor contributing to the pathophysiology of neuropsychiatric disorders, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). A piling evidence points to astrocytes as a central integrator of brain response to stress hormones, including GCs. In this review, we discuss a biphasic regulation of astrocyte metabolism by GCs. According to the hypothesis, astrocytes undergo metabolic adaptations in response to GC: acute exposure leads to the enhancement of astrocyte metabolism through upregulation of glycolysis, mitochondrial activation, and glutamate clearance. In turn, prolonged GC exposure induces a metabolic shift toward branched-chain amino acid and lipid catabolism, promoting mitochondrial reactive oxygen species (ROS) production and impairing key homeostatic functions, including the astrocyte-neuron lactate shuttle and calcium signaling. Progressive disruption of astrocytes' supporting function may subsequently lead to synaptic dysregulation and energy imbalance in stress-related brain pathology. We postulate that a detailed understanding of this dynamic regulation is necessary for targeting astrocyte-specific metabolic mechanisms in neuropsychiatric disorders.

Keywords:  astrocyte metabolism; brain energy metabolism; glucocorticoid signaling; neuroenergetics

DOI:  https://doi.org/10.1111/jnc.70394
Mol Neurobiol. 2026 Mar 11. pii: 493. [Epub ahead of print]63(1):

Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.

Aneta Houfkova, Monika Schmidt.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, predominantly in the elderly (Alzheimer Disease International et al., 2015). Although amyloid-β peptide (Aβ), particularly in its oligomeric forms, has long been linked to AD pathogenesis (Chen 9:1205-1235 2017, Gaspar 2 394-400 2010), the mechanisms underlying its cellular toxicity remain unclear. Mitochondrial dysfunction is a consistent feature of AD (D'Alessandro 107:102713 2025), yet how Aβ drives these alterations is not fully understood. This review integrates recent evidence showing that Aβ accumulates on mitochondrial membranes (Cenini 21:3257-3272 2016, Manczak 23:5131-5146 2006, Sirk 5:1989-2003 2007), providing a mechanistic link between amyloid pathology and mitochondrial damage. We discuss how membrane-associated Aβ disrupts mitochondrial protein import by impairing the translocase of the outer membrane (TOM) complex (Cenini 21:3257-3272 2016, Sirk 5:1989-2003 2007) and interferes with voltage-dependent anion channel 1 (VDAC1) (Smilansky 52:30670-30683 2015), a key regulator of metabolite exchange and apoptosis. We further emphasize the role of mitochondria-associated membranes (MAMs) as critical sites for Aβ generation and transfer to mitochondria, where dysregulated cholesterol metabolism may amplify MAM activity and Aβ accumulation (Area-Gomez and Schon 38:90-96 2017, Monaghan 2:240287 2025). Altogether, we propose that mitochondrial membrane localization of Aβ is a central mechanism linking amyloid pathology to mitochondrial dysfunction in aging, highlighting new directions for mitochondria-targeted therapeutic strategies in AD.

Keywords:  Amyloid-β; Cholesterol; Mitochondria; Mitochondria-associated membranes; Proteostasis; Translocase of outer membrane; Voltage-dependent anion channel

DOI:  https://doi.org/10.1007/s12035-026-05786-z
J Clin Med. 2026 Mar 01. pii: 1884. [Epub ahead of print]15(5):

Metabolic Dysfunction in Alzheimer's Disease: Brain Glucose Hypometabolism as an Early Precursor to Amyloid and Tau Pathology.

Rafail C Christodoulou, Daniel Eller, Platon S Papageorgiou, Efthalia Angelopoulou, Evros Vassiliou, Sokratis G Papageorgiou.

  Objective: Alzheimer's disease (AD) is traditionally characterized by amyloid-β and tau pathology; however, accumulating evidence indicates that metabolic and inflammatory dysfunctions are early, central contributors to disease development. This narrative review explores how metabolic disturbances influence AD pathophysiology. Methods: A comprehensive literature search was performed on PubMed, Embase, and Scopus. Selected studies were original studies or reviews published in English within the past five years involving human subjects. Case reports, case series, editorials, and non-human studies were excluded. A total of 64 articles were reviewed and summarized. Results: Cerebral glucose hypometabolism, mitochondrial impairment, insulin resistance, oxidative stress, and neuroinflammation were observed throughout the AD spectrum. These metabolic changes often appeared before significant amyloid accumulation and were more closely linked to tau pathology and cognitive decline. Early microglial activation was linked to transient glucose hypermetabolism, progressing to glucose hypometabolism and neurodegeneration as the disease advanced. Conclusions: AD is associated with a gradual breakdown of metabolic and inflammatory homeostasis, which occurs before and promotes the development of traditional neuropathological features. Addressing early metabolic vulnerabilities may be essential for effective disease intervention and prevention.

Keywords:  Alzheimer’s disease; Apoε4; glucose metabolism; metabolic failure; proteinopathies; type 3 diabetes

DOI:  https://doi.org/10.3390/jcm15051884
Mov Disord. 2026 Mar 10.

Elevation of Stearoyl-Coenzyme A Desaturase and Monounsaturated Fatty Acids in Parkinson's Disease Serum.

Finula I Isik, Russell Pickford, Michelle Chua, Simon J G Lewis, Nicolas Dzamko, Woojin Scott Kim.

   BACKGROUND: Emerging evidence indicates that dysregulation of monounsaturated fatty acids (MUFAs), synthesized by the enzyme stearoyl-coenzyme A desaturase (SCD), impacts on α-synuclein pathology in the Parkinson's disease (PD) brain.
OBJECTIVE: The objective of this study was to analyze SCD and MUFA-enriched lipids in the periphery of patients with sporadic PD compared with healthy control subjects.
METHODS: Serum SCD protein was quantified using enzyme-linked immunosorbent assay in patients with PD (n = 40) and control subjects (n = 41). Lipidomic profiling was performed using liquid chromatography-mass spectrometry and LipidSearch software. Statistical analyses included Mann-Whitney U tests and Welch's t tests with false discovery rate (FDR) correction.
RESULTS: SCD levels were higher in PD (mean = 1702 pg/ml) compared with control subjects (1158 pg/ml; P = 2.2 × 10-4; Cohen's d = 0.73). Lipidomics showed elevated MUFA content in four lipid classes: methylphosphatidylcholine, phosphatidylcholine, dihexosylceramide, and triglycerides (FDR < 0.05).
CONCLUSIONS: Increased SCD and MUFA-enriched lipids indicate altered membrane and sphingolipid metabolism in PD, consistent with central disease pathology, that present a potential for novel biomarker development for PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  Parkinson's disease; lipid; monounsaturated fatty acid; stearoyl‐CoA desaturase

DOI:  https://doi.org/10.1002/mds.70264
Trends Neurosci. 2026 Mar 11. pii: S0166-2236(26)00014-7. [Epub ahead of print]

The impact of dendritic mitochondrial heterogeneity on synapse function.

Mikel L Cawley, Shannon Farris.

  Mitochondria are energy- and metabolite-producing organelles that are differentially distributed throughout neuronal axons and dendrites to meet unique energy demands. Emerging evidence indicates that mitochondria in dendrites can be molecularly, structurally, and functionally distinct depending on cell types or even nearby synaptic inputs. This suggests that mitochondrial heterogeneity not only serves individual cell types but also plays a role in supporting the diversity of synaptic functions and connectivity patterns across different brain areas. This review highlights recent studies that contribute to our understanding of how heterogeneity in dendritic mitochondrial morphology, dynamics, and function converges to support cell- and compartment-specific metabolic demands and diverse postsynaptic properties.

Keywords:  bioenergetics; brain; local translation; neuron; plasticity; postsynapse

DOI:  https://doi.org/10.1016/j.tins.2026.01.011
Alcohol Clin Exp Res (Hoboken). 2026 Mar;50(3): e70267

Traumatic brain injury and alcohol: A narrative review of the role of mitochondrial dysfunction and ferroptosis in neurocognitive outcomes.

Xavier R Chapa-Dubocq, Sydney Vita, Roberto Guzmán-Hernández, Patricia E Molina.

  Traumatic brain injury (TBI) is a major global health concern, affecting over 30 million individuals annually and leading to significant disability and mortality. In the United States, the health burden of TBI is compounded by the high incidence of alcohol involvement, with up to 50% of cases occurring in intoxicated individuals and approximately 26% of patients consuming alcohol post-injury. This review synthesizes current research exploring the complex interplay between TBI and alcohol misuse, with a particular focus on their combined effects on mitochondrial function, energy metabolism, and cellular redox homeostasis. We discuss how TBI-induced mitochondrial dysfunction, manifested as impaired adenosine triphosphate (ATP) production, excessive reactive oxygen species (ROS) generation, and subsequent depletion of glutathione, intersects with alcohol-mediated metabolic reprogramming, resulting in disrupted glucose metabolism and a shift toward glutaminolysis. This metabolic perturbation predisposes neural tissue to lipid peroxidation and ferroptosis, an iron-dependent form of cell death that is characterized by the peroxidation of polyunsaturated fatty acid-containing phospholipids. Here we highlight how alterations in glutamate homeostasis in combination with exacerbated neuroinflammatory signaling contribute to post-TBI cognitive impairments and hinder the recovery process. Integrating findings from biomarker studies and preclinical models, we highlight the critical need for targeted therapies that address these interconnected molecular pathways. A comprehensive understanding of these pathways promises to uncover druggable targets leading to novel neuroprotective strategies, offering hope for improved clinical outcomes in patients suffering from TBI, particularly those with concurrent alcohol exposure.

Keywords:  alcohol misuse; ferroptosis; mitochondrial dysfunction; oxidative stress; traumatic brain injury (TBI)

DOI:  https://doi.org/10.1111/acer.70267
Nutrients. 2026 Feb 26. pii: 749. [Epub ahead of print]18(5):

Polyunsaturated Fatty Acid Balance Modulates Microglial State in a Murine Model of Oxygen-Induced Neovascularization.

Esther S Kim, Meng-Chin Lin, Cheng-Hsiang Lu, David Casero, Brian Aguirre, Joanne Brown, Olawande Olagoke, Camilia R Martin, Madhuri Wadehra, Kara L Calkins, Alison Chu.

  Background/Objectives: The retina is enriched in polyunsaturated fatty acids (PUFAs) which are indispensable for normal vision, and recent clinical studies have shown that dietary supplementation of ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) can provide a protective role against retinopathy of prematurity (ROP). Our study aims to understand the mechanisms by which altering ω-6-and ω-3-polyunsaturated fatty acids (PUFAs) in the eye can protect against pathologic retinal neovascularization (NV). Methods: We interrogated the effects of endogenous ω-3-PUFA enrichment using transgenic fat-1 mice which convert ω-6-PUFAs to ω-3-PUFAs in the oxygen-induced retinopathy (OIR) murine model. In the OIR model, mice are exposed to 75% oxygen from postnatal day 7 (P7) to P12, then returned to room air (RA). We used a combination of immunofluorescence, bulk retinal RNA sequencing, and lipid mediator profiling by UHPLC-MS/MS in P17 mouse retinas to identify mechanisms underlying the protective effect against NV seen in fat-1 mice exposed to OIR. Results:Fat-1 OIR mice were protected against the development of retinopathy, demonstrating 15.1% less vaso-obliteration (75.5% relative reduction) after OIR and a 6.1% reduction in neovascularization (71.8% relative reduction) at P17 (p < 0.0001 for both). We found a dampened transcriptional response to OIR in the retina of fat-1 mice as compared to WT mouse retinas (198 vs. 782 genes, adjusted p-value < 0.01). Pathway analyses confirmed these findings, with significant OIR-induced transcriptional shifts in angiogenesis (adjusted p-value < 10-27), inflammation (adjusted p-value < 10-25), and microglial activation pathways (adjusted p-value < 10-9) in WT mouse retina that were not observed in fat-1 mice. Enrichment scores obtained through the integration of our bulk transcriptomics data with cell-resolved retina data indicate that the protective phenotype observed in fat-1 mice could be associated with intrinsic differences in microglia cell subtypes between WT and fat-1 mice. In situ, WT OIR mice demonstrated an increase in Iba1+ microglia compared to WT RA mice, whereas fat-1 OIR mice showed no difference when compared to fat-1 RA mice. Three ARA-derived oxylipins, 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin D2 (PGD2), and thromboxane B2 (TXB2) demonstrated a pattern of upregulation in WT OIR compared to WT RA, but no upregulation in fat-1 OIR mice compared to fat-1 RA. Two EPA-derived specialized pro-resolving mediators and two LA-derived oxylipins were also differentially expressed. Conclusions: These findings show that a lower ω-6:ω-3 protects against neovascularization and is associated with attenuation of hyperoxia-induced microglial recruitment and activation, as well as inflammation and angiogenic signaling.

Keywords:  angiogenesis; hypoxia; microglia; oxygen-induced retinopathy; polyunsaturated fatty acids; retina; retinopathy of prematurity

DOI:  https://doi.org/10.3390/nu18050749
J Cereb Blood Flow Metab. 2026 Mar 12. 271678X261415784

Ultra-high field 31P functional magnetic resonance spectroscopy reveals NAD+ dynamics in brain energy metabolism during visual stimulation.

Antonia Kaiser, Fatemeh Anvari Vind, Joao Mn Duarte, Ileana Jelescu, Yan Lin, Xin Yu, Mark Widmaier, Daniel Wenz, Lijing Xin.

  We investigated dynamic changes in nicotinamide adenine dinucleotide (NAD+) metabolism in the human occipital lobe using ultra-high field 31P functional magnetic resonance spectroscopy (fMRS) at 7 T. Twenty-five healthy volunteers (mean age 24 ± 4 years, 10 females) performed a visual task alternating between fixation and flashing checkerboard stimuli. 31P MRS spectra were acquired from a visual cortex voxel functionally localized by prior functional magnetic resonance imaging (fMRI). Linear mixed-effects modeling revealed a significant reduction in NAD+ concentrations during the first stimulation block, while no significant change was observed during the second block. No significant changes were observed for other high-energy phosphate metabolites (ATP, phosphocreatine, and inorganic phosphate), indicating specificity in the NAD+ response. Exploratory analyses, dividing the blocks in two halves, suggested further reductions in NAD+ and tNAD in the second halves of both stimulation blocks, though these trends were not statistically significant. Our findings demonstrate the feasibility of using fMRS at 7 T to detect stimulus-induced dynamics in cerebral NAD+ metabolism in vivo, providing insights into the interplay between glycolysis and oxidative phosphorylation during neural activation.

Keywords:  31P; NAD+(H); energy metabolism; fMRS; visual stimulation

DOI:  https://doi.org/10.1177/0271678X261415784
Prostaglandins Leukot Essent Fatty Acids. 2026 Mar 05. pii: S0952-3278(26)00008-6. [Epub ahead of print]209 102730

Short-term docosahexaenoic acid rich diet prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice.

Rana Raffoul, Jessica Avila Lopez, Annick Vachon, Benoit Laurent, Mélanie Plourde.

   BACKGROUND: Metabolism of docosahexaenoic acid (DHA), an omega-3 (Ω3) fatty acid (FA), differs between carriers of the epsilon 4 allele of the apolipoprotein E (APOE4)-the main genetic risk factor for late-onset Alzheimer's disease-and APOE3 carriers. Dietary DHA has been shown to prevent cognitive decline in APOE4 carriers. However, whether DHA must be consumed the whole life is unclear. We hypothesized that a DHA intake started later in life and for a shorter duration prevents cognitive decline in APOE4 mice.
OBJECTIVE: To investigate three dietary durations of DHA on the prevention of cognitive decline in APOE4 mice.
METHODS: Mice knock-in for the human APOE3 (control, n = 84; 34 males/50 females) or APOE4 (n = 84; 39 males/45 females) allele were fed either a DHA-free control diet for 8 months or a diet rich in calcium salt DHA (0.5 g DHA/100 g diet) for 2, 4 or 8 months. Recognition memory was assessed using the novel object recognition test. DHA was quantified using gas chromatography.
RESULTS: APOE4 mice fed the control diet did not recognize the novel object as the APOE3 mice did suggesting cognitive decline in APOE4 mice. However, a DHA-Ca rich diet for 2 and 4 months prevented cognitive deficits in males (2M-P = 0.0414, 4M-P = 0.0073) and females (2M-P < 0.0001). 2-months DHA-Ca rich diet was associated with 18-25% higher cortical relative percentage of DHA in females and males compared to the control diet (Females-P = 0.0031; Males-P = 0.0010).
CONCLUSION: In APOE4 mice, it is not necessary to consume DHA-calcium salt throughout life to prevent cognitive decline.

Keywords:  Apolipoprotein E; Cognitive decline; Diet duration; Docosahexaenoic acid

DOI:  https://doi.org/10.1016/j.plefa.2026.102730
Int J Biol Sci. 2026 ;22(5): 2720-2735

APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.

Yu-Hsin Yen, Fang Yuan, Daijiao Tang, Jing-Fang Luo, Chen Ming, Phil-Jun Kang, Huanxing Su, Cheong-Meng Chong, Su-Chun Zhang.

   Background: Mitochondrial dysfunction is widely regarded as a central and early feature of Alzheimer's disease (AD) pathology. Prior studies suggest that the accumulation of amyloid precursor protein (APP) within mitochondria contributes to this dysfunction. Mutations in presenilin-1 (PS1), which account for most cases of early-onset familial AD (FAD), have also been shown to impair mitochondrial function. In this study, we investigated how APP influences PS1 mutation-induced mitochondrial dysfunction in human cortical neurons derived from patient induced pluripotent stem cells (iPSCs).
Methods: We analyzed transcriptomic and proteomic datasets from postmortem sporadic AD cortex to identify key dysregulated pathways. To functionally interrogate selected mechanisms, we established a panel of CRISPR/Cas9-engineered human iPSC lines, including PS1 mutant lines (PS1+/F105C and PS1+/A246E), an APP knockout derivative (APP-/-_PS1+/F105C), and their isogenic wild-type controls. These iPSCs were differentiated into cortical neurons for functional studies. Following directed differentiation into cortical neurons, biochemical analyses and super-resolution imaging were conducted to evaluate mitochondrial and neuronal phenotypes.
Results: Analyses of sporadic AD cortical transcriptomes and proteomes identified mitochondrial dysfunction as a prominently altered pathway. In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout.
Conclusions: These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD.

Keywords:  Alzheimer's disease; CRISPR; amyloid precursor protein; iPSCs; mitochondrial dysfunction; presenilin 1

DOI:  https://doi.org/10.7150/ijbs.120062
Imaging Neurosci (Camb). 2026 ;pii: IMAG.a.1159. [Epub ahead of print]4

Sex and age differences in brain metabolism and cognition in adolescents.

Anjali Balaganesh, Taylor M Zuleger, Zexuan Liu, Jed A Diekfuss, Jonathan A Dudley, Weihong Yuan, Kim D Barber Foss, Kim M Cecil, Scott Bonnette, Gregory D Myer, Candace C Fleischer.

  Adolescence is a period of neural development, marked by maturation of brain structure and function. While sex- and age-related markers of structural brain development are documented, neurochemical and cognitive changes are less understood. Our goal was to evaluate neurochemistry and cognition in adolescents as a function of sex and age. Magnetic resonance spectroscopy quantified brain metabolites, and attention networking, digital trail making, and cued task switching tests measured cognition in 354 healthy adolescents. Groupwise comparisons and linear regressions evaluated sex- and age-related effects, respectively. Males were differentiated from females in cognitive performance and brain metabolite concentrations, including myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine. Males performed tasks with faster speed while females demonstrated better accuracy. Decreases in Glx concentration and faster reaction times were associated with increasing age, indicative of maturing brain function during adolescence. These findings highlight adolescence as a period of active brain development.

Keywords:  adolescence; brain development; brain metabolites; cognition; magnetic resonance spectroscopy

DOI:  https://doi.org/10.1162/IMAG.a.1159
Brain Behav Immun. 2026 Mar 11. pii: S0889-1591(26)00279-5. [Epub ahead of print] 106531

Endogenous progesterone deficiency impairs neonatal brain development via microglial dysregulation under chronic hypoxia.

Yichen Yan, Gang Liu, Yue Cui, Cong Li, Huiwen Chen, Zhongqun Zhu.

   BACKGROUND: Several studies have confirmed the important role of progesterone in fetal and neonatal brain development. Chronic hypoxia in the fetal period may mediate neurodevelopmental and cognitive impairment in offspring by interfering with placental steroid hormone synthesis, but the mechanism is unclear.
METHODS: We systematically evaluated the effects of hypoxia on placental endocrine-fetal neuro-cognitive function by constructing a model of chronic hypoxia from fetal to early childhood, combined with progesterone supplementation, multi-omics of placenta and brain samples, microglial morphological analysis, and behavioral testing.
RESULTS: Chronic hypoxia significantly inhibited placental steroid synthase, leading to a concurrent decrease of progesterone levels in the fetal circulation and brain. Progesterone deficiency in the brain activates microglia, which in turn drives excessive inflammation under chronic hypoxic conditions, thereby interrupting oligodendrocyte differentiation and causing myelination deficits. Chronic hypoxia could also lead to impairment of spatial memory and learning ability shown by behavioral tests. During hypoxic pregnancy, administration of exogenous progesterone restored the progesterone gradient between the placenta and brain, inhibited abnormal activation of microglia, promoted myelination, and reversed cognitive deficits.
CONCLUSION: Chronic hypoxia downregulates placenta-derived progesterone through the "placenta-neural axis", which in turn leads to cognitive impairment through the microglia-myelin pathway. Progesterone supplementation during pregnancy can provide a theoretical basis for clinical intervention.

Keywords:  Chronic fetal hypoxia; Microglial activation; Myelination; Neurodevelopmental impairment; Placental progesterone; Progesterone supplementation

DOI:  https://doi.org/10.1016/j.bbi.2026.106531
Mol Neurobiol. 2026 Mar 14. pii: 499. [Epub ahead of print]63(1):

Lipid Messengers: Mechanisms and Clinical Applications of Exosomal Lipids in Neurodegenerative Diseases.

Yiyin Zhao, Minjie Pan, Songbin He, Xiaojing Zhou.

  Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, represent an escalating global health burden owing to their complex pathophysiology and limited therapeutic options. Exosomes, nanoscale extracellular vesicles (30-150 nm) capable of crossing the blood-brain barrier (BBB), have emerged as critical mediators of intercellular communication in the central nervous system. While research has predominantly focused on exosomal proteins and nucleic acids, the functional significance of exosomal lipids in neurodegeneration is increasingly recognized. This review outlines the biological characteristics of exosome lipids. Then, we focus on three core mechanisms: how lipid imbalance drives neuronal damage (including membrane dysfunction, lipid peroxidation, and mitochondrial energy crisis), how the lipid-mediated inflammatory network regulates microglial activation and BBB integrity, and how the lipid microenvironment affects the folding, aggregation, and cross-cell transmission of pathological proteins. Critically, these mechanisms form a mutually reinforcing vicious cycle, jointly driving the progression of the disease. Based on this framework, we have summarized the specific alterations of exosomal lipids in diseases such as Alzheimer's disease and Parkinson's disease. The clinical potential of exosomal lipids as liquid biopsy biomarkers and drug delivery carriers is discussed, alongside current challenges including technical standardization, heterogeneity analysis, and quantitative accuracy. A comprehensive understanding of exosomal lipid dynamics is essential for developing novel diagnostic and therapeutic strategies for neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Exosomal lipids; Lipidomic; Neurodegenerative diseases; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-026-05794-z
Mol Neurobiol. 2026 Mar 08. pii: 490. [Epub ahead of print]63(1):

β-hydroxybutyrate Modulates Neuroinflammatory Responses and Astrocyte Reactivity in an In Vitro Model of Traumatic Brain Injury.

Zuzanna Rauk, Patrycja Maciak, Zuzanna Setkowicz, Olga Barczyk-Woźnicka, Marek Romek, Grzegorz Tylko, Marcin Samiec, Małgorzata Duda.

  The ketogenic diet has attracted increasing interest for its potential neuroprotective effects, mediated by β-hydroxybutyrate (BHB), a ketone body influencing energy metabolism and inflammation. This study examined whether BHB supplementation modulates cellular responses to injury in an in vitro scratch model of traumatic brain injury (TBI). Primary cortical and hippocampal neuron-glia cultures derived from neonatal rats were maintained for 21 days in vitro (DIV). Cultures were supplemented with 5 mM BHB from DIV14 to DIV21. At DIV21, mechanical scratch injury was applied, and cellular responses were assessed 6 h and 24 h post-injury using live-cell migration imaging, Western blotting (GFAP, NeuN), cytokine profiling, immunocytochemistry, and electron microscopy. BHB supplementation was associated with increased astrocyte density in injured cortical and hippocampal cultures and with shifts in astrocyte morphology toward bipolar and intermediate phenotypes, suggesting modulation of astrocyte reactivity. In BHB-supplemented cortical cultures, neuronal density within the injury area was higher compared with non-supplemented controls. BHB reduced levels of the pro-inflammatory cytokine IL-1β and modulated the expression profiles of GM-CSF, IFNγ, and Neuropilin-1, in a region- and time-dependent manner. GFAP expression in hippocampal cultures displayed a biphasic response, indicating dynamic astrocyte regulation following injury. Ultrastructural analysis revealed injury-induced cellular alterations, while BHB-supplemented cultures exhibited features consistent with improved cellular integrity. Collectively, these findings suggest that BHB modulates astrocyte-associated inflammatory responses and supports cellular adaptation following mechanical injury in neuron-glia cultures. While limited to an in vitro setting, this study provides insight into potential mechanisms by which BHB may influence neuroinflammatory processes after TBI.

Keywords:  Astrocyte reactivity; Autophagy; Neuroinflammation; Primary neuron–glia cultures; Traumatic brain injury; β-hydroxybutyrate

DOI:  https://doi.org/10.1007/s12035-026-05759-2
Ageing Res Rev. 2026 Mar 10. pii: S1568-1637(26)00091-7. [Epub ahead of print] 103099

Oligodendrocyte Dysfunction in Alzheimer's Disease: Integrating Spatial Epigenomics and Metabolic Circuitry in Demyelination - A Critical Review.

Lian Jian, Yuqing Liu, Weijun Peng.

  Traditional Alzheimer's disease (AD) research has predominantly focused on neuronal pathology within the amyloid-tau-neurodegeneration (ATN) framework, emphasizing β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTS), and neuroinflammation as primary drivers of disease progression. Recently, converging evidence suggests that oligodendrocytes (OLs) and myelin abnormalities are not merely downstream consequences of neuronal injury. Instead, OL dysfunction may emerge early and actively shape disease trajectories. In this critical review, we synthesize findings from spatial epigenomics, metabolic circuitry analysis, single-nucleus RNA sequencing (snRNA-seq), and multimodal neuroimaging to reassess the OLs contributions to AD pathophysiology. We further summarizetherapeutic strategies that target OL dysfunction, including metabolic rescue approaches, epigenetic modulation, remyelination-oriented interventions, and approaches that suppress OL-derived Aβ. Overall, we propose an "OL epigenetic-metabolic axis" as an underappreciated pathological hub in AD. This framework challengesthe conventional victim-perpetrator narrative by repositioning OLs from passive casualties to context-dependent drivers and amplifiers of neurodegeneration. By clarifying how spatially patterned epigenetic dysregulation intersects with metabolic collapse to impair myelin integrity and axonal support, this review provides a rationale for developing innovative neuroprotective strategies aimed at OL repair, remyelination, and metabolic restoration.

Keywords:  Alzheimer's disease; Demyelination; Metabolic circuitry; Oligodendrocyte; Spatial epigenomics

DOI:  https://doi.org/10.1016/j.arr.2026.103099
Front Neurosci. 2026 ;20 1729102

Are neurodegenerative diseases late-onset neurodevelopmental disorders? Tracing the developmental origins of neuronal vulnerability.

Julian Cheron, Adrian Ranga, Jerome Bonnefont.

  Neurodegenerative diseases are traditionally viewed as age-associated conditions, characterized by distinct biochemical, cellular, and clinical features. However, emerging evidence suggests that their origins may trace back to much earlier stages of life. In this review, we synthesize insights from molecular genetics, developmental neurobiology, and systems neuroscience to examine the hypothesis that selective neuronal vulnerability can arise from developmental misprogramming. We explore how early-life processes-ranging from neurogenesis to synaptic maturation and circuit formation-can imprint long-lasting susceptibilities that manifest as degeneration decades later. Crucially, we highlight that many neurological disorders share early developmental commonalities that may predispose individuals to neurodegenerative vulnerability later in life. This is most apparent in familial forms of these diseases but may also emerge through embryonic or perinatal interactions with environmental or polygenic risk factors. Furthermore, we emphasize the importance of human-specific developmental features, which not only advance our understanding of brain formation but also reveal unique vulnerabilities to neurodegenerative diseases-insights that are increasingly accessible through advances in 3D organoid modeling. Together, these perspectives support a conceptual reframing of neurodegeneration as a late-onset neurodevelopmental disorder. This shift opens promising avenues for early diagnosis, prevention, and precision therapeutics, redirecting focus from late-stage intervention to fostering developmental resilience.

Keywords:  brain development; brain organoids; developmental misprogramming; human brain evolution; neurodegenerative diseases; selective neuronal vulnerability

DOI:  https://doi.org/10.3389/fnins.2026.1729102