bims-medebr 2026-03-29 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–03–29
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondrial lactate venting limits oxidative stress.
Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions.
Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases.
On the Origin of the Brain Semi-Heavy Water Deuterium MR Signal Following Administration of Deuterated Metabolic Substrate: A Cautionary Tale.
[Research progress on the involvement of glucose transporter-mediated cerebral glucose metabolism in the regulation of sepsis-associated encephalopathy].
Membrane Molecular Species Remodeling as a Signature of ω-3 Fatty Acid Action in Cultured Neural Cells.
α-linolenic acid-rich diet boosts docosahexaenoic acid levels and restores lipid balance in the brain parenchyma and vasculature of APOE4 mice.
Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer's Disease (LOAD).
Improvements in high-yield detection and localisation of cholesterol in murine brains using water cluster beam secondary ion mass spectrometry.
Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition.
Distribution and functional significance of rodent cerebellar glycogen.
Inorganic phosphate and the rapid mobilization of metabolic energy in neurons.
Parkinson's Disease: From Metabolism to Genetics-A Comprehensive Review.
Early Reduction in Mitochondrial Membrane Potential in Synaptic Mitochondria Contribute to Synaptic Pathology in the EAE Mouse Model of Multiple Sclerosis.
Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
Therapeutic Targeting of Microglial Hexokinase-2 Recalibrates Inflammasome Activation and Improves Functional Recovery After Traumatic Brain Injury.
Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.
The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.
Mild neonatal hypoxia targets synaptic maturation, disrupts adult hippocampal learning and memory and is associated with CK2-mediated loss of synaptic calcium-activated potassium channel KCNN2 activity.
Sex-dimorphic VMN Ghrh neuron metabolic sensor and neurotransmitter marker transcriptional adaptation to recurrent insulin-induced hypoglycemia.
Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells.
Eicosapentaenoic acid reprograms cerebrovascular metabolism and impairs repair after brain injury, with relevance to chronic traumatic encephalopathy.
The Ovine Brain as a Model for Human Neurodevelopment: Immunohistochemical Profiling of Brain Maturation Markers in Preterm Lambs.
Pyruvate kinase M2 in Alzheimer's disease: from dysregulation to therapeutic inhibition.
Restoring mitochondrial lipid homeostasis with arachidonic acid supplementation to alleviate cognitive impairment in schizophrenia patients.
Endoplasmic Reticulum-Mitochondrial Crosstalk in Calcium Regulation: Mechanistic Insights and Therapeutic Implications in Traumatic Brain Injury.

Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]

Mitochondrial lactate venting limits oxidative stress.

Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.

  Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.

Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
Neuron. 2026 Mar 25. pii: S0896-6273(26)00089-9. [Epub ahead of print]

Lysosomal salvage of neuronal lipids enables glial infiltration of synaptic regions.

Emma K Theisen, Irma Magaly Rivas-Serna, Peiwen Cheng, Ryan J Lee, Connon I Thomas, Anza Darehshouri, Taylor R Jay, Govind Kunduri, Tasha T Nguyen, Vera Mazurak, M Thomas Clandinin, Thomas R Clandinin, John P Vaughen.

  The complex morphologies of neurons and glia emerge through profound changes in membrane lipids and proteins during development. Lysosomes are central regulators of membrane remodeling, and mutations that affect lipid turnover in lysosomes are frequently associated with neurological disease. However, how these lysosomal functions might shape brain development remains incompletely understood. By analyzing lipid levels in the Drosophila brain, we discover transient increases in specific sphingolipids during development. This lipid bolus reflects biosynthetic inputs from both neurons and glia, and requires lysosomal catabolism for mature neuronal physiology to emerge. Remarkably, sphingolipid catabolism in glia is substantially driven by the phagolysosomal salvage of neuronal membranes to produce very long-chain ceramide phosphoethanolamine (CPE) lipids. CPE lipids are cell-autonomously required for glial autophagy and ramification into synaptic regions, and a genetic CPE biosensor localizes to infiltrated glial processes. Thus, developmentally regulated lysosomal activity obligately couples neuron-glia metabolic interactions to program dynamic glial morphogenesis.

Keywords:  GBA; LSDs; VLCFAs; arborization; autophagy; ceramide phosphoethanolamine; glia; glucocerebrosidase; lysosomal storage diseases; neurodevelopment; phagocytosis; sphingolipids; very long chain fatty acids

DOI:  https://doi.org/10.1016/j.neuron.2026.02.006
Metabolites. 2026 Mar 11. pii: 189. [Epub ahead of print]16(3):

Physiological Functions of Side-Chain-Retaining Sterols in the Brain and Their Roles in Neurodegenerative Diseases.

Yoshimitsu Kiriyama, Akira Nakatsuma, Hiroshi Tokumaru, Hisayo Sadamoto, Hiromi Nochi.

  Although the brain comprises only 2% of total body weight, it contains approximately 23% of the total cholesterol of the body. In the brain, cholesterol plays a critical role as a structural component of cell membranes and myelin sheaths. However, the blood-brain barrier restricts cholesterol influx from the systemic circulation into the brain. As a result, the brain synthesizes cholesterol de novo and regulates its metabolism independently. Desmosterol, a cholesterol precursor produced during cholesterol biosynthesis, and cholesterol metabolites, 24S-hydroxycholesterol and chenodeoxycholic acid, are sterols with structurally retained side chains. These side-chain-retaining sterols have traditionally been regarded as intermediates in the cholesterol synthesis process or as metabolites for cholesterol excretion, but accumulating evidence indicates that they also function as physiologically active signaling molecules that influence brain function via nuclear receptors, such as liver X receptors, and membrane receptors, such as NMDA receptors. Through nuclear receptors, these side-chain-retaining sterols regulate the transcription of genes involved in lipid transport, inflammation control, and amyloid clearance, while their membrane receptor action enables rapid synaptic effects. These side-chain-retaining sterols mediate metabolic crosstalk between neurons and glial cells and contribute to maintaining cholesterol balance in the developing brain. Furthermore, these side-chain-retaining sterols have been shown to affect amyloid-β clearance, α-synuclein aggregation, neuroinflammation, mitochondrial function, and remyelination. Dysregulation of these side-chain-retaining sterols is associated with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Overall, side-chain-retaining sterols are important regulators of brain physiology. This review focuses on the current knowledge regarding the physiological functions of side-chain-retaining sterols in the brain and their roles in neurodegenerative diseases.

Keywords:  24S-hydroxycholesterol; Alzheimer’s disease; CDCA; Huntington’s disease; LXR; Parkinson’s disease; cholesterol; desmosterol; multiple sclerosis; neurogenerative diseases

DOI:  https://doi.org/10.3390/metabo16030189
Magn Reson Med. 2026 Mar 24.

On the Origin of the Brain Semi-Heavy Water Deuterium MR Signal Following Administration of Deuterated Metabolic Substrate: A Cautionary Tale.

Joseph J H Ackerman, Xia Ge, Nick Rensing, Jeffrey J Neil, Liu Lin Thio, Joel R Garbow.

   PURPOSE: To evaluate the extent to which the appearance of HOD in the brain following systemic administration of a deuterated substrate is due to local brain metabolism versus body metabolism.
METHODS: [6,6-2H2]glucose, which is transported across the blood-brain barrier (BBB), and [6,6-2H2]fructose (Fruc), which does not cross the BBB, were administered to four mouse cohorts. Cohorts included wild-type mice, glucose transporter deficiency mice, which have decreased brain glucose uptake from the blood, and littermate control mice. A separate wild-type cohort received a 15-μL intramuscular (leg) injection of D2O. Brain-localized DMRS experiments employed the ISIS single-voxel protocol at 11.74 T.
RESULTS: Following leg D2O injection, semi-heavy water (HOD) appears within the brain in minutes, reaching steady state shortly thereafter. Body metabolism of [6,6-2H2]fructose produces HOD that also appears in the brain within minutes following subcutaneous administration, with an initial rate (mM/min) substantially greater than following administration of [6,6-2H2]glucose. Deuterated glucose from body metabolism of [6,6-2H2]fructose also appears in the brain. The terminal rates for HOD appearance in the brain are indistinguishable for the four cohorts examined despite there being up to a five-fold difference in brain concentration (mM) of deuterium-labeled glucose.
CONCLUSION: Body production of HOD dominates the initial increase of HOD in brain following administration of [6,6-2H2]fructose and likely contributes significantly to the increase of HOD in brain following administration of [6,6-2H2]glucose. Interpretation of HOD concentrations as representative of organ-specific metabolism requires careful consideration of control experiments and assessment of HOD contributions from body metabolism of the administered deuterated substrate.

Keywords:  DMI; HOD; MRI; deuterium; fructose; mouse

DOI:  https://doi.org/10.1002/mrm.70347
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2026 Jan;38(1): 202-206

[Research progress on the involvement of glucose transporter-mediated cerebral glucose metabolism in the regulation of sepsis-associated encephalopathy].

Chunxia Ma, Youqian Han, Wenzhu Tian, Mengfei Chen.

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by a systemic inflammatory response, in the absence of direct central nervous system infection, structural brain abnormalities, or clinical/laboratory evidence of other types of encephalopathy. It is a common complication in sepsis, and its pathogenesis has not yet been fully elucidated. Recent studies have revealed that dysregulated cerebral glucose metabolism plays an important role in the development of SAE, in which glucose transporters (GLUTs) are critically involved. This article reviews the research progress on the involvement of brain glucose metabolism mediated by GLUTs in the regulation of SAE. The study focuses on: 1) The expression and function of GLUT1, GLUT3 and GLUT4 in brain tissue. 2) The function and expression of GLUTs in brain tissue are regulated by multiple factors: estrogen, cytokines, metabolic state and mitochondrial status. 3) The mechanisms of GLUTs in SAE and related brain disorders (such as neurodegenerative diseases associated with aging, cerebral hemorrhage, meningitis, encephalopathy caused by human immunodeficiency virus infection and encephalopathy caused by burns or burns combined with infection). 4) Potential therapeutic strategies for SAE based on glucose metabolism regulation: improving the expression of GLUTs associated with blood-brain barrier function; modulating the function of GLUTs involved in neuroinflammation; enhancing mitochondrial function, reducing oxidative stress, and increasing adenosine triphosphate production to indirectly boost GLUTs expression and activity; metabolic reprogramming-adjusting key metabolic enzymes or pathways to alter cellular metabolic characteristics and adapt to the energy demands during sepsis. The aim is to provide a theoretical basis for a deeper understanding of the pathophysiological mechanisms of SAE and the development of new therapeutic targets.

DOI: https://doi.org/10.3760/cma.j.cn121430-20250515-00474
ASN Neuro. 2026 ;18(1): 2644959

Membrane Molecular Species Remodeling as a Signature of ω-3 Fatty Acid Action in Cultured Neural Cells.

Kyndall R Nicholas, Hennrique Taborda Ribas, Kevin D Browne, Kamryn R Purpura, Peining Xu, Ashika Mani, Elizabeth N Krizman, Clementina Mesaros, D Kacy Cullen.

  Omega-3 polyunsaturated fatty acids (ω3 PUFAs) are critical structural components of neuronal membranes, yet the molecular specificity of their incorporation within neural cells remains incompletely defined. We integrated untargeted and targeted lipidomics with lipid ontology analysis and coarse-grained membrane simulations to characterize remodeling in primary rat cortical neurons and neuron-astrocyte co-cultures following supplementation with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or docosapentaenoic acid (DPA). Each ω3 PUFA produced a distinct lipidomic signature. DHA showed the most consistent incorporation, selectively enriching phosphatidylethanolamine (PE) species-particularly PE(18:0/22:6) and PE(18:1/22:6)-associated with membrane curvature and organelle organization. Ontology analysis linked DHA supplementation to intrinsic curvature-related membrane features, and membrane simulations demonstrated enhanced collective bilayer bending without substantial changes in overall membrane thickness. EPA preferentially increased EPA-containing PE species without elevating DHA levels, whereas DPA effects were variable and culture-dependent, indicating selective metabolic handling of individual ω3 species. Differences between neurons and neuron-astrocyte co-cultures underscore the importance of cellular context in ω3-driven remodeling. By resolving ω3 incorporation at molecular species resolution and linking compositional changes to predicted membrane behavior, this study provides a structural framework for understanding how dietary ω3 fatty acids may influence neuronal membrane organization and cellular resilience.

Keywords:  Astrocytes; brain lipids; docosahexaenoic acid; fatty acid/transport; glycerophospholipids; lipidomics; lipids; membrane remodeling; molecular species; neurons

DOI:  https://doi.org/10.1080/17590914.2026.2644959
J Nutr Biochem. 2026 Mar 24. pii: S0955-2863(26)00094-X. [Epub ahead of print] 110352

α-linolenic acid-rich diet boosts docosahexaenoic acid levels and restores lipid balance in the brain parenchyma and vasculature of APOE4 mice.

Alicia Leikin-Frenkel, Orly Ravid, Meir Liberman, Dana Atrakchi, Victoria Lamport, Daniel Rand, Dror Harats, Hussein N Yassine, Harini Sampath, Daniel M Michaelson, Michal Schnaider-Beeri, Sigal Liraz-Zaltsman, Itzik Cooper.

  The APOE4 allele significantly increases Alzheimer's disease (AD) risk, often linked to brain lipid imbalance. This study investigated lipid profiles in the brain parenchyma and brain blood vessels (BBV) of APOE3 and APOE4-humanized female mice, assessing the protective effects of an alpha-linolenic acid (ALA)-rich diet on lipid composition and memory in APOE4 mice. Mice received either a Control or an ALA-rich flaxseed oil diet for six months. Lipid profiles were analyzed in brain parenchyma, BBV, plasma, and liver, alongside memory performance. In vitro studies explored human brain endothelial cell conversion of ALA to docosahexaenoic acid (DHA). APOE4 mice, compared to APOE3 controls, exhibited significant lipid depletion in brain parenchyma, including reduced cholesterol (32%), phospholipids (10%), and DHA (57%). The ALA-rich diet beneficially restored lipid levels in APOE4 brain parenchyma, increased DHA-containing phospholipids, and improved memory. This diet also elevated n-3 fatty acids and DHA within the BBV, particularly in APOE4 phosphatidylserine, and upregulated lipid-related genes (PLA2, LDLR). In vitro data confirmed brain endothelial cells synthesize DHA via the ∆6 desaturase pathway, a process suppressed by desaturase inhibitors or external DHA. Collectively, these findings suggest the BBV acts as a crucial hub for lipid homeostasis. An ALA-rich diet effectively mitigates lipid imbalance in APOE4 mice by promoting lipid unsaturation, enhancing DHA synthesis and its incorporation into complex lipids, thereby improving cognitive performance. This research positions dietary ALA as a promising nutritional intervention for APOE4 carriers.

Keywords:  Alpha linolenic acid; Alzheimer’s disease; DHA; blood‒brain barrier; brain lipid homeostasis; cognition; unsaturation; ∆6 desaturase

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110352
Cells. 2026 Mar 19. pii: 549. [Epub ahead of print]15(6):

Inherent Lipid Composition Abnormalities in Astrocytes Associated with Late-Onset Alzheimer's Disease (LOAD).

Bruce M Cohen, Eunjung Koh, Kandice R Levental, Ilya Levental, Kai-Christian Sonntag.

  Lipid abnormalities have been observed in brain, cerebrospinal fluid (CSF), and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which of these abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived brain cells. These cells lack markers associated with aging and environmental exposures. The iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Astrocytes are crucial to neural activity and health, and altered astrocyte functions are associated with LOAD pathology. Lipidomics analyses were performed on whole-cell and mitochondria-enriched fractions. Large reductions in cholesterol esters (CEs) and imbalances in fatty acids (FAs) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. The findings identify abnormalities in CEs, as well as in FAs, as inherent abnormalities and likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.

Keywords:  LOAD; astrocytes; cholesterol; dementia risk; fatty acids; iPSC; induced pluripotent stem cells; late-onset Alzheimer’s disease; lipids; mitochondria

DOI:  https://doi.org/10.3390/cells15060549
Anal Bioanal Chem. 2026 Mar 26.

Improvements in high-yield detection and localisation of cholesterol in murine brains using water cluster beam secondary ion mass spectrometry.

Matija Lagator, Irma Berrueta Razo, Sadia Sheraz, Nicholas P Lockyer.

  Cholesterol is a neutral lipid widely implicated in neurological and other physiological processes. However, it is difficult to detect and precisely localise in situ using mass spectrometry imaging techniques due to low sensitivity and matrix suppression by co-localised lipids. Here, we present the application of large water gas cluster ion beams (GCIBs) for cholesterol analysis and localisation in murine brains using secondary ion mass spectrometry (SIMS). Optimal GCIB parameters were established through analysis of cholesterol standards. These clusters were then used to analyse whole brain sections with minimal sample preparation. Molecular images obtained with water clusters show that cholesterol is distributed across the whole brain, with variations in intensity. In addition, large water clusters were shown to simultaneously maximise secondary ion yields while reducing matrix effects for in situ cholesterol analysis. Depth profiling further revealed that different brain regions produced varying sputter yields. This study demonstrates that large water clusters are very well suited for cholesterol analysis in murine brains. Because this approach requires no derivatisation or matrix addition, it is likely to make analysis faster, simpler, and less prone to matrix effects.

Keywords:  Brain tissue; Cholesterol; GCIB; Mass spectrometry imaging; Matrix effects; Secondary ion mass spectrometry; Water clusters

DOI:  https://doi.org/10.1007/s00216-026-06448-8
Neuron. 2026 Mar 26. pii: S0896-6273(26)00135-2. [Epub ahead of print]

Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition.

Nickoleta Delivanoglou, Kennedi T Todd, Francisco Almeida, Shanon Rego, Amogh Changavi, Myriam Spajer, Virginia Estades Ayuso, Liliana M Pinho-Correia, Guadalupe Sanchez, Sofia P das Neves, Megan J Barber, Racquelle Schrader, Patricia Sacilotto, Yuka A Martens, Michael G Heckman, Guojun Bu, Rudolph E Tanzi, Jean-Leon Thomas, John D Fryer, Tiago Gil Oliveira, Karthik Shekhar, Sandro Da Mesquita.

  Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially reverted upon colony-stimulating factor 1 receptor (CSF1R) inhibition. Suppressing innate immunity reduced neuroinflammation and restored cognitive function in E4/E4 females, while exacerbating neuroinflammation and accelerating cognitive decline in E4/E4 males. Finally, in line with the E4/E4 humanized mouse model data, we show that APOE4 expression is linked to sexually dimorphic leukocyte activation profiles in the human brain. This study highlights the need for personalized therapies when targeting APOE, brain immunity, and meningeal lymphatics to promote cognitive resilience in both females and males.

Keywords:  APOE4; CSF1R inhibitor; brain lipids; cognition; human brain leukocytes; lymphatic drainage; macrophages; meninges; neuroinflammation; sexual dimorphism

DOI:  https://doi.org/10.1016/j.neuron.2026.02.030
iScience. 2026 Apr 17. 29(4): 115192

Distribution and functional significance of rodent cerebellar glycogen.

Sonam Akther, Ashley Bomin Lee, Ayumu Konno, Antonis Asiminas, Marta Vittani, Tsuneko Mishima, Hirokazu Hirai, Claire Francesca Meehan, Jordi Duran, Joan Guinovart, Hitoshi Ashida, Tsuyoshi Morita, Otto Baba, Ryuichi Shigemoto, Maiken Nedergaard, Hajime Hirase.

  The mammalian brain stores glucose, the main circulating energy substrate, as glycogen. In rodents, the cerebellum contains relatively high glycogen levels, yet its cellular and subcellular distribution remains poorly defined. Using monoclonal antibodies against glycogen, we examined its distribution in the mouse cerebellar cortex. Glycogen was predominantly localized to Bergmann glia (BG) processes in the molecular layer and was also detected in Purkinje cells (PCs), the principal cerebellar neurons. To assess the functional significance of cerebellar glycogen, we analyzed behavior in mice lacking glycogen synthase 1 (Gys1) in BG or PCs using a floxed Gys1 line. Gys1 deficiency in either PCs or GFAP-positive cells reduced anxiety-like behavior, whereas combined deletion caused PC degeneration and ataxia. These findings reveal a critical role for glycogen metabolism in both astrocytes and neurons in cerebellar function.

Keywords:  Cellular neuroscience; Molecular neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.115192
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2602529123

Inorganic phosphate and the rapid mobilization of metabolic energy in neurons.

Paul C Rosen, Shivang Sullere, Panhui Fu, Juan R Martínez-François, Daniel J Brooks, Erica Kim, Chenghua Gu, Gary Yellen.

  Neurons experience brief, intense periods of energy demand when they are excited, but how they rapidly coordinate energy expenditure with production is incompletely understood. Part of the difficulty has been measuring the levels of molecules involved in this metabolic response with spatiotemporal precision in single live cells. Here, we engineered a quantitative fluorescent biosensor to monitor cytosolic inorganic phosphate (Pi), a fundamental component of energy metabolism that has a classically proposed but largely neglected role in activating glycolysis. Using two-photon fluorescence lifetime imaging, we observed millimolar increases in Pi within seconds of stimulating mouse neurons both ex vivo and in vivo. Drawing on results from metabolic modeling, biosensor imaging, and enzymology, we argue that Pi is a sensitive reporter of energy usage that potently links metabolic energy supply with demand in neurons. Quantitative live-cell imaging of Pi should be a valuable approach for studying bioenergetics more generally.

Keywords:  fluorescence lifetime imaging; fluorescent biosensors of metabolism; glycolytic regulation; neuronal energy metabolism

DOI:  https://doi.org/10.1073/pnas.2602529123
Curr Issues Mol Biol. 2026 Feb 26. pii: 254. [Epub ahead of print]48(3):

Parkinson's Disease: From Metabolism to Genetics-A Comprehensive Review.

Cauan Duarte, Edislane Barreiros de Souza, João Rafael Dias-Pinto, Rodrigo Pinheiro Araldi.

  Parkinson's disease (PD) is a progressive neurodegenerative disorder in which metabolic, inflammatory and proteostatic disturbances converge to drive dopaminergic neuron loss and widespread network failure. In this narrative review, we synthesize clinical, epidemiological and experimental evidence to organize PD pathophysiology around three interconnected metabolic axes: mitochondrial dysfunction and impaired glucose and lipid metabolism; chronic oxidative stress; and glial reprogramming and neuroinflammation, with α-synuclein acting as a central integrator at their interface. We then map how currently available dopaminergic, neuromodulatory and rehabilitative therapies interact with these axes, largely providing downstream symptomatic compensation while leaving core metabolic and inflammatory drivers only partially addressed. Next, we review RNA sequencing (RNA-Seq) and related transcriptomic studies in human brain and peripheral tissues, highlighting convergent differentially expressed genes in mitochondrial, synaptic, immune and proteostasis pathways, as well as major methodological challenges and opportunities for molecular subtyping and biomarker discovery. Together, these lines of evidence support a systems-level view of PD in which α-synuclein-centered metabolic failure and glial dysregulation are key therapeutic targets and in which high-quality RNA-Seq, integrated with advanced bioinformatics, may help define biologically grounded PD endotypes and accelerate the development of truly disease-modifying interventions.

Keywords:  Parkinson’s disease; RNA-Seq; bioinformatics; mitochondrial dysfunction; neuroinflammation; oxidative stress; α-synuclein

DOI:  https://doi.org/10.3390/cimb48030254
Int J Mol Sci. 2026 Mar 11. pii: 2579. [Epub ahead of print]27(6):

Early Reduction in Mitochondrial Membrane Potential in Synaptic Mitochondria Contribute to Synaptic Pathology in the EAE Mouse Model of Multiple Sclerosis.

Dalia R Ibrahim, Karin Schwarz, Ajay Kesharwani, René Tinschert, Shweta Suiwal, Frank Schmitz.

  Multiple sclerosis (MS) is a highly disabling chronic autoimmune disease of the central nervous system with neuroinflammatory and neurodegenerative alterations found in the white and grey matter of the brain. The pathogenesis of MS is complex and not fully understood. Mitochondrial dysfunctions are suspected to play an important role. The visual system is often affected in MS. Optic neuritis is a frequent symptom, but also the retina itself, including retinal synapses appear compromised in MS independent from demyelination of the optic nerve. A previous study demonstrated synapse-specific alterations of mitochondria in photoreceptor synapses in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS at day 9 after injection, an early time point in pre-clinical EAE. In the present study, we analysed even earlier stages of pre-clinical EAE for possible alterations of synaptic mitochondria. For this purpose, we performed qualitative and quantitative immunolabelling analyses of the mitochondrial cristae organising protein MIC60 at retinal synapses and functional analyses by measuring synaptic mitochondrial membrane potential (during rest and depolarisation-induced exocytosis) and visually guided behaviour (optometry analyses). At day 3 after injection, morphological and functional data were indistinguishable between MOG/CFA-injected EAE mice and CFA-injected control mice. But already on day 5 after injection, we observed a decreased expression of the mitochondrial MIC60 protein at synaptic mitochondria, a decreased synaptic mitochondrial membrane potential at rest, an enhanced drop of mitochondrial membrane potential during stimulated exocytosis and a decreased visual performance of the respective EAE mice. These data argue that synaptic pathology in the EAE retina begins as early as day 5 after injection. Our data propose that dysfunctions of mitochondria play an important role already at the very early stages of synaptic pathology in EAE.

Keywords:  EAE; MIC60; mitochondria; mitochondrial membrane potential; multiple sclerosis; retina; ribbon synapse

DOI:  https://doi.org/10.3390/ijms27062579
Mol Genet Metab. 2026 Mar 17. pii: S1096-7192(26)00189-7. [Epub ahead of print]148(2): 109906

Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.

André B P van Kuilenburg, Hanna Mandel, Tameemi Abdalla Moady, Ronen Sloma, Ayalla Fedida, René Leen, Judith Jansen-Meijer, Tamar Paperna, Vered Fleisher Sheffer, Doreen Dobritzsch, Ori Hochwald, Nicole N van der Wel, Anita E Grootemaat, Semyon Chulsky, Mika S Rootman, Ayelet Eran, Maha A Yousef, April Dinwiddie, Joshua Manor, Clara D M Van Karnebeek, Limor Kalfon, Tova Hershkovitz, Galit Tal, Tzipora C Falik Zaccai.

  Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We describe three infants from two unrelated families who presented clinically with neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure, progressing to either a persistent vegetative state or early death. One patient remains alive at the age of six years. Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range. Notably, brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects. Exome sequencing identified a homozygous, unreported missense variant in GLS (NM_014905.5:c.1174G > A; p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant (NM_014905.5:c.1031 T > C; p.Leu344Pro) in the proband from family 2. Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency. In addition, patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function. The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects.

Keywords:  Encephalopathy; GLS; Glutaminase deficiency; Glutamine; Hyperammonemia

DOI:  https://doi.org/10.1016/j.ymgme.2026.109906
bioRxiv. 2026 Mar 03. pii: 2026.03.01.708896. [Epub ahead of print]

Therapeutic Targeting of Microglial Hexokinase-2 Recalibrates Inflammasome Activation and Improves Functional Recovery After Traumatic Brain Injury.

Claudia Mera-Reina, Juan F Codocedo, Paul B Fallen, Jack Scott, Cristian A Lasagna-Reeves, Gary E Landreth.

  Traumatic brain injury (TBI) initiates a secondary inflammatory cascade in which sustained microglial activation contributes to long-term neurological dysfunction. Microglial inflammatory states depend on glycolytic reprogramming, suggesting that targeted modulation of metabolic regulators may attenuate post-traumatic inflammation while preserving essential immune functions. Hexokinase-2 (HK2), a rate-limiting glycolytic enzyme, regulates inflammatory signaling and inflammasome activation in microglia in neurodegenerative contexts; however, its role in TBI remains undefined. We therefore examined whether partial suppression of microglial HK2 modulates inflammatory responses following severe TBI. HK2 was robustly induced in microglia during the sub-acute phase after injury. Pharmacological inhibition of HK2 improved motor coordination without impairing locomotion or cognitive performance and selectively reduced inflammasome-related gene expression and ASC accumulation, particularly within the hippocampal hilus. Importantly, HK2 antagonism slowed microglial proliferation while preserving efferocytic capacity. Partial genetic reduction of microglial HK2 phenocopied these molecular and behavioral effects, supporting an HK2-dependent mechanism. Together, these findings identify microglial HK2 as a therapeutically targetable regulator of inflammatory amplification after TBI. Partial modulation of this pathway attenuates secondary neuroinflammation while maintaining critical microglial functions, highlighting HK2 as a promising strategy to improve functional recovery after traumatic brain injury.

Keywords:  Hexokinase-2; Traumatic Brain Injury; microglia; neuroinflammation

DOI:  https://doi.org/10.64898/2026.03.01.708896
Biomedicines. 2026 Mar 16. pii: 682. [Epub ahead of print]14(3):

Mitochondrial Dysfunction in the Inflammatory Process of Neurodegenerative Diseases.

Salvatore Nesci.

  Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.

Keywords:  inflammation; mitochondrial dysfunction; oxidative stress; respiratory complexes

DOI:  https://doi.org/10.3390/biomedicines14030682
Neuro Oncol. 2026 Mar 21. pii: noag063. [Epub ahead of print]

The 1p/19q co-deletion induces targetable and imageable vulnerabilities in glucose metabolism in oligodendrogliomas.

Suresh Udutha, Georgios Batsios, Céline Taglang, Anne Marie Gillespie, Pavithra Viswanath.

   BACKGROUND: The 1p/19q co-deletion is a hallmark of oligodendrogliomas. The goal of this study was to exploit the metabolic vulnerabilities induced by the 1p/19q co-deletion for the treatment and imaging of oligodendrogliomas.
METHODS: We used stable isotope tracing, mass spectrometry, and genetic and pharmacological approaches to interrogate [U-13C]-glucose metabolism in patient-derived oligodendroglioma models (SF10417, BT88, BT54, TS603, NCH612). We examined whether tracing [6,6'-2H]-glucose metabolism using deuterium metabolic imaging (DMI) provided an early readout of treatment response.
RESULTS: The glycolytic enzyme enolase 1 (ENO1; chromosome 1p36.23) was downregulated in patient-derived oligodendroglioma cells and patient tissue due to the 1p/19q co-deletion and histone hypermethylation. Conversely, inactivation of the CIC transcriptional repressor, driven by activated mitogen-activated protein kinase (MAPK) signaling, upregulated the ENO2 isoform specifically in oligodendrogliomas. Genetic ablation of ENO2 or pharmacological inhibition using POMHEX inhibited proliferation with nanomolar potency but was not cytotoxic to oligodendroglioma cells. Mechanistically, ENO2 loss abrogated [U-13C]-glucose metabolism to lactate but shunted glucose towards biosynthesis of serine and purine nucleotides, an effect that was driven by the rate-limiting enzyme for serine synthesis, phosphoglycerate dehydrogenase (PHGDH). Importantly, combining the PHGDH inhibitor D8 with POMHEX resulted in synthetic lethality in vitro and induced tumor regression in vivo. Furthermore, DMI of lactate production from [6,6'-2H]-glucose provided an early readout of response to combination therapy that preceded MRI-detectable alterations and reflected extended survival.
CONCLUSIONS: We have identified ENO2 and PHGDH as metabolic vulnerabilities induced by the 1p/19q co-deletion in oligodendrogliomas and [6,6'-2H]-glucose as a non-invasive tracer of early response to therapy.

Keywords:  ENO2; Oligodendroglioma; PHGDH; deuterium metabolic imaging; serine biosynthesis

DOI:  https://doi.org/10.1093/neuonc/noag063
J Neurosci. 2026 Mar 23. pii: e1643252026. [Epub ahead of print]

Mild neonatal hypoxia targets synaptic maturation, disrupts adult hippocampal learning and memory and is associated with CK2-mediated loss of synaptic calcium-activated potassium channel KCNN2 activity.

Art Riddle, Taasin Srivastava, Kang Wang, Eduardo Tellez, Hanna O'Neill, Xi Gong, Abigail O'Niel, Jaden A Bell, Jacob Raber, Matthew Lattal, James Maylie, Stephen A Back.

Preterm infants frequently sustain brief hypoxic insults of unclear clinical significance. Since preterm survivors commonly sustain life-long memory impairment without apparent gray matter injury, we tested whether mild hypoxia alone without ischemia could persistently disrupt adult hippocampal learning and memory mechanisms without causing brain injury. We developed a mixed sex neonatal mouse model of mild hypoxia that generated clinically relevant oxygen desaturation, but without responses typically associated with hypoxia-ischemia including bradycardia, seizures, neuroinflammation and neuronal or glial degeneration. RNA transcriptomic studies identified that the expression of immature hippocampal synaptic components was broadly targeted by mild hypoxia. Neonatal hypoxia resulted in hippocampal learning and memory deficits and abnormal maturation of CA1 neurons that persisted into adulthood. Memory deficits were accompanied by reduced adult hippocampal CA3-CA1 synaptic strength and LTP and abolished synaptic activity of calcium-sensitive SK2 channels, a key regulator of spike timing-dependent neuroplasticity, including LTP and memory encoding. Structural illumination microscopy revealed reduced synaptic density without altered synaptic SK2 distribution. Persistent loss of SK2 activity was mediated by increased CK2 phosphorylation of synaptic calmodulin and restored by CK2 blockade. Clinically relevant mild hypoxia in neonatal mice is thus sufficient to disrupt hippocampal maturation into adulthood independently of cerebral gray or white matter injury and trigger persistent loss of synaptic potassium SK2 channel activity that disrupts excitatory synaptic function. Our findings suggest that neonatal hypoxia contributes to the broad spectrum of neurobehavioral, cognitive and learning disabilities that paradoxically persist into adulthood without overt gray matter injury in survivors of preterm birth.Significance Statement After preterm birth, isolated mild hypoxic events occur commonly during intensive care, but their long-term impact on neurodevelopmental outcomes remains unclear. Prior studies have mostly focused on the effect of severe or prolonged hypoxic events associated with brain injury, inflammation and seizures. We identified that neonatal brain development coincides with a maturational window when mild hypoxia is sufficient to broadly target immature hippocampal synaptic components with resultant disturbances in learning and memory mechanisms that persist into adulthood without the injurious consequences of more severe hypoxia or hypoxia-ischemia. Our findings suggest that hypoxia-dependent synaptic dysmaturation may contribute significantly to adverse outcomes in preterm survivors and raises the potential for alternative therapeutic strategies focused on re-tuning of synaptic activity to enhance learning and memory.

DOI: https://doi.org/10.1523/JNEUROSCI.1643-25.2026
Neuropeptides. 2026 Mar 22. pii: S0143-4179(26)00026-0. [Epub ahead of print]117 102610

Sex-dimorphic VMN Ghrh neuron metabolic sensor and neurotransmitter marker transcriptional adaptation to recurrent insulin-induced hypoglycemia.

Rajesh Yadav, Subash Sapkota, Karen P Briski.

  Ventromedial hypothalamic nucleus/dorsomedial division (VMNdm) metabolic-sensory growth hormone-releasing hormone (Ghrh) neurons operate within the brain circuitry that maintains systemic glucostasis. Sex-specific counterregulatory hormone adaptation to recurrent insulin-induced hypoglycemia (RIIH) entails undiscovered CNS mechanisms. Combinative single-cell immunocytochemistry/laser-microdissection/multiplex qPCR methods were employed here to determine if RIIH alters VMNdm Ghrh neuron neurotransmission according to sex. Precedent insulin administration resulted in attenuated hypoglycemic up-regulation of male rat Ghrh neuron glucose sensor gene expression. Females exposed to RIIH acquired negative glucose transporter-2 and positive glucokinase transcriptional reactivity to dysglycemia. VMNdm Ghrh neurons express mRNAs for 5'-AMP-activated protein kinase catalytic subunit variants. Hypoglycemia-associated amplification of those transcripts in the male was exacerbated (PRKAA1) or reversed (PRKAA2) by RIIH; meanwhile females showed transcript up-regulation during recurring but not singular hypoglycemia. RIIH caused opposite, sex-specific adaptation of VMNdm Ghrh neuron Ghrh and Ghrh receptor gene transcription. Ghrh neuron transcripts for counterregulation-enhancing glutamate and nitric oxide marker proteins showed diminution or amplification of transcriptional responses, respectively, in males, but did not habituate to RIIH in females. Hypoglycemic inhibition of glutamate decarboxylase (GAD)-1 and - 2 mRNAs, markers for counterregulatory inhibitor γ-aminobutyric acid size variants, in male Ghrh neurons was correspondingly unaffected or attenuated by RIIH. Meanwhile, negative GAD2 transcriptional reactivity in the female was exacerbated following precedent hypoglycemia. Ongoing research aims to establish, for each sex, whether and how VMNdm Ghrh neuron metabolic sensor functional acclimation to RIIH may affect counterregulatory neurotransmitter release and to determine how adjustments in integrated neurochemical discharge may affect brain glucostatic network function.

Keywords:  Growth hormone-releasing hormone; Laser-catapult-microdissection; Multiplex qPCR; Recurrent insulin-induced hypoglycemia; Ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.1016/j.npep.2026.102610
Oncogene. 2026 Mar 25.

Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells.

Jun-Kyum Kim, Min Gi Park, Seok Won Ham, Seunghyun Yoon, Sua Kim, Junseok Jang, Hyejin Kim, Nayoung Hong, Jong Min Park, Cheol Gyu Park, Min Ji Park, Sang-Hun Choi, Jung Yun Kim, Hee-Young Jeon, Sunyoung Seo, Seon Yong Lee, Yeri Lee, Hee Jin Cho, Minseo Gwak, Eun-Jung Kim, Kiyoung Eun, Yong Jae Shin, Do-Hyun Nam, Se Hoon Kim, Seung Jun Yoo, Hyunggee Kim.

Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.

DOI: https://doi.org/10.1038/s41388-026-03736-6
Cell Rep. 2026 Mar 25. pii: S2211-1247(26)00213-5. [Epub ahead of print] 117135

Eicosapentaenoic acid reprograms cerebrovascular metabolism and impairs repair after brain injury, with relevance to chronic traumatic encephalopathy.

Eda Karakaya, Burak Berber, Onur Eskiocak, Jazlyn Edwards, Randy Bent Barker, Sarah Jamil, Weiguo Li, Yasir Abdul, Maria Ericsson, Thor Stein, Ann McKee, Adviye Ergul, Semir Beyaz, Onder Albayram.

  Repetitive mild traumatic brain injury (rmTBI) precedes chronic traumatic encephalopathy (CTE) and involves neurovascular dysfunction. Omega-3 polyunsaturated fatty acids (PUFA) are promoted as neuroprotective but their long-term effects after brain injury remain uncertain. We uncover a metabolic vulnerability associated with cerebral accumulation of eicosapentaenoic acid (EPA), a major PUFA derived from fish oil. In a fish oil diet model, EPA accumulates at baseline yet is selectively depleted after rmTBI, consistent with mobilization during injury-associated metabolic remodeling. This pattern coincides with matrix remodeling, endothelial degeneration, and impaired neurovascular function. Cortical transcriptomics indicate reduced angiogenic programs with increased fatty acid metabolism, and lipidomics links EPA to maladaptive lipid engagement. Mechanistic studies using metabolically adapted endothelial cells show that EPA selectively impairs reparative function. Analysis of postmortem CTE brain tissue reveals parallel vascular and metabolic gene expression changes, strengthening translational relevance. Together, these findings challenge the assumption of uniform omega-3 neuroprotection after brain injury.

Keywords:  CP: metabolism; CP: neuroscience; CTE; EPA; TBI; angiogenesis; chronic traumatic encephalopathy; context-dependent vulnerability; eicosapentaenoic acid; endothelial metabolism; extracellular matrix remodeling; neurovascular unit; precision nutrition; traumatic brain injury

DOI:  https://doi.org/10.1016/j.celrep.2026.117135
J Comp Neurol. 2026 Mar;534(3): e70149

The Ovine Brain as a Model for Human Neurodevelopment: Immunohistochemical Profiling of Brain Maturation Markers in Preterm Lambs.

Yoann Rodriguez, Anne Leostic, Olivier Le Coz, Vincent Mauffré, Joanne Fortemps, Lucile Cavarec, Fabienne Constant, Marine Denis, Paul Berveiller, Aude Tessier, Olivier Sandra, Leslie Schwendimann, Pierre Gressens, François Vialard, Emmanuelle Motte-Signoret.

  Preterm birth is known to severely impact the neurological development of newborns with long-lasting complications and higher risks of neurological disorders. Sheep (Ovis aries) is well known as a pre-clinical model in therapeutic studies, such as extra-uterine support. The aim of our study was to investigate the relevance of the lamb as a pre-clinical model for preterm birth when cortical maturation of preterm and term lamb is addressed. Cesarean sections were performed on time-dated pregnant ewes to obtain 13 lambs at 100 days and 140 days of pregnancy each (corresponding to 24 and 36 weeks of pregnancy in humans, respectively). Brains were collected and separated in frontal lobe, temporo-parietal lobe, occipital lobe, and cerebellum. Immunohistochemistry staining was used for each brain area by targeting neurons, interneurons, synaptic vesicles, oligodendrocytes, myelin, astrocytes, and microglia. Quantifications were normalized by the surface area of analysis. Overall, 140-days late preterm lambs have significantly higher mean positivity for interneurons, synaptic vesicles, oligodendrocytes, astrocytes, and myelin than 100-days extremely preterm lambs. Similarly, significantly higher mean positivity for neurons was found in the cerebellum of 140-days term lambs. No significant difference was observed regarding microglia. Based on the cellular and structural markers used in this study, brain development in lamb seems to follow an antero-posterior direction similarly to what was reported in humans. Further studies with more specific markers and in-depth analysis will allow for a more accurate and exhaustive description of brain development in lamb.

Keywords:  brain development; immunohistochemical comparison. RRID:NCBITaxon_9940, RRID:AB_2298772, RRID:AB_3107026, RRID:AB_10013382, RRID:AB_839504, RRID:AB_2267671, RRID:AB_94971, RRID:AB_477523, RRID:SCR_018041, RRID:SCR_026521, RRID:AB_2340771, RRID:AB_2340590, RRID:SCR_027461, RRID:SCR_018257, RRID:SCR_001905, RRID:SCR_000432, RRID:SCR_019186, RRID:SCR_027454, RRID:SCR_027455, RRID:SCR_021240; ovine model; preterm birth

DOI:  https://doi.org/10.1002/cne.70149
Brain Commun. 2026 ;8(2): fcag054

Pyruvate kinase M2 in Alzheimer's disease: from dysregulation to therapeutic inhibition.

Esmaeel G Gojani, Robert J Sutherland, Majid H Mohajerani.

  Pyruvate kinase M2 (PKM2) has emerged as a critical regulator of Alzheimer's disease pathophysiology. This review synthesizes current evidence demonstrating how PKM2 dysregulation contributes to cognitive decline by driving Warburg-like metabolic reprogramming, altering post-translational modifications and modulating protein-protein interactions. These processes collectively impair cell-cycle control, transcriptional regulation and cytoskeletal stability in neuronal cells. We further examine the impact of PKM2 on neuroinflammation, highlighting its context-dependent roles in microglia and astrocytes. In addition, we provide a comprehensive evaluation of natural and synthetic PKM2 modulators with therapeutic potential in Alzheimer's disease, summarizing their mechanisms and reported outcomes. Clarifying the molecular basis of PKM2-mediated neurodegeneration and rigorously testing these modulators in preclinical models will be essential steps towards developing PKM2-targeted strategies for Alzheimer's disease intervention.

Keywords:  Alzheimer's disease; PKM2; PKM2 modulator; Warburg effect; neuroinflammation

DOI:  https://doi.org/10.1093/braincomms/fcag054
J Adv Res. 2026 Mar 22. pii: S2090-1232(26)00268-7. [Epub ahead of print]

Restoring mitochondrial lipid homeostasis with arachidonic acid supplementation to alleviate cognitive impairment in schizophrenia patients.

Yan Gao, Dandan Wang, Qian Wang, Jinfeng Wang, Shuhui Li, Feng Lei, Jiansong Zhou, Xiaowen Hu, Chunling Wan.

   INTRODUCTION: While mitochondrial dysfunction is implicated in schizophrenia, comprehensive understanding of mitochondrial lipid dysregulation in disease pathogenesis remains limited.
OBJECTIVES: To elucidate lipid-driven mitochondrial pathology in schizophrenia and developing nutritional interventions to ameliorate cognitive impairment in schizophrenia through mitochondrial lipid homeostasis restoration.
METHODS: Here, this study investigated a total of 93 schizophrenia patients (61.3% male) and 34 matched healthy controls (41.2% male). Comprehensive mitochondrial lipidomic analyses using ultrahigh performance liquid chromatography-mass spectrometry were conducted to characterize pathological alterations in patients. Building on identification of arachidonic acid (AA) deficiency in schizophrenia-related cognitive impairment, we conducted a six-week nutritional intervention to evaluate AA supplementation's therapeutic potential. Integrated mitochondrial lipidomic and transcriptomic profiling was performed to explore AA intervention-induced molecular changes and underlying mechanisms.
RESULTS: Comparative analyses demonstrated significantly perturbed mitochondrial lipid profiles in schizophrenia patients, characterized by elevated oxidized lipids and AA deficiency. These metabolic disturbances exhibited strong positive correlations with cognitive impairment severity. Six-week AA supplementation improved cognitive performance through enhanced reaction speed, increased memory accuracy, and reduced decision-making errors. Concurrently, AA intervention restored mitochondrial lipid homeostasis by eliminating excessive levels of oxidative lipids. Enrichment analysis highlights key molecular pathways changed in mitophagy and ROS-induced ferroptosis.
CONCLUSION: Our study identifies mitochondrial lipid dyshomeostasis as a pathological hallmark in schizophrenia and clarifies that AA supplementation may restore lipid balance, alongside with coordinating activation of mitophagy and ferroptosis suppression. These molecular corrections underlie the clinical efficacy of cognitive improvements, positioning mitochondrial lipid modulation as a promising therapeutic strategy for schizophrenia.

Keywords:  Arachidonic acid; Cognition; Ferroptosis; Mitochondria; Oxidative stress; Schizophrenia

DOI:  https://doi.org/10.1016/j.jare.2026.03.047
Mol Neurobiol. 2026 Mar 25. pii: 521. [Epub ahead of print]63(1):

Endoplasmic Reticulum-Mitochondrial Crosstalk in Calcium Regulation: Mechanistic Insights and Therapeutic Implications in Traumatic Brain Injury.

Harapriya Baral, Deepali Kumari, Vikrant Rahi, Ravinder K Kaundal.

  The endoplasmic reticulum (ER) and mitochondria are fundamental organelles that govern a wide array of cellular processes and maintain intracellular homeostasis through highly specialized and interconnected functions. Their intimate structural and functional coupling at mitochondria-associated membranes (MAMs) enables the regulated exchange of Ca2⁺, lipids, and metabolites, thereby coordinating key physiological processes. Accumulating evidence underscores the critical role of ER-mitochondrial communication in the maintenance of intracellular Ca2⁺ homeostasis. Traumatic brain injury (TBI), however, disrupts this finely tuned inter-organelle crosstalk, triggering a complex cascade of pathological events characterized by Ca2⁺ dysregulation, ER stress, impaired protein folding, mitochondrial dysfunction, and activation of cell death pathways. This review provides a comprehensive synthesis of current knowledge on MAM-mediated Ca2⁺ transport and delineates how its dysregulation exacerbates cellular stress responses following TBI. We examine the contribution of Ca2⁺ imbalance to ER stress signalling, protein misfolding, and the pathological shift toward excessive mitochondrial fission, culminating in compromised bioenergetics and loss of cellular integrity. Furthermore, we discuss Ca2⁺ dysregulation-driven cell death mechanisms in the injured brain and evaluate emerging therapeutic strategies to restore MAMs function and Ca2⁺ signalling. Collectively, the interplay between Ca2⁺ dysregulation, ER stress, and mitochondrial dysfunction emerges as a central axis underlying neuronal loss after TBI. Elucidating these mechanisms may inform the development of targeted interventions to mitigate secondary injury and preserve neuronal function following TBI.

Keywords:  Calcium dysregulation; ER-stress; MAMs; Mitochondrial dynamics; TBI; UPRs

DOI:  https://doi.org/10.1007/s12035-026-05818-8