bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2026–07–19
forty papers selected by
Regina F. Fernández, Johns Hopkins University
  1. The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
  2. Peroxisomal import is circadian in glia and regulates sleep and lipid metabolism.
  3. Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.
  4. Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
  5. Astrocytic lipid dysregulation as an early driver of neurodegeneration.
  6. Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
  7. Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1 H-MRS Following Oral Keto-Ester Consumption.
  8. Understanding molecular role of lipids for Alzheimer's disease.
  9. Insulin resistance and obesity: Drivers of energy crisis for Alzheimer's disease.
  10. Brain-specific ORP6 deficiency in mice disrupts systemic lipid metabolism and impairs hippocampal-dependent learning and memory.
  11. Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.
  12. Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.
  13. Enhanced Energy Metabolism and Developmental Signaling in Neonatal Brains of Female Piglets Parenterally Fed with 18-Carbon n-3 Fatty Acid-Based Vegaven Compared with Fish Oil-Containing Lipid Emulsion.
  14. Metabolic drivers of Alzheimer's disease pathogenesis: Impairments in glucose utilization, lipid homeostasis, and alternative substrate metabolism.
  15. Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.
  16. Therapeutic targeting of brain bioenergetics in Alzheimer's disease addressing insulin resistance, glucose hypometabolism, and mitochondrial dysfunction.
  17. 7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in a mouse model of Alzheimer's disease.
  18. Nutritional Strategies Targeting Glucose Metabolism to Slow Cognitive Ageing: A Scoping Review of Human Trials.
  19. FABP7: A Regulator of Neuro-Immune Metabolic Networks and Therapeutic Vulnerabilities in Glioma.
  20. Single-cell analysis of sterol-induced Ca2＋ signaling in human astrocytes by dynamic mode decomposition.
  21. "Cytochrome P450-Mediated Vitamin D and Cholesterol Metabolism in the Pathophysiology of Neurodevelopmental Disorders".
  22. Cerebral Glucose Hypometabolism in Alzheimer's Disease: A Meta-Analysis and Transcriptomic-Neuroimaging Study.
  23. Adults with Obesity and Hyperglycemia have Higher Arachidonic and Docosahexaenoic Acid in Subcutaneous Adipose Tissue.
  24. Serum lipidomics reveals class-specific lipid remodelling and altered acyl chain composition in Parkinson's disease.
  25. FDG-PET in Traumatic Brain Injury and Postconcussive Sequelae.
  26. Mitofusin-2 in ventral striatal D1 neurons regulates effort-based motivation through sex-specific mitochondrial-synaptic reprogramming.
  27. Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.
  28. Sterol biosynthesis, brain development, and disease.
  29. Brain mitochondria as key drivers of cognition and behaviour.
  30. Antidepressant Effects of L-Arginine and Its Role in Brain Energy Metabolism.
  31. Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
  32. Focused ultrasound blood-brain barrier opening reveals a paradoxical remote metabolic response in the primate brain.
  33. Lactylation drives oligodendrocyte differentiation and (re)myelination.
  34. Dithionite quenching of NBD-labeled lipids reveals artificial lipid droplet purity and neutral lipid surface accessibility.
  35. Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.
  36. Bioenergetic impairment-induced Tau acetylation: Converging pathways in Alzheimer's disease.
  37. VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.
  38. Limited contribution of the lactate receptor HCAR1 to exercise-induced behavioral and hippocampal adaptations.
  39. Longitudinal urine metabolomics predicts high-grade brain injury in very preterm infants.
  40. Association between elevated blood glucose level and brain injuries (IVH/WMI) in preterm infants.
  1. Mol Neurodegener. 2026 Jul 17.
    The complex lipidome as a driver of tissue-specific pathology in adrenoleukodystrophy.
    Stephan Kemp, Marc Engelen, Yorrick R J Jaspers.
      X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, encoding a peroxisomal membrane transporter required for the import of very-long-chain fatty acids (VLCFA) into peroxisomes for degradation. ABCD1 deficiency leads to VLCFA accumulation in plasma and tissues. The resulting disease has a highly variable clinical presentation. In males, this manifests as cerebral demyelination, progressive myelopathy, and adrenal insufficiency, alone or in combination. Women predominantly develop myelopathy, while cerebral disease and adrenal insufficiency are rare, occurring almost exclusively in cases of extreme X-inactivation skewing toward the mutant allele. The lipid-mediated mechanisms linking VLCFA accumulation to tissue-specific pathology remain incompletely understood. Here, we review evidence that VLCFA-containing complex lipids, rather than free VLCFAs alone, are central mediators of tissue-specific pathology in ALD and discuss the therapeutic implications of this lipid-centric perspective. VLCFAs are incorporated into a broad range of complex lipids, including phosphatidylcholines, lysophosphatidylcholines, cholesterol esters, triacylglycerols, sphingomyelins, ceramides, and plasmalogens. The degree of lipid dysregulation increases with acyl chain length and saturation. VLCFA-containing lipid species correlate with disease severity across all clinical phenotypes. In the brain, VLCFA-containing phosphatidylcholines accumulate before demyelination onset, cholesterol ester accumulation is associated with neuroinflammatory cascades, and plasmalogen depletion reflects early oxidative damage. In the spinal cord, VLCFA-containing myelin lipids are associated with non-inflammatory axonopathy, mitochondrial dysfunction, and microglial phagocytic activation. In the adrenal gland, VLCFA accumulation in cholesterol ester-rich lipid droplets impairs ACTH receptor signaling and sequesters cholesterol from steroidogenic pathways. Enzymatic regulators of VLCFA homeostasis, including ELOVL1, SCD1, and the omega-oxidation enzymes CYP4F2 and CYP4F3B, are potential therapeutic targets for substrate reduction. Plasma VLCFA-lipid profiles correlate with disease severity across all affected tissues, positioning lipidomic profiling as a potential clinical instrument for risk stratification and treatment monitoring. Secondary lipid mediators amplify primary VLCFA toxicity through distinct, cell-type-specific pathways. The near-exclusive occurrence of cerebral ALD and adrenal insufficiency in women with extreme X-inactivation skewing suggests that partial reduction of the VLCFA lipid burden, rather than complete normalization, may be sufficient to prevent severe disease manifestations. This has direct implications for substrate-reduction therapy development.
    Keywords:  Adrenal insufficiency; ELOVL1; Leukodystrophy; Lipidomics; Lysophosphatidylcholine; Myelopathy; Neuroinflammation; Substrate reduction therapy; Very-long-chain fatty acids; X-linked adrenoleukodystrophy
    DOI:  https://doi.org/10.1186/s13024-026-00975-9
  2. PLoS Biol. 2026 Jul 15. 24(7): e3003901
    Peroxisomal import is circadian in glia and regulates sleep and lipid metabolism.
    Anurag Das, Irma Magaly Rivas-Serna, Ankur Kumar, Lakpa Sherpa, Kerui Huang, Hia Kalita, Marlene Dorneich-Hayes, Ruiqi Liu, Vera C Mazurak, John P Vaughen, Hua Bai.
      Peroxisomes are critical organelles that detoxify cellular waste while also catabolizing and anabolizing lipids. How peroxisomes coordinate protein import and support metabolic functions across complex tissues and timescales remains poorly understood in vivo. Using the Drosophila brain, we discover a striking enrichment of peroxisomes in the neuronal soma and the cortex glia that enwrap them. Unexpectedly, import of peroxisomal proteins into cortex glia, but not neurons, oscillated across time and peaked in the early morning. Rhythmic peroxisomal import in cortex glia autonomously required the circadian clock and Peroxin 5 (Pex5; peroxisomal biogenesis factor 5 homolog), with import persistently elevated in clock mutants. Notably, reducing Pex5 in cortex glia, but not neurons, caused hyperactivity and reduced total sleep. Moreover, brain lipid metabolism was dramatically altered upon Pex5 knockdown, with glia impacting sphingolipids and triacylglycerols, and neurons impacting phospholipids. The cell-type specificity of these Pex5 phenotypes highlights unique roles for peroxisomal import in both sleep and lipid metabolism in the brain.
    DOI:  https://doi.org/10.1371/journal.pbio.3003901
  3. Alzheimers Dement (N Y). 2026 Jul-Sep;12(3):12(3): e70285
    Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E.
    Sara Badesso, María Espelosín, Cristina Alonso, Alejandro Montilla, Maria Collantes, Mar Cuadrado-Tejedor, Ana García-Osta.
       INTRODUCTION: Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.
    METHODS: The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APPNL-G-F AD mouse model using a translational gene-delivery approach with a blood-brain barrier-penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.
    RESULTS: PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.
    DISCUSSION: These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.
    Keywords:  Alzheimer´s disease; PLA2G4E; lipids; synaptic plasticity
    DOI:  https://doi.org/10.1002/trc2.70285
  4. Res Sq. 2026 Jul 06. pii: rs.3.rs-10105855. [Epub ahead of print]
    Neuronal Mitochondrial Dysfunction Drives Astrocytic Mitochondrial Transfer after TBI: Reveals the Therapeutic Potential of astrocytic EV-Mito.
    Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.
      Mitochondria are dynamic organelles essential for neuronal survival and synaptic function, and their dysfunction is a key consequence of excitotoxicity following traumatic brain injury (TBI). While intercellular mitochondrial transfer and exogenous mitochondrial transplantation have emerged as mechanisms to restore cellular bioenergetics, its in vivo relevance in the central nervous system remains incompletely understood. Here, we used astrocyte and neuron-specific mitochondrial reporters (GFP or Dendra2) in mice to assess cell-type-specific mitochondrial morphology, bioenergetics, and transfer 24hrs after TBI. Neurons exhibited marked mitochondrial dysfunction, including altered morphology and reduced bioenergetic capacity across somatic, synaptic, and non-neuronal fractions. In contrast, astrocytic mitochondria showed morphological changes but preserved bioenergetic function. Concomitantly, astrocyte-to-neuron mitochondrial transfer was significantly increased following injury, although transfer to synapses remained limited. Single-cell RNA sequencing of astrocytes revealed upregulation of genes involved in extracellular vesicle (EV) biogenesis and mitochondrial translation following injury compared to controls. In vitro co-culture studies confirmed that astrocytes transfer mitochondria to neurons via EVs containing mitochondria (EV-mito). Isolated EV-mito from astrocyte-conditioned media improves neuronal mitochondrial function under NMDA (N-methyl-D-aspartate) induced excitotoxic conditions. Together, these findings demonstrate that neuronal mitochondrial dysfunction drives astrocyte-mediated mitochondrial transfer as an adaptive neuroprotective response after TBI. This process preserves neuronal bioenergetics in the soma and neurites but not at synapses, highlighting both its therapeutic potential and spatial limitations.
    DOI:  https://doi.org/10.21203/rs.3.rs-10105855/v1
  5. Nat Rev Neurol. 2026 Jul 13.
    Astrocytic lipid dysregulation as an early driver of neurodegeneration.
    Woojin Scott Kim, Glenda M Halliday.
      Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.
    DOI:  https://doi.org/10.1038/s41582-026-01238-3
  6. Int J Mol Sci. 2026 Jul 07. pii: 6073. [Epub ahead of print]27(13):
    Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
    Ana Beatriz Ramos, Vanessa Alexandra Morais.
      Increasing evidence highlights a tight interplay between lipid metabolism and mitochondrial homeostasis in neurons, with disruptions in either pathway amplifying cellular vulnerability. PTEN-induced kinase 1 (PINK1), a familial Parkinson's disease (PD)-related gene and a key regulator of mitochondrial quality control and homeostasis, emerges at the intersections of lipid metabolic pathways, influencing membrane composition, fatty acid utilization, and neuronal energy balance. Within this review, we discuss the role of mitochondria as hubs for lipid metabolism, the mechanisms and functional consequences of neuronal lipid handling, and the complex bidirectional relationship between lipid dysregulation and PD pathology. Special focus is given to lipid-mitochondria crosstalk and how PINK1 orchestrates this interface to maintain neuronal homeostasis. Finally, we consider therapeutic perspectives that target lipid and mitochondrial pathways, highlighting strategies to restore cellular function and PD pathology.
    Keywords:  PINK1; Parkinson’s disease; lipids; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms27136073
  7. bioRxiv. 2026 Jul 09. pii: 2026.07.04.736442. [Epub ahead of print]
    Challenges and Solutions in Quantifying Brain β-Hydroxybutyrate (BHB) with 1 H-MRS Following Oral Keto-Ester Consumption.
    Mansimran Virk, Kennedy T Connors, Razi Kitaneh, Marcella M Mignosa, Scott McIntyre, Terence W Nixon, Kelly DeMartini, Stephanie O'Malley, John H Krystal, Henk M De Feyter, Gustavo A Angarita, Graeme F Mason, Robin A de Graaf, Chathura Kumaragamage.
       Purpose: β-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy ( 1 H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study.
    Methods: Two separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite.
    Results: Brain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations (∼0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal.
    Conclusions: Separate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.
    DOI:  https://doi.org/10.64898/2026.07.04.736442
  8. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00098-7. [Epub ahead of print]153 191-210
    Understanding molecular role of lipids for Alzheimer's disease.
    Riddhi Upadhyay, Gowshika Velmurugan, Deena Krishnan, R Sivasamy, Murugan Sevanan, Subashchandrabose Chinnathambi.
      Human health and neurological functions are significantly impacted by lipids, the fundamental building block of cell membranes. The central nervous system is rich in lipids, and they are evidently disturbed in neurological conditions and neurodegenerative diseases like Alzheimer's disease (AD). Alteration in lipid profile is highly linked with aging. During early onset of AD, there is a noted lipid peroxidation and modifications of fatty acids at the level of lipid rafts in the neuronal cells. AD is an age-linked neurodegenerative condition with multifaceted etiology, with combining genetic and environmental risk factors, which lacks disease-modifying therapies. While the aberrant deposition of lipids was shown in the initial studies of AD neuropathology. Clinically, lipidomic and metabolomic research have constantly exposed the changes in the levels of various lipid classes emerging in early onset of AD individuals. Also, decades of investigations have discovered multifactorial link between lipid metabolism and key AD pathogenic pathway such as amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. Herewith, we highlighted the features that impact lipid composition in neuronal cells, and the association of different lipids with known aspects of AD pathogenesis, and potential therapeutics that aim lipid crossroads.
    Keywords:  Aging; Alzheimer’s disease; Fatty acids; Lipid raft; Lipids; Tau
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.011
  9. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00048-6. [Epub ahead of print]187 39-90
    Insulin resistance and obesity: Drivers of energy crisis for Alzheimer's disease.
    Pooja Singh, Bhupesh Vaidya, Pallavi Upadhayay, Shyam Sunder Sharma, Ashok Kumar Datusalia.
      Alzheimer's disease (AD) is increasingly recognized as a disorder driven not only by classical neuropathological hallmarks but also by profound disturbances in brain energy metabolism. Growing evidence points to insulin resistance and obesity as major contributors to this metabolic crisis, linking peripheral metabolic dysfunction to central neurodegenerative processes. This chapter explores AD in the light of bioenergetic failure, highlighting the epidemiological and mechanistic connections between impaired insulin signaling, excess adiposity, and cognitive decline. The chapter further highlights how obesity-related inflammation, adipokine imbalance, and gut-brain axis dysregulation accelerates central insulin resistance and neuronal vulnerability. Evidence for glucose hypometabolism, mitochondrial failure, and disrupted astrocyte-neuron metabolic coupling in AD is reviewed, positioning amyloid and tau pathology as downstream consequences of sustained energy insufficiency. Finally, emerging therapeutic strategies aimed at restoring metabolic balance ranging from insulin-based interventions to lifestyle and mitochondria-targeted approaches are discussed, underscoring the potential of metabolic restoration as a disease-modifying strategy in Alzheimer's disease.
    Keywords:  Alzheimer’s Disease; Brain Energy Metabolism; Insulin Resistance; Mitochondrial Dysfunction; Obesity
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.018
  10. Neurosci Lett. 2026 Jul 11. pii: S0304-3940(26)00182-5. [Epub ahead of print]884 138682
    Brain-specific ORP6 deficiency in mice disrupts systemic lipid metabolism and impairs hippocampal-dependent learning and memory.
    Arlette A Kasongo, Benjamin Bhunu, Dominique M Boucher, Viyashini Vijithakumar, Salah Hussein Aly, Christina Emerton, Maxime W C Rousseaux, Diane C Lagace, Mireille Ouimet.
      Cholesterol homeostasis in the central nervous system is essential for neuronal health and cognitive function. Among the oxysterol-binding protein (OSBP)-related proteins (ORPs), a conserved family of lipid transfer proteins, ORP6 has emerged as a brain-enriched isoform with potential roles in metabolic regulation and neuroprotection.Here, we generated a brain-specific Osbpl6 conditional knockout (Osbpl6Δbrain) to investigate its contribution to lipid metabolism and brain function. Loss of ORP6 in the brain lead to increased body weight and higher total cholesterol, driven primarily by increased low-density lipoprotein (LDL) cholesterol.Within the brain, Osbpl6Δbrain mice displayed elevated levels of amyloid beta oligomers (AβO) and impaired hippocampal-dependent learning and memory, as assessed by the Morris water maze and contextual fear conditioning. Together, these results identify brain ORP6 as a key regulator of lipid homeostasis, underscoring its essential role in maintaining cholesterol balance and protecting cognitive function.
    Keywords:  Amyloid beta; Cognition; Lipid metabolism; Oxysterol-bindingprotein-like6
    DOI:  https://doi.org/10.1016/j.neulet.2026.138682
  11. Mol Metab. 2026 Jul 16. pii: S2212-8778(26)00105-5. [Epub ahead of print] 102421
    Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.
    Sebastian F Salathe, Benjamin A Kugler, Edziu Franczak, Xin C Davis, Frederick B Boakye, Julie Allen, Kyle L Fulghum, Eric D Queathem, E Matthew Morris, Patrycja Puchalska, Peter A Crawford, John P Thyfault.
      Ketone body metabolism is linked to brain health benefits, including delaying age-related cognitive decline. Exercise, particularly when combined with an overnight fast, stimulates ketone body turnover and improves brain metabolism and cognition. Yet, whether ketone metabolism is obligatory for this response is unknown. Here, we use chronic exercise via voluntary wheel running plus time-restricted feeding (VWR+TRF) to explore whether ketones mediate exercise-induced brain health benefits in middle-aged mice. To distinguish the roles of neuronal ketone metabolism vs. hepatic ketone production, we studied middle-age female neuronal-specific SCOT knockout mice and hepatocyte-specific HMGCS2 knockout mice, respectively. VWR+TRF was compared to sedentary ad-libitum fed mice to assess the impact on whole-body metabolism, cognition, and hippocampal molecular adaptations. VWR+TRF upregulated systemic lipid oxidation in all mice during the fasting period. In female SCOT-Neuron-KO mice, we show impaired responses to VWR+TRF in indices of short- and long-term memory. Proteomic analysis of isolated hippocampi revealed that SCOT-Neuron-KO mice failed to globally upregulate key facilitators of synaptic function, including leucine-rich repeated transmembrane proteins, neurexins, and neuroligins. In female HMGCS2-Liver-KO mice, impaired responses to VWR+TRF in indices of short-term memory were paired with an upregulation in hippocampal ketogenesis machinery, suggesting potential in vivo evidence of cerebral ketogenesis, a mechanism mitigating an otherwise more pronounced behavioral phenotype. Together, these findings suggest that neuronal ketone body utilization is essential for, while hepatic-derived ketone bodies contribute to, the full cognitive and synaptic adaptations to VWR+TRF, supporting ketone metabolism as a key mechanistic link between metabolic state and brain health in midlife.
    Keywords:  Ketogenesis; Learning; Lipid Metabolism; Memory; Mitochondria; Voluntary Wheel Running
    DOI:  https://doi.org/10.1016/j.molmet.2026.102421
  12. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00027-9. [Epub ahead of print]187 281-330
    Metabolic reprogramming in Alzheimer's disease: Interaction between receptor tyrosine kinase signaling, noncoding RNAs, and Neuron-Glia energy networks.
    Ankita Karmakar, Puja Roycowdhury, Priyanka Sengupta, Debashis Mukhopadhyay.
      Alzheimer's disease (AD) is increasingly understood as a disorder involving impaired brain energy metabolism rather than being solely caused by amyloid and tau pathology. This chapter offers a comprehensive overview of how glucose hypometabolism, mitochondrial dysfunction, and disrupted neuron-astrocyte metabolic coupling collectively creates an "energy crisis" in vulnerable neuronal circuits. Early issues with glucose transport (GLUT1/3/4), reduced glycolytic flux, TCA cycle problems, and excessive mitochondrial fission all contribute to decreased ATP production and increased oxidative stress. Along with these metabolic disturbances, receptor tyrosine kinase (RTK) pathways-including insulin/IGF-1, TrkB/BDNF, FGFRs, and EGFR-lose their regulatory control, leading to insulin resistance, synaptic failure, and increased vulnerability to Aβ and tau toxicity. The chapter also highlights noncoding RNAs (miRNAs and lncRNAs) as key post-transcriptional regulators of metabolic and RTK signaling networks. Harmful miRNAs (such as miR-34a, miR-210-3p) suppress glycolytic enzymes and mitochondrial genes, while protective miRNAs (miR-23a/b, miR-455-3p, miR-195) decrease in AD. Metabolic lncRNAs, like EPB41L4A-AS1, decline with age and contribute to NAD⁺ depletion and bioenergetic imbalance. Recognizing the link between RTK dysregulation and ncRNA-driven metabolic control reveals new therapeutic possibilities to restore mitochondrial function, enhance neurotrophic support, and re-establish energy balance in the AD brain.
    Keywords:  Alzheimer’s disease; Metabolism; Mitochondrial dysfunction; NcRNA; RTK
    DOI:  https://doi.org/10.1016/bs.irn.2026.02.007
  13. Curr Dev Nutr. 2026 Jul;10(7): 109400
    Enhanced Energy Metabolism and Developmental Signaling in Neonatal Brains of Female Piglets Parenterally Fed with 18-Carbon n-3 Fatty Acid-Based Vegaven Compared with Fish Oil-Containing Lipid Emulsion.
    Eliana Lucchinetti, Phing-How Lou, Fulin Wang, Mirielle L Pauline, Mahabub Alam, Pamela R Wizzard, Zain Patel, Qiumin Tan, Patrick N Nation, Catherine J Field, Eytan Wine, Stefanie D Krämer, Paul W Wales, Justine M Turner, Michael Zaugg.
       Background: Vegaven, an intravenous lipid emulsion based on 18-carbon n-3 (ω-3) fatty acids, reduces the accumulation of lipopolysaccharide (LPS) in peripheral organs including the brain of parenterally fed piglets compared with fish oil-containing SMOFlipid. Inflammation may impair brain energy metabolism and growth signaling.
    Objectives: This study aimed to compare key brain metabolic and developmental signaling pathways with the use of different lipid emulsions for parenteral nutrition (PN).
    Methods: In this study, 3-4-d-old female piglets were randomly assigned to isocaloric isonitrogenous PN with Vegaven (VEGA, N = 10) or SMOFlipid (SMOF, N = 9). After 14 d of PN, plasma and tissue samples were collected.
    Results: LPS and tumor necrosis factor-α were lower in brain tissue samples (prefrontal cortex) of VEGA compared with SMOF. Brain pyruvate dehydrogenase activity and the ketone body β-hydroxybutyrate in both liver and brain were higher in VEGA. In contrast, there was higher phosphorylation and activation of adenosine 5'-monophosphate-activated protein kinase (pThr172AMPK), a sensor of energy stress and master regulator of catabolic metabolic pathways, in brain samples of SMOF without compensatory increase in fatty acid oxidation. Anabolic signaling in the brain was higher in VEGA compared with SMOF, as indicated by higher insulin receptor substrate-1 and Akt-substrate of 160 kDa abundance, and higher phosphorylation of mammalian target of rapamycin (pSer2448mTOR), essential for axon growth, dendrite arborization, and memory function. The transcription factors cAMP-response-element-binding-protein-1 (pSer133CREB1) and c-Jun, critical for brain development, showed higher nuclear abundance in brain samples of VEGA compared with SMOF.
    Conclusions: In neonatal brains of parenterally fed female piglets, Vegaven reduced inflammation and enhanced energy metabolism and developmental signaling compared with SMOFlipid.
    Keywords:  c-Jun; cAMP-response-element-binding-protein-1; energy metabolism; female sex; insulin; lipid emulsions; lipopolysaccharide; parenteral nutrition; stearidonic acid; α-linolenic acid
    DOI:  https://doi.org/10.1016/j.cdnut.2026.109400
  14. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00049-8. [Epub ahead of print]187 349-383
    Metabolic drivers of Alzheimer's disease pathogenesis: Impairments in glucose utilization, lipid homeostasis, and alternative substrate metabolism.
    Shiva Chaudhary, Shreya Verma, Vidisha Kumari, Meghana Tare.
      Alzheimer's disease (AD) is one of the widespread neurodegenerative disorders, marked by the accumulation of amyloid-β plaques, neurofibrillary tangles of hyperphosphorylated Tau protein, and the gradual loss of neurons. While genetic and environmental factors have been associated with its onset, metabolic dysfunction has also been identified as one of the initial and most significant contributors its pathogenesis. The mitochondria are at the centre of this problem; their compromised function affects some crucial aspects of the neuronal health. Neurons have high energy demands so they are quite sensitive to the changes in the supply of the fuel. During AD pathogenesis, the loss of glucose transporters and the downregulation of key glycolytic enzymes deprives neurons of essential energy reserve. This metabolic dysregulation is further exacerbated by dysregulated lipid metabolism, pathological lipid droplet accumulation and ApoE4-driven failures in lipid trafficking which collectively leads to the oxidative stress, neuroinflammation, and Aβ aggregation. This situation is further aggravated by amino acid imbalances specifically within the glutamate-glutamine cycle. To counter this, ketone bodies have emerged as an alternative fuel source, capable of partially bypassing the impaired glucose oxidation while also demonstrating neuroprotective properties. Moreover, systemic metabolic disorders including type 2 diabetes mellitus, insulin resistance, obesity, and metabolic syndrome significantly amplify these deficits, functioning as major risk factors for AD onset and progression. Even the gut-brain axis plays a role in adding to the complexity. Taken together, these metabolic health changes not only reshape our understanding of AD but also open potential prospects for early detection through metabolic biomarkers and for novel therapeutic strategies targeting mitochondrial bioenergetics, glucose restoration, and ketogenic interventions.
    Keywords:  Alzheimer’s disease; Glucose metabolism; Ketone bodies; Lipid droplets; Metabolism; Mitochondria; β-oxidation
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.019
  15. Int J Mol Sci. 2026 Jul 06. pii: 6066. [Epub ahead of print]27(13):
    Energy Homeostasis Disruption in Neurological Disorders: Mitochondrial Dysfunction, High-Energy Phosphate Transfer, and Extracellular ATP-Dependent Purinergic Dysregulation.
    Hirotaka Tao, Koichi Fujisawa.
      Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK-AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer's disease, Parkinson's disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation.
    Keywords:  energy homeostasis; extracellular ATP-dependent purinergic dysregulation; glia-dependent inflammation; high-energy phosphate transfer; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms27136066
  16. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00033-4. [Epub ahead of print]187 91-132
    Therapeutic targeting of brain bioenergetics in Alzheimer's disease addressing insulin resistance, glucose hypometabolism, and mitochondrial dysfunction.
    Jatin Jangra, Isha Mahindru, Rajnish Kumar.
      Alzheimer's disease (AD) is a progressive, age-associated multifactorial neurodegenerative disorder characterised by cognitive decline, synaptic dysfunction, and neuronal loss. Despite over a century of research, effective disease-modifying therapies remain elusive owing to its conundrum pathophysiology. In recent years, AD is increasingly recognised as a complex metabolic disorder characterised by impaired cerebral glucose metabolism, insulin resistance, and mitochondrial dysfunction. These interconnected metabolic disturbances emerge early in the disease state and collectively potentiate other pathologies such as accumulation of amyloid-β (Aβ) plaques, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction, thereby establishing bioenergetic failure as a primary factor governing AD progression rather than a downstream phenomenon. While traditional drug development strategies targeting Aβ have failed in clinical trials (limited to monoclonal antibodies), emerging therapeutic models integrating energy failure, thiamine signalling, and insulin-like growth factor (IGF) signalling as upstream events show significant promise in countering downstream neurodegeneration. This chapter summarises the mechanistic framework linking bioenergetic breakdown to AD pathology, with potential therapeutic opportunities aimed at restoring mitochondrial function, enhancing glucose utilisation, and correcting insulin signalling, further opening new avenues for multimodal interventions and identification of progressive metabolic dysfunction biomarkers to aid diagnostic processes.
    Keywords:  Alzheimer’s disease; Brain bioenergetics; Glucose metabolism; Insulin resistance; Mitochondrial dysfunction; Type 3 diabetes
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.005
  17. Sci Rep. 2026 Jul 14.
    7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in a mouse model of Alzheimer's disease.
    Kayalvizhi Radhakrishnan, Yiyu Zhang, Oluwaseun Mustapha, Thaddeus K Weigel, Clint M Upchurch, Xiaodong Tian, Franklin Herbert, Wenyuan Huang, Norbert Leitinger, Ukpong B Eyo, Huiwang Ai, Heather A Ferris.
      Oxidative stress is a prominent feature of Alzheimer's disease (AD). Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we showed that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. When 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC and reduced reactive oxygen species in astrocytes. Taken together, these findings suggest that 7-KC, via microglia activation, contributes to increased astrocyte oxidative stress in the 3xTg mouse model of AD. This study contributes to understanding one of the drivers of the vicious cycle of oxidative stress seen in mouse models of AD whereby increased reactive oxygen species drive cholesterol oxidation, resulting in additional oxidative stress.
    Keywords:  7-ketocholesterol; Alzheimer’s disease; Astrocytes; Cholesterol; Genetically encoded sensor; Microglia; ROS sensor; Reactive oxygen species
    DOI:  https://doi.org/10.1038/s41598-026-61753-7
  18. Am J Clin Nutr. 2026 Jul 15. pii: S0002-9165(26)00243-1. [Epub ahead of print] 101434
    Nutritional Strategies Targeting Glucose Metabolism to Slow Cognitive Ageing: A Scoping Review of Human Trials.
    Malika G Fernando, Kirstin Sullivan, Mary Simons, Alexia Squillace, Hosen Kiat, Ralph N Martins.
      Cerebral glucose hypometabolism is a hallmark of cognitive aging and Alzheimer's Disease (AD), underscoring the need for nutritional strategies that support brain energy metabolism. This scoping review synthesized evidence from human interventions evaluating alternative energy substrates and nutrients that support cerebral energy metabolism and their effects on cognition in older-adults. The review followed PRISMA-ScR guidelines. MEDLINE, EMBASE, and Scopus were searched for studies published during 2014-2024, involving adults aged ≥60 years, with Mild Cognitive Impairment (MCI), AD, subjective cognitive decline, or normal cognition. Thirty-two studies were included, investigating Medium Chain Triglycerides (MCTs), ketogenic diets, omega-3 fatty acids, amino acids, histidine-containing dipeptides, serotonin precursors, and dietary fat modification. Cognitive outcomes were global and domain-specific measures including memory, executive function, and attention, while other outcomes included functional capacity, neuroimaging markers, inflammation, mood, and quality-of-life. Omega-3 supplementation showed mixed evidence with cognitive benefits reported particularly in MCI populations receiving higher DHA doses and longer intervention durations (≥1 g/day, ≥6 months). Ketogenic/MCT-based strategies improved cognitive function in MCI and early-AD, with effects tied to plasma ketone levels; however, benefits were not consistently observed. Limited evidence suggested that anserine/carnosine supplementation may improve verbal memory and executive function, particularly in adults aged ≥70 years and APOE4 carriers. L-arginine improved global cognition in frail hypertensive older-adults, while tryptophan and amino acid interventions demonstrated domain-specific or age-dependent effects, rather than consistent improvements. Findings were heterogeneous across interventions and populations. Cognitive benefits were most evident in early disease-stages, with sufficient dosing and adherence. Several studies reported favourable biomarker, inflammatory, metabolic, or quality-of-life outcomes despite limited cognitive effects. Overall, nutritional strategies targeting brain energy metabolism show promise for supporting cognitive health. However, substantial heterogeneity, small sample sizes, short intervention durations, and inconsistent cognitive outcomes limit the strength of the evidence. Future research should prioritise biomarker-based, longer-term, and multimodal approaches to clarify efficacy and clinical applicability.
    Keywords:  Alternative energy substrates; Alzheimer’s disease; cognitive impairment; dementia; ketogenic diets; omega-3 supplementation
    DOI:  https://doi.org/10.1016/j.ajcnut.2026.101434
  19. Cancers (Basel). 2026 Jun 23. pii: 2029. [Epub ahead of print]18(13):
    FABP7: A Regulator of Neuro-Immune Metabolic Networks and Therapeutic Vulnerabilities in Glioma.
    Yool Lee, Yeena Kee, Sukanya Bhoumik, Carlos C Flores, Jorge Zepeda-Reyes, Dylan A Nasinec, Peyton Burpee, Monte Schell, Yuji Owada, Jason R Gerstner.
      Fatty acid-binding protein 7 (FABP7) is a multifunctional lipid chaperone that is enriched in radial glia and astrocytes within the central nervous system (CNS) and is frequently upregulated in glioma. Beyond its established roles in glial development, lipid homeostasis, and circadian regulation, growing evidence positions FABP7 at the intersection of tumor metabolism, neuronal activity, and immune modulation in the brain. In this review, we integrate the physiological functions of FABP7 in glial cells with its tumor-intrinsic and microenvironmental roles in glioma. We summarize how gliomas co-opt FABP7-dependent metabolic, transcriptional, and post-transcriptional programs to promote stemness, lipid remodeling (e.g., altered fatty acid composition, lipid droplet formation, and lipid peroxidation resistance), inflammatory signaling, and invasive growth, including nuclear FABP7-mediated transcriptional activation linked to oncogene status. Furthermore, we discuss the role of FABP7 in shaping the tumor-neuro-immune interface, including regulating immunosuppressive gene networks, pro-tumoral macrophage polarization, resistance to T-cell-induced ferroptosis and immunotherapy, and tumor microtube-mediated integration into neuronal circuits to support glioma progression. Finally, we highlight therapeutic opportunities and challenges, including small-molecule FABP7 inhibitors, brain-directed delivery strategies, chronotherapeutic considerations, and combination approaches with immunotherapy. Collectively, this work positions FABP7-centered metabolic, circadian, and neuro-immune networks as potential vulnerabilities in glioma, linking fundamental glial biology to glioma therapeutics.
    Keywords:  FABP7; cancer immunotherapy; glioma; lipid metabolism; post-transcriptional regulation; tumor microenvironment; tumor microtubes
    DOI:  https://doi.org/10.3390/cancers18132029
  20. Cell Calcium. 2026 Jul 09. pii: S0143-4160(26)00060-6. [Epub ahead of print]136 103167
    Single-cell analysis of sterol-induced Ca2＋ signaling in human astrocytes by dynamic mode decomposition.
    Miklas P W Larsen, Line Lauritsen, Amanda T Pauli, Rasmus Jensen, Ralf Zimmermann, Max Lehmann, Pablo Wessig, Daniel Wüstner.
      Ca2＋ signaling in astrocytes is a central mechanism of intercellular communication in the brain and plays a key role in regulating neuronal excitability, synaptic plasticity, and energy metabolism. Disruption of astrocytic Ca2＋ dynamics is a characteristic of neurodegenerative diseases, as are deviations in cholesterol trafficking and metabolism, which are essential for maintaining membrane structure and function. Although recent studies have begun to explore links between Ca2＋ signaling and sterol homeostasis in astrocytes, unbiased analytical workflows and mechanistic insight into how cholesterol and related sterols regulate astrocytic Ca2＋ dynamics remain limited. Here, we apply dynamic mode decomposition to dissect and classify Ca2＋ signals obtained from time-lapse imaging of human astrocytes. Using both synthetic and experimental datasets, we show that delay-embedded dynamic mode decomposition combined with clustering separates heterogeneous Ca2＋ activity into distinct dynamical states. This analysis reveals that increasing cholesterol levels shift astrocytes toward more active oscillatory states, whereas acute cholesterol depletion suppresses Ca2＋ activity. In addition, pretreatment with the oxysterols 24-, 25-, and 27-hydroxycholesterol impaired cholesterol-induced Ca2＋ oscillations. Together, this work presents a general computational framework for decomposing and analyzing complex spatiotemporal Ca2＋ signals, with broad applicability to quantitative imaging in cell biology.
    Keywords:  Astrocytes; Calcium imaging; Clustering; Dynamic mode decomposition; Fluorescence; Microscopy; Signaling
    DOI:  https://doi.org/10.1016/j.ceca.2026.103167
  21. J Steroid Biochem Mol Biol. 2026 Jul 17. pii: S0960-0760(26)00153-6. [Epub ahead of print] 107087
    "Cytochrome P450-Mediated Vitamin D and Cholesterol Metabolism in the Pathophysiology of Neurodevelopmental Disorders".
    Balachandar Vellingiri, Masako Kinoshita, Ajay Elangovan, Bhawna Dahiya, Nitin Kumar, Deenathayalan Uvarajan, Hiroya Ohara, Siva Sundara Kumar Durairajan, Zothan Siama, Arul Narayanasamy, Dharmendra Kumar Khatri, Dibbanti HariKrishnaReddy, Arvinder Wander, Mahalaxmi Iyer.
      Cytochrome P450 (CYP450) enzymes play critical roles in the pathophysiology of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), Rett syndrome (RTT), and attention-deficit/hyperactivity disorder (ADHD). Although traditionally associated with hepatic and intestinal xenobiotic metabolism, several CYP450 isoforms are expressed in the central nervous system, where they regulate essential pathways involving vitamin D and cholesterol-two molecules fundamental to neural development, synaptogenesis, and membrane homeostasis. The cholesterol-CYP27A1-27-hydroxycholesterol (27-OHC)-liver X receptor (LXR) axis has emerged as a critical regulator of neurodevelopment, influencing INSIG proteins, LXRs, and LDL receptors. Additionally, members of the CYP1A, CYP2B, CYP2C, and CYP3A families contribute to neuroendocrine balance and fetal brain maturation. Dysregulation of these pathways may contribute to synaptic dysfunction, neuronal hyperexcitability, and metabolic imbalance observed in NDDs. This review highlights the interplay between CYP450 enzymes, vitamin D metabolism, and cholesterol homeostasis, emphasizing their mechanistic relevance in ASD and related disorders, and discusses the therapeutic potential of targeting CYP450-mediated pathways to restore metabolic and neurodevelopmental equilibrium.
    Keywords:  27-hydroxycholesterol; Cholesterol homeostasis; Cytochrome P450; Neurodevelopmental disorders; Oxysterols; Vitamin D metabolism
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.107087
  22. Curr Alzheimer Res. 2026 Jul 08.
    Cerebral Glucose Hypometabolism in Alzheimer's Disease: A Meta-Analysis and Transcriptomic-Neuroimaging Study.
    Chu-Xin Huang, Yi Pan, Han Xiao, Jing-Hang Wang, Jun Liu.
       INTRODUCTION: Cerebral glucose hypometabolism is known to occur in Alzheimer's Disease (AD). However, the spatial pattern of these metabolic alterations remains inconsistent across studies, and the molecular mechanisms linking regional metabolic vulnerability to gene expression profiles are poorly understood, thus highlighting the neuroimaging-transcriptomics gap.
    METHODS: We performed a coordinate-based meta-analysis of 18F-fluorodeoxyglucose positron emission tomography data from 17 studies. This involved 888 AD individuals and 529 healthy controls. Spatial correlation analysis of metabolic alterations and transcriptomic gene data from the Allen Human Brain Atlas was performed. Enrichment analysis was conducted to explore biological processes associated with the identified genes.
    RESULTS: Compared with healthy controls, AD patients showed significant glucose hypometabolism in regions including the bilateral precuneus, median cingulate/paracingulate gyri, posterior cingulate gyri, angular gyri, inferior parietal gyri, supramarginal gyri, middle occipital gyri, middle temporal gyri, inferior temporal gyri, the left inferior frontal gyrus (triangular part), and anterior cingulate/ paracingulate gyrus. Spatial correlation analysis revealed that these changes were correlated with 2,701 genes. The identified genes were mainly involved in biological processes such as the DNA metabolic process, chromatin remodeling, chromatin/kinase binding, and mitochondrion organization.
    DISCUSSION: The meta-analysis and transcriptomic-neuroimaging study revealed consistent patterns of brain metabolism and AD-associated gene sets. We also identified related biological processes. These results link microscale gene expression to macroscale glucose hypometabolism and offer new mechanism perspectives.
    CONCLUSION: This study maps AD-related glucose hypometabolism to specific transcriptional profiles, providing novel insights into the molecular basis of metabolic alterations in AD.
    Keywords:  Allen human brain atlas; Alzheimer’s disease; FDG-PET; glucose metabolism; meta-analysis
    DOI:  https://doi.org/10.2174/0115672050470646260624045159
  23. J Lipid Res. 2026 Jul 17. pii: S0022-2275(26)00136-7. [Epub ahead of print] 101106
    Adults with Obesity and Hyperglycemia have Higher Arachidonic and Docosahexaenoic Acid in Subcutaneous Adipose Tissue.
    Sabrina Ziai, Mihir Parikh, Narjes Mosavari, Ruxandra D Rotarescu, Chuck T Chen, Richard P Bazinet, André Tchernof, Anthony J Hanley, Adam H Metherel, Jacqueline L Beaudry.
      In obesity, fatty acid (FA) accumulation may impair AT function, promoting insulin resistance and development of type 2 diabetes mellitus (T2DM). However, the contribution of visceral AT (VAT) and subcutaneous AT (SAT) specific FAs to metabolic dysregulation in obesity and T2DM remains unclear, highlighting the importance of examining the FA composition between AT depots. This study examined differences in FA profile and lipid fractions across AT depots in individuals with obesity and hyperglycemia. The primary focus was on polyunsaturated fatty acids (PUFAs) given their relevance to cardiometabolic health. Thirty participant-matching VAT and SAT samples from bariatric surgery donors (BMI ≥ 30 kg/m2) were examined and were further stratified into groups of fasted normoglycemia or hyperglycemia. For the total FA profile, the concentrations (μmol/g) of arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were higher in the SAT compared to VAT depot; ARA and DHA concentrations were higher in the hyperglycemia compared to normoglycemia group. Further analysis in six different lipid fractions including triacylglycerol, diacylglycerol, monoacylglycerol, free fatty acids, phospholipid and cholesteryl esters exhibited similarly higher ARA, EPA, and DHA in the SAT compared to VAT depot. However, differences between normoglycemia and hyperglycemia groups were fraction- and FA-specific, rather than uniform across all lipid classes. These results demonstrate that VAT and SAT depots differentially store FAs as a function of glycemic status in obesity, highlighting distinct differences in PUFA metabolism and availability that may have important implications for AT function and metabolic health.
    Keywords:  Eicosapentaenoic acid; Fatty Acid Metabolism; Lipids; Omega-3 fatty acids; Phospholipids; Triacylglycerol
    DOI:  https://doi.org/10.1016/j.jlr.2026.101106
  24. Parkinsonism Relat Disord. 2026 Jul 09. pii: S1353-8020(26)00252-X. [Epub ahead of print]150 108425
    Serum lipidomics reveals class-specific lipid remodelling and altered acyl chain composition in Parkinson's disease.
    Jack Price, Mari Muldmaa, Katrin Sikk, Pille Taba, Luke Whiley, Sulev Kõks.
       BACKGROUND: Lipid metabolism is increasingly implicated in Parkinson's Disease (PD) pathology, yet the specific lipid classes and acyl chain compositions involved, and their relationship with PD clinical symptoms, remain poorly characterised.
    OBJECTIVES: We aimed to identify serum lipid signatures that differentiate people with PD (PwPD) from healthy controls and to evaluate associations with levodopa-induced dyskinesia (LID).
    METHODS: Serum collected from 58 PwPD and 58 age- and sex-matched non-PD controls was analysed using targeted liquid chromatography - mass spectrometry (LC-MS). Group differences were assessed using univariate and multivariate approaches. Logistic regression was used to identify lipids associated with LID among PwPD.
    RESULTS: Significantly lower levels of glycerolipids and glycerophospholipids were observed in PwPD compared to controls, alongside higher levels of lysophosphatidylethanolamines (LPE) and lysophosphatidylcholines (LPC). Analysis of individual lipid species revealed a lipid remodelling of the acyl chain composition of glycerolipids and glycerophospholipids, with decreased esterified arachidonic, adrenic, docosapentaenoic, and docosahexaenoic acids. Non-esterified arachidonic acid (p = 5.80e-6) and eicosapentaenoic acid (p = 3.65e-10) were elevated in PwPD. In secondary analyses, no lipids discriminated between PwPD with and without LID; however, these models were constrained by modest subgroup sizes and clinical heterogeneity between groups, limiting conclusions regarding lipid-based discrimination of LID status.
    CONCLUSIONS: These findings demonstrate disease-associated remodelling of acyl chain composition across multiple lipid classes in PD, particularly selective depletion of esterified polyunsaturated fatty acids from glycerolipids and glycerophospholipids. Replication in independent cohorts is warranted to establish whether these pathways represent viable therapeutic targets.
    Keywords:  Arachidonic acid; Glycerolipids; Glycerophospholipids; Levodopa-induced dyskinesia; Lipidomics; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.108425
  25. PET Clin. 2026 Jul 17. pii: S1556-8598(26)00051-9. [Epub ahead of print]
    FDG-PET in Traumatic Brain Injury and Postconcussive Sequelae.
    Rizwan Naseer, Melika Mirbod, Yousr Hasan, Abass Alavi, Cyrus Ayubcha.
      Traumatic brain injury (TBI) produces complex and evolving metabolic disturbances that are not fully captured by structural imaging. 2-deoxy2-(18F)fluoro-d-glucose ([18F]FDG) PET provides critical insight into these changes, demonstrating an initial hypermetabolic phase followed by chronic hypometabolism associated with injury severity and clinical outcomes. Repetitive TBI results in widespread metabolic dysfunction across key brain regions. While tau and amyloid PET imaging offer mechanistic insights, their clinical utility remains limited due to inconsistent findings. [18F]FDG PET currently represents the most reliable imaging modality for assessing TBI-related metabolic abnormalities, though further standardization and longitudinal research are needed.
    Keywords:  Amyloid PET; Brain metabolism; Chronic traumatic encephalopathy; Concussion; FDG PET; Neuroimaging; Tau PET; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.cpet.2026.05.006
  26. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2601657123
    Mitofusin-2 in ventral striatal D1 neurons regulates effort-based motivation through sex-specific mitochondrial-synaptic reprogramming.
    Alessandro Chioino, Dogukan H Ulgen, Olivia Zanoletti, Isabelle Guillot de Suduiraut, Ashley M Maynard, Elisenda Sanz, Albert Quintana, Simone Astori, Carmen Sandi.
      Effort-based motivation varies widely across individuals and affects well-being, yet the molecular and neuronal mechanisms that set motivational capacity remain incompletely understood. Mitochondrial function is emerging as a critical regulator of behavior, and mitofusin-2 (MFN2) is a key mediator of mitochondrial fusion and endoplasmic reticulum-mitochondria coupling. Here, we asked how downregulation of Mfn2 in dopamine receptor type-1-expressing medium spiny neurons (D1-MSNs) contributes to effort-based motivation and stress coping in male and female mice by integrating electrophysiology, neuronal and synaptic morphology, immunohistochemistry, mitochondrial readouts, RNA in situ hybridization, RiboTag, and behavioral analyses. MFN2 deficiency resulted in fragmented dendritic mitochondria and remodeled synaptic inputs in ventral striatal D1-MSNs, with no cellular impact in dorsomedial striatal D1-MSNs. Although MFN2 deficiency elicited sex-dependent synaptic and structural alterations, both sexes showed reduced recruitment of accumbal D1-MSNs during motivated behavior and impaired effort-based motivation and stress coping. Translatome profiling revealed shared depletion of mitochondrial pathways in both sexes, with more pronounced suppression of oxidative phosphorylation and TCA cycle programs in males. Strikingly, only males also exhibited coordinated downregulation of ribosomal programs together with enrichment of synaptic pathways, with high representation of genes regulating glutamate receptor cycling and PSD remodeling, providing a mechanistic framework for the observed synaptic alterations. Pathway-level network inference further supported coupling among mitochondrial, translational, and synaptic programs in males. These findings identify MFN2-dependent mitochondrial integrity in ventral striatal D1-MSNs as a critical determinant of motivational capacity and reveal sex-specific molecular and cellular responses through which mitochondrial dysfunction converges on similar motivational deficits.
    Keywords:  mitochondria; motivation; ventral striatum
    DOI:  https://doi.org/10.1073/pnas.2601657123
  27. Mol Ther Adv. 2026 Sep 10. 34(3): 201781
    Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex deficiency.
    Anna Keegan, Özge Çetin, Ellie M Chilcott, Juan Antinao Diaz, Simon Eaton, Simon N Waddington, John R Counsell, Shamima Rahman, Rajvinder Karda.
      Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder most frequently caused by pathogenic variants in PDHA1, leading to neurodevelopmental delay and early mortality, thus necessitating brain-targeted interventions. Using a brain-specific Pdha1 knockout mouse model, we compared intracerebroventricular delivery of AAV9 capsid and a recently described synthetic neurotropic AAV-F capsid, both expressing human PDHA1 coding sequence driven by a constitutive CAG promoter. Newborn mice received titer-matched AAV9, AAV-F, or AAV9 at 10-fold higher dose. Low-dose AAV-F and high-dose AAV9 significantly improved survival and restored PDH enzyme activity, metabolite profiles, and brain histopathology to near wild-type levels. However, mice treated by postnatal day 100 (P100) showed impaired motor function. Importantly, AAV-F achieved broad CNS transduction with minimal liver expression, thus outperforming low-dose AAV9. These results support the therapeutic potential of AAV-based gene therapy for PDHD and highlight AAV-F as a promising capsid for efficient, CNS-specific delivery.
    Keywords:  AAV-F; adeno-associated virus; clincal translation and pyruvate dehydrogenase deficiency; gene supplementation; neonatal gene therapy; preclinical
    DOI:  https://doi.org/10.1016/j.omta.2026.201781
  28. J Clin Invest. 2026 Jul 15. pii: e208000. [Epub ahead of print]136(14):
    Sterol biosynthesis, brain development, and disease.
    Eric S Peeples, Zeljka Korade, Karoly Mirnics.
      Cholesterol biosynthesis is indispensable for CNS development and function. The developing brain relies almost entirely on intrinsic sterol synthesis to support membrane biogenesis, axonal outgrowth, synaptogenesis, and myelination. Pathogenic variants in sterol biosynthetic enzymes, including DHCR7 and DHCR24, result in complex neurodevelopmental disorders such as Smith-Lemli-Opitz syndrome and desmosterolosis. In addition to cholesterol-lowering drugs (statins), some other pharmacological agents such as antipsychotics, antidepressants, and beta blockers can also inhibit cholesterol biosynthesis due to off-target effects. This inhibition produces dual pathophysiological effects: cholesterol depletion and accumulation of its precursor, 7-dehydrocholesterol, an exceptionally oxidizable molecule that spontaneously generates toxic oxysterols. Given the intense demand for cholesterol synthesis in the developing brain, prenatal exposure to sterol biosynthesis-inhibiting medications may have far-reaching effects. In this Review, we describe convergent biochemical, genetic, and epidemiologic data that implicate developmental sterol dysregulation as a modifiable risk factor for neurodevelopmental pathology and underscore the urgent need for routine sterol pathway safety assessment in drug development and prenatal pharmacotherapy.
    DOI:  https://doi.org/10.1172/JCI208000
  29. Nat Rev Neurosci. 2026 Jul 13.
    Brain mitochondria as key drivers of cognition and behaviour.
    Carmen Sandi, Mary Kay Lobo, Fiona Hollis, Yusuke Hirabayashi, Jaime de Juan-Sanz, Juan P Bolaños.
      Cognition and behaviour arise from computations in neural circuits, which can differ in their readiness for recruitment or in the computations and behavioural outputs that they generate. Mitochondria contribute to both circuit properties and their variability by shaping the cellular processes on which circuit function depends. Across neurons and glia, mitochondria provide bioenergetic support, regulate Ca2+ dynamics and reactive oxygen species levels, influence neurotransmitter synthesis and turnover, and sustain quality control programmes that preserve cellular integrity. The capacity of mitochondria to provide this support and their plasticity have been linked to circuit architecture, engagement and adaptation, with implications for learning and memory, reward and reinforcement, state-trait anxiety and motivation. Here we describe two complementary modes of mitochondrial support: a baseline mode, in which mitochondria sustain circuit architecture and physiological properties over long timescales, and an activity-evoked mode, in which local mitochondrial outputs support synaptic transmission and plasticity. Distinguishing these two modes helps to explain how behavioural modulators, including stress hormones, immune activity and metabolic signals, can shape behaviour by altering either baseline mitochondrial control of circuit readiness or activity-evoked mitochondrial support during circuit engagement.
    DOI:  https://doi.org/10.1038/s41583-026-01061-1
  30. Iran Biomed J. 2026 Apr 27.
    Antidepressant Effects of L-Arginine and Its Role in Brain Energy Metabolism.
    T Mantashashvili, L Nakaidze, M Shengelia, N Koshoridze.
       Background: Mitochondrial dysfunction and impaired cellular energy metabolism are increasingly recognized as key contributing factors in depression. This study evaluated the amino acid L-arginine as a potential agent for behavioral rescue and bioenergetic restoration using a corticosterone-induced rat model of depression.
    Methods: Male rats were randomly assigned to four groups (n = 10): control (DMSO intraperitoneally [i.p.] + water oral gavage), corticosterone-induced depression (20 mg/kg, i.p. for 14 days), L-arginine treatment (150 mg/kg, oral gavage for 14 days), and fluoxetine (10 mg/kg, oral gavage for 14 days). To ensure handling equivalence, all oral administrations were performed via gavage (1.0 mL/100 g). Behavioral rescue was assessed via open field, forced swim (FST), and tail suspension (TST) tests. Hippocampal energy metabolism and PI3K/Akt/mTOR pathway activation were analyzed.
    Results: L-arginine significantly improved the hippocampal bioenergetic profile, demonstrating efficacy comparable to the positive control fluoxetine. It led to a significant reduction in immobility time during FST and TST, alongside restoring glycolysis, the tricarboxylic acid cycle, and mitochondrial respiratory chain activities. Concurrently, L-arginine enhanced the activation state of the PI3K/Akt/mTOR signaling pathway (phosphorylated Akt/Akt and p-mTOR/mTOR ratios) and improved the functional state of the mitochondrial permeability transition pore. These metabolic and signaling improvements strongly correlated with the rescue of depressive-like behaviors.
    Concludion: Our findings demonstrate that L-arginine possesses potent antidepressant-like potential, mediated through bioenergetic restoration and signaling pathway modulation. By activating key metabolic processes in the hippocampus, L-arginine effectively restores impaired cellular energy homeostasis, suggesting its promise as a metabolic modulator for alleviating neurobiological disturbances associated with depressive conditions.
    DOI:  https://doi.org/10.61882/ibj.5314
  31. bioRxiv. 2026 Jul 11. pii: 2026.07.11.737778. [Epub ahead of print]
    Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
    Yohannes Ambaw, Alissa Nana, Li Zhuoning, Shubham Singh, Mara Monetti, Bruce L Miller, Salvatore Spina, Lea Tenenholz Grinberg, William W Seeley, Tobias C Walther, Robert Farese.
      Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick disease's, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.07.11.737778
  32. Sci Adv. 2026 Jul 17. 12(29): eaed4944
    Focused ultrasound blood-brain barrier opening reveals a paradoxical remote metabolic response in the primate brain.
    Soroosh Sanatkhani, Dong Liu, Fabian Munoz, Jack Grinband, Elisa E Konofagou, Vincent P Ferrera.
      Low-intensity focused ultrasound (LIFU) is a promising technique for opening the blood-brain barrier (BBB) for drug delivery, but its physiological consequences in remote brain regions remain a major blind spot for clinical safety and efficacy. To address this gap, we performed the quantitative mapping of brain metabolism following a focal LIFU-induced BBB opening in a nonhuman primate model, using quantitative BOLD MRI to measure the oxygen extraction fraction (OEF). We report a paradoxical response: While the targeted striatum showed no significant metabolic changes, we observed a profound and spatially specific increase in OEF in the homologous contralateral striatum, an effect predominantly driven by the putamen. These findings demonstrate that focal BBB opening is not merely a localized vascular event but a potent neuromodulatory intervention that induces metabolic stress in distant, untreated brain regions, a discovery with critical implications for the safe and effective clinical translation of all focal brain therapies.
    DOI:  https://doi.org/10.1126/sciadv.aed4944
  33. Neuron. 2026 Jul 15. pii: S0896-6273(26)00481-2. [Epub ahead of print]114(14): 2492-2494
    Lactylation drives oligodendrocyte differentiation and (re)myelination.
    Aksheev Bhambri, Lu O Sun.
      In this issue of Neuron, Bao et al. identify a metabolic-epigenetic axis essential for myelin development and repair.1 Lactate, a major energy source for oligodendrocytes, promotes oligodendrocyte differentiation and myelin repair, at least in part, through the lactylation of key enzymes, including lactate dehydrogenase A (LDHA).
    DOI:  https://doi.org/10.1016/j.neuron.2026.06.013
  34. J Lipid Res. 2026 Jul 17. pii: S0022-2275(26)00135-5. [Epub ahead of print] 101105
    Dithionite quenching of NBD-labeled lipids reveals artificial lipid droplet purity and neutral lipid surface accessibility.
    Jiyao Chai, Lingshuang Wu, Yong Mi Choi, Shujuan Gao, Daniel Canals, Abdou Rachid Thiam, Erwin London, Michael V Airola.
      Artificial lipid droplets (aLDs) provide a controllable platform for studying lipid biochemistry, but their use is limited by contamination with other membrane structures and the lack of quantitative methods to assess sample purity. Here, we establish dithionite quenching of NBD-labeled lipids as a simple approach to evaluate aLD purity. The approach relies on dithionite's ability to selectively quench NBD fluorophores exposed in the phospholipid monolayer of aLDs and in the outer leaflet of liposome bilayers, but not those protected within the inner leaflet of liposome bilayers. Consistent with liposome contamination, bulk aLD preparations exhibit incomplete quenching, which can be separated by sucrose gradient centrifugation into liposome-like and droplet-enriched populations based on quenching behavior. Guided by this assay, sonication conditions were optimized to increase aLD purity and reduce liposome contamination. A biotin-streptavidin immobilization strategy further enabled stable imaging of individual aLDs. Finally, we applied dithionite quenching to probe the accessibility of neutral lipids within aLDs. This revealed hydrophobicity-dependent quenching kinetics of neutral lipids, with less hydrophobic diacylglycerols showing greater surface exposure within aLDs than more hydrophobic triacylglycerols and cholesterol esters. Taken together, these establish dithionite quenching of NBD-labeled lipids as a simple quantitative method for assessing aLD purity and demonstrate its utility for studying lipid accessibility.
    Keywords:  dithionite quenching; lipid droplets; neutral lipids
    DOI:  https://doi.org/10.1016/j.jlr.2026.101105
  35. Neurobiol Aging. 2026 Jul 10. pii: S0197-4580(26)00122-3. [Epub ahead of print]168 23-36
    Lipid metabolism is a key central, systemic and gut microbial feature of the decline in rat hippocampal function during middle age.
    Maria Giovanna Caruso, Sebastian Dohm-Hansen, Francisco Donoso, Zoë A P Williams, Stefanie Grabrucker, Aonghus Lavelle, Jane A English, Sarah Nicolas, Olivia F O'Leary, Yvonne M Nolan.
      Middle age is emerging as a turning point in brain ageing, prognostic of future cognitive health and amenable to intervention. Metabolic and proteomic differences during this period are not yet fully understood and may potentially influence functions of the hippocampus, a brain area that regulates memory and anxiety. While the gut microbiota is implicated in brain ageing, the relationship between the gut microbiota, the metabolic state, and hippocampal proteome in middle age has not been investigated. We hypothesise that peripheral metabolic or protein features are associated with hippocampal vulnerability in middle age. Therefore, young adult and middle-aged rats were assessed for behavioural, proteomic, metabolic, and gut microbiota differences. Proteomic profiling of the hippocampus revealed differential expression of proteins indicative of altered synaptic signalling. Concurrently, adult hippocampal neurogenesis was decreased in middle age. Hippocampal microglia exhibited a lipid rich, inflammatory phenotype in middle age which correlated with poorer memory performance. CSF and serum proteomic and metabolomic analyses identified dysregulated lipid-related pathways potentially contributing to hippocampal vulnerability in middle age. Furthermore, 16S rRNA sequencing revealed reduced abundance of bacteria involved in lipid metabolism regulation. However, faecal microbiota transfer from young to middle aged rats was not sufficient to robustly improve hippocampus-dependent spatial memory. Together, these findings highlight dysfunctional lipid metabolism as a key feature of middle age that may contribute to decline in hippocampal function. Given that the scope for intervention is limited during older age, targeting biomarkers involved in metabolic and lipid homeostasis may be pivotal for the development of pharmacological or lifestyle-based interventions during middle age which could ultimately delay future cognitive ageing.
    Keywords:  CSF; Gut microbiota; Hippocampus; Lipid metabolism; Microglia; Middle age; Neurogenesis
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.07.001
  36. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00050-4. [Epub ahead of print]187 17-38
    Bioenergetic impairment-induced Tau acetylation: Converging pathways in Alzheimer's disease.
    Basavaraju K C, Poornima Priyadarshini.
      Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder in which disruptions in cellular energy metabolism play a central role in its progression. The dysregulated metabolism of carbohydrates, proteins, fatty acids, and nucleic acids collectively impairs neuronal bioenergetics, leading to mitochondrial dysfunction and reduced ATP production. This impaired energy metabolism trigger a cascade of cellular stress responses, including endoplasmic reticulum (ER) stress, oxidative and inflammatory responses, and increased generation of amyloid-β (Aβ), thereby exacerbating neuronal vulnerability. A critical downstream consequence of bioenergetic failure is the altered epigenetic and post-translational regulatory enzymes, particularly the acetyltransferase EP300 and the NAD+-dependent deacetylases known as sirtuins. An imbalance in the activity of these enzymes promotes the abnormal tau acetylation, which disrupts tau-microtubule interactions and promotes tau aggregation, ultimately accelerating neurodegeneration. Emerging evidence suggests tau acetylation as a mechanistic link between metabolic dysfunction and hallmark pathological characteristics of AD, suggesting bioenergetic impairment directly regulate tau pathology. Thus, understanding the metabolic pathways that drive tau acetylation may offer new therapeutic targets aimed at restoring neuronal energy balance, re-establishing acetylation homeostasis, and potentially slowing the progression of AD.
    Keywords:  Alzheimer’s; Bioenergetics; EP300; Neuronal bioenergetics; Sirtuins; Tau acetylation
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.020
  37. Glia. 2026 Sep;74(9): e70203
    VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7.
    Yue Liang, Tong Chang, Leping Yan, Jiayi Li, Yihe Zhang, Jianhua Ding, Yinquan Fang, Gang Hu.
      Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.
    Keywords:  Parkinson's disease; VPS35; astrocyte; lipid droplet; lysosome; microglia
    DOI:  https://doi.org/10.1002/glia.70203
  38. eNeuro. 2026 Jul 14. pii: ENEURO.0005-26.2026. [Epub ahead of print]
    Limited contribution of the lactate receptor HCAR1 to exercise-induced behavioral and hippocampal adaptations.
    Nikolaj Klahn, Vidar Jensen, Silje Bøyum, Cecilie Morland, Jens Randel Nyengaard, Mikkel Thy Thomsen.
      Physical exercise influences hippocampal function and behavior, and lactate has emerged as a candidate signaling molecule linking metabolic activity to neuroplasticity. One proposed mediator is the hydroxycarboxylic acid receptor 1 (HCAR1), but its contribution to behavioral and hippocampal adaptations to exercise remains unclear. We combined studies of HCAR1 knockout (KO) mice with analyses of human postmortem hippocampal tissue to assess whether HCAR1 is required for behavioral or synaptic responses to exercise and to characterize its spatial distribution in human hippocampus. Wild-type (WT) and HCAR1 KO mice of either sex underwent a 3-week high-intensity interval treadmill program or sedentary handling. Behavioral responses were assessed using the splash test and three-chamber sociability assay, and dentate gyrus (DG) field recordings evaluated synaptic transmission and excitability. In parallel, HCAR1 expression was quantified in hippocampal tissue from individuals with major depressive disorder (MDD) and non-depressed controls. Exercise reduced grooming and increased locomotion similarly across genotypes, indicating largely preserved behavioral responses in the absence of HCAR1. HCAR1 KO control mice exhibited delayed initiation of social interaction, not observed in exercised mice. Electrophysiology revealed subtle genotype-dependent differences in DG responsiveness following exercise, without major changes in short-term plasticity. In the small available cohort, HCAR1 showed a predominantly perivascular distribution across hippocampal subregions in both MDD and control cases. Together, these findings indicate that HCAR1 is not required for the primary behavioral and synaptic outcomes measured here following exercise, while leaving open a contribution to more specific aspects of hippocampal function under these or other conditions.Significance Statement Exercise-induced increases in brain lactate have been proposed to influence hippocampal plasticity and behavior, in part through activation of the lactate receptor HCAR1. By testing HCAR1 knockout mice across behavioral and hippocampal electrophysiological outcomes, and by characterizing HCAR1 distribution in human hippocampal tissue, we find that loss of HCAR1 does not substantially alter the behavioral measures assessed or the main behavioral responses to exercise. Human hippocampal HCAR1 showed a predominantly perivascular distribution in both MDD cases and controls. These findings suggest that HCAR1 is not broadly required for the exercise-associated outcomes measured here, while leaving open a role under specific physiological or pathological conditions.
    DOI:  https://doi.org/10.1523/ENEURO.0005-26.2026
  39. Pediatr Res. 2026 Jul 15.
    Longitudinal urine metabolomics predicts high-grade brain injury in very preterm infants.
    Thomas Kuncewicz, Magdalena Zasada, Marta Olszewska, Aleksandra Kowalik, Joanna Berska, Jolanta Bugajska, Przemko Kwinta.
      Molecular profiling of preterm infants' urine offers a promising noninvasive strategy to identify biomarkers. In this prospective study, urine samples were collected from 64 preterm infants ( < 32 weeks gestation) on postnatal days 1-4, 6, 8, 28 and at term-equivalent age. Forty-three metabolites and neurotransmitters were quantified by LC-MS/MS. Brain injury severity was quantified using the MRI-derived Global Brain Abnormality Score, capturing white matter, cortex, deep grey matter, and cerebellar injury. Distinct temporal patterns of urinary metabolites were associated with global brain injury severity. Early energy-related elevations (lactate, α-hydroxybutyrate) were followed by broader alterations in amino acid, fatty acid, and tryptophan-kynurenine pathways between postnatal days 3-6, defining a promising neurosurveillance window that may implicate mitochondrial dysfunction, oxidative stress, and excitotoxicity as relevant injury mechanisms. At the default decision threshold, multi-block modeling identified 100% of severe injury patients (AUC = 0.849) using day 3-6 data. Exploratory prediction of region-specific MRI anomaly was most robust for cerebellum (AUC = 0.891; full model) and white matter (AUC = 0.724; early model). Urine metabolomics may detect evolving preterm brain injury before MRI at term-equivalent age, with notable results between days 3 and 6. Combining metabolomic insights with clinical and imaging data could allow earlier risk assessment and neuroprotective treatment in preterm infants. IMPACT: Serial urine metabolomics in very preterm infants captures dynamic metabolic disturbances associated with brain injury. Urine patterns show possibly region-specific brain vulnerability. Days 3-6 define a critical window for stratifying risk of severe brain injury at term-equivalent age, shifting focus toward earlier care decisions.
    DOI:  https://doi.org/10.1038/s41390-026-05289-6
  40. BMC Pediatr. 2026 Jul 16.
    Association between elevated blood glucose level and brain injuries (IVH/WMI) in preterm infants.
    Renée Lampe, Ursula Felderhoff-Müser, Irina Sidorenko, Marcus Krüger, Eva Lück, Ekaterini Michales, Uwe Sassen, Christian Brickmann.
       INTRODUCTION: The likelihood of developing preterm brain injury such as intraventricular hemorrhage (IVH) or cystic white matter injury (cWMI) largely depends on gestational age. However, its pathogenesis is multifactorial, and accounting of additional risk factors is important for preventing brain injury. Glucose is one of the most important energy sources for the brain. Both high and low blood glucose level may be associated with the onset and progression of brain disorders.
    METHODS: To evaluate the relation between preterm brain injury (IVH/cWMI) and blood glucose level, univariate statistical analyses of retrospective data of 109 extremely and very preterm infants was performed. The analyzed data included 14 prenatal and infant diagnoses and 32 regularly measured parameters.
    RESULTS: Mean values of whole blood glucose levels in preterm infants diagnosed with IVH or cWMI was higher than in controls indicating that elevated blood glucose level is associated with development of preterm brain injury. Mean values were higher both before and after diagnosis of IVH or cWMI, and even significantly exceeded the hyperglycemia threshold of 125 mg/dL following IVH diagnosis. Furthermore, a significant or moderate association was revealed between elevated blood glucose level and 8 medical diagnoses, as well as 21 routinely measured parameters.
    CONCLUSION: Our study emphasizes the importance of regularly monitoring blood glucose levels in preterm infants and keeping it within a safe range.
    Keywords:  Extremely and very preterm infants; Hyperglycemia; Hypoglycemia; Intraventricular hemorrhage; White matter injury; Whole blood glucose
    DOI:  https://doi.org/10.1186/s12887-026-07341-0
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