bims-medebr 2026-07-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–07–05
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.
Beyond fat storage: neuronal lipid droplets regulate whole-body metabolism.
Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
Cortical Cholesterol Deficit and Reduced Network Excitability in ApoE-Deficient Mice.
From tumors to neurons: mass spectrometry imaging in spatial lipidomics.
A Super-Resolution Approach for Astrocyte-Specific Molecular Imaging Reveals the Nanoscale Distribution of Monoacylglycerol Lipase, the Metabolic Node Between Endocannabinoid and Prostaglandin Signaling.
PCSK9 at the intersection of lipid metabolism, immunometabolism, and psychiatric disorders: A narrative review.
GLUT1-driven glycolytic reprogramming in microglia promotes neuroinflammation and cognitive deficits in sepsis-associated encephalopathy.
Ketone Bodies Derived From Medium-Chain Triglycerides Support Brain Metabolism and Function Under Hypoglycemia in Type 1 Diabetes Mellitus.
Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.
Standardized Immunofluorescence Imaging of Tunneling Nanotubes and Mitochondrial Transfer Between Astrocytes and Neurons.
Therapeutic potential of liver X receptor agonist GW3965 in preserving myelin integrity following traumatic brain injury.
Metabolic dysfunction in multiple sclerosis: Elevated lactate and impaired post-exercise creatine response in the anterior cingulate cortex.
Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics.
Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum.
Region-specific dysregulation of proline metabolic enzymes underlying mitochondrial dysfunction in the postmortem brains of patients with schizophrenia.
CTSS regulates macrophage lipid metabolic reprogramming and white matter repair after intracerebral hemorrhage.
Tau protein as a regulator of mitochondrial function and dynamics.
Evolution of the Neurometabolic Cascade of Traumatic Brain Injury.
Lipid Metabolic Labeling to Study Site- and Lipid-Specific Long-Chain S-Acylation Dynamics.

bioRxiv. 2026 Jun 17. pii: 2026.06.14.732179. [Epub ahead of print]

Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.

Esraa Gabal, Thi Kim Oanh Nguyen, Tetiana Kovalenko, Huanyao Gao, Noa Rappaport, Cory Funk, Priyanka Baloni, Eugenia Trushina.

Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.

DOI: https://doi.org/10.64898/2026.06.14.732179
Trends Endocrinol Metab. 2026 Jul 02. pii: S1043-2760(26)00148-7. [Epub ahead of print]

Beyond fat storage: neuronal lipid droplets regulate whole-body metabolism.

Diana U Rodrigues, Julie Jacquemyn, Maria S Ioannou.

  Lipid droplets are dynamic organelles long thought to form in neurons only during disease. However, a study by Manceau et al. discovered that lipid droplets are not only present in healthy neurons but also regulate whole-body metabolism when formed in hunger-responsive neurons in the brain.

Keywords:  activity; energy; lipid droplets; metabolism; neuron; sex-effect

DOI:  https://doi.org/10.1016/j.tem.2026.06.004
J Biol Chem. 2026 Jun 29. pii: S0021-9258(26)02178-2. [Epub ahead of print] 113306

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.

Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.

  Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

Keywords:  Barth syndrome; Cardiolipin; Lipid saturation; Mitochondria; Tafazzin

DOI:  https://doi.org/10.1016/j.jbc.2026.113306
Front Immunol. 2026 ;17 1737175

Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.

Lan Zhang, Xinyue Yang, Xiaolin Ai.

  Microglia play dual and context-dependent roles in the central nervous system, contributing both to the maintenance of brain homeostasis and the propagation of neuroinflammatory responses. Under pathological conditions, microglia undergo profound glycolytic reprogramming, characterized by a shift from oxidative phosphorylation to enhanced aerobic glycolysis. This review focuses on the glucose-glycolysis-lactate metabolic axis and its pivotal role in microglial immunometabolism. We elucidated how key glycolytic enzymes (e.g., HK2, PKM2) and metabolites (e.g., lactate, pyruvate, ATP) regulate microglial function through both metabolic and non-metabolic mechanisms. Furthermore, therapeutic strategies that target this glycolytic shift to alleviate neuroinflammation were discussed. A deeper understanding of microglial glycolytic reprogramming may provide critical insights for developing novel therapies for neurodegenerative diseases.

Keywords:  glycolysis; metabolic reprogramming; microglia; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1737175
Arch Biochem Biophys. 2026 Jul 03. pii: S0003-9861(26)00192-X. [Epub ahead of print] 110921

Cortical Cholesterol Deficit and Reduced Network Excitability in ApoE-Deficient Mice.

Harun Başoğlu, Ayşe Yeşim Göçmen, Ertuğrul Yiğit, Selcen Aydin-Abidin, Hüseyin Avni Uydu, Hilal Öztürk, Hatice Keser, İsmail Abidin.

  Apolipoprotein E (ApoE) is a key regulator of cholesterol transport in both the periphery and the central nervous system and is the major genetic risk factor for late-onset Alzheimer's disease. Although ApoE deficiency is known to elevate circulating cholesterol levels, its consequences for brain cholesterol homeostasis, synaptic integrity, and cortical network excitability remain incompletely understood. In the present study, ApoE knockout (ApoE-/-) and wild-type (WT) mice were used to evaluate systemic and brain cholesterol levels, synaptic protein expression, and cortical electrophysiological activity. ApoE deficiency resulted in significantly elevated serum cholesterol levels compared with wild-type mice. In contrast, cortical cholesterol levels were significantly reduced in ApoE-/- mice, whereas hippocampal cholesterol levels remained unchanged. Consistent with altered cortical lipid homeostasis, synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) levels were significantly decreased in ApoE-deficient animals. At the functional level, ApoE deficiency was associated with reduced basal cortical network activity, reflected by lower electrocorticographic (ECoG) power. Moreover, pharmacological excitation with 4-aminopyridine (4-AP) produced a markedly attenuated increase in cortical excitability in ApoE-deficient mice. Inflammatory markers, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), showed no differences between WT and ApoE-/- mice. Similarly, oxidative stress markers measured in cortex and hippocampus did not indicate a consistent increase in oxidative damage. These findings demonstrate that ApoE deficiency is associated with a multilevel disruption characterized by elevated peripheral cholesterol, reduced cortical cholesterol availability, synaptic protein loss, and diminished cortical network excitability under both basal and hyperexcitable conditions. The results highlight a potential link between impaired brain cholesterol homeostasis and altered synaptic network function in the cortex of ApoE-deficient mice.

Keywords:  ApoE deficiency; cholesterol metabolism; cortical network activity; electrocorticography; synaptic proteins

DOI:  https://doi.org/10.1016/j.abb.2026.110921
Anal Methods. 2026 Jun 29.

From tumors to neurons: mass spectrometry imaging in spatial lipidomics.

Bharath S Kumar.

Lipids are fundamental biomolecules that regulate cellular structure, energy metabolism, and signaling, and their dysregulation is increasingly implicated in the pathogenesis of cancer and neurological disorders. Although conventional lipidomics has provided valuable insights into global lipid composition, it lacks spatial information essential for understanding tissue-level heterogeneity. Mass spectrometry imaging (MSI) has emerged as a transformative, label-free analytical platform that enables spatially resolved molecular mapping of lipids directly within biological tissues. Utilizing complementary ionization techniques such as matrix-assisted laser desorption/ionization (MALDI), desorption electrospray ionization (DESI), and secondary ion mass spectrometry (SIMS), MSI allows simultaneous detection of hundreds to thousands of lipid species while preserving their two- and three-dimensional spatial context. Recent technological advances have significantly improved spatial resolution, lipid identification, and biological interpretation through integration with multimodal imaging and machine learning approaches. In cancer research, spatial lipidomics have revealed heterogeneous lipid distributions within tumor microenvironments, providing insights into metabolic reprogramming, tumor progression, and therapeutic resistance. In neuroscience, MSI-based neurolipidomics has enabled region-specific characterization of lipid alterations associated with neurodegeneration, neuroinflammation, and myelin pathology. Despite ongoing challenges related to standardization, isomeric lipid discrimination, and data integration, MSI continues to reshape our understanding of lipid biology. This review highlights recent methodological innovations and biological applications of MSI, underscoring its growing impact on spatial lipidomics in cancer and neuroscience.

DOI: https://doi.org/10.1039/d6ay00170j
Glia. 2026 Sep;74(9): e70186

A Super-Resolution Approach for Astrocyte-Specific Molecular Imaging Reveals the Nanoscale Distribution of Monoacylglycerol Lipase, the Metabolic Node Between Endocannabinoid and Prostaglandin Signaling.

Miklós Zöldi, István Katona.

  Astrocytes play essential roles in brain function and disorders. Yet, compared to neurons, our knowledge of the physiological and pathological signaling mechanisms in astrocytes remains limited. As a major challenge, the ultrathin (~10-100 nm) processes of astrocytes render high-throughput quantitative molecular imaging within well-defined cellular contexts very difficult. Here, we introduce a single-molecule localization microscopy-based methodology that achieves unprecedented resolution of the intricate astrocytic arbor in intact brain circuits. Postnatal tagging of the plasma membrane by electroporation in mice resulted in selective and sparse labeling of hippocampal astrocytes and enabled the complete visualization of individual astrocytes with nanoscale precision by using STochastic Optical Reconstruction Microscopy (STORM). We also developed high-yield and easy-to-implement approaches to segment, measure, analyze, and visualize nanoscale molecular information within astrocytic compartments. As a proof-of-concept, we could readily differentiate between synaptic and astrocytic proteins by using dual-color STORM super-resolution imaging. Moreover, we identified cell-type-specific differences in the distribution of monoacylglycerol lipase (MAGL), an enzyme regulating synaptic plasticity in neurons and coupling endocannabinoid signaling to prostaglandin signaling in astrocytes. Our findings demonstrate the feasibility of nanoscale molecular measurements within ultrathin astrocytic processes. Moreover, the results provide insights into the synapse-independent nanoscale arrangement of the astrocytic MAGL pool that controls neuroinflammatory processes.

Keywords:  MAGL; STORM; astrocyte; endocannabinoid; mgll; prostaglandin; super‐resolution imaging

DOI:  https://doi.org/10.1002/glia.70186
Brain Behav Immun Health. 2026 Aug;55 101289

PCSK9 at the intersection of lipid metabolism, immunometabolism, and psychiatric disorders: A narrative review.

Folkert H van Bruggen, Roger S McIntyre.

  Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central regulator of lipid metabolism and a well-established determinant of cardiovascular risk. In addition to its hepatic role in cholesterol homeostasis, PCSK9 is increasingly linked to immunometabolic processes that overlap with biological alterations commonly observed in psychiatric disorders, including dyslipidemia, insulin resistance, and low-grade systemic and neuroinflammation. This narrative review synthesizes experimental, genetic, and clinical evidence on lipid metabolism and PCSK9-related pathways in psychiatric disorders. Disorder-specific patterns of peripheral lipid abnormalities are reviewed alongside evidence for altered central lipid composition and cholesterol turnover in major psychiatric and neuropsychiatric conditions. Available data on PCSK9 expression and regulation within the central nervous system (CNS) are summarized, together with studies examining circulating PCSK9 levels in relation to metabolic burden, inflammation, and psychiatric symptomatology. Overall, the literature positions PCSK9 within interconnected metabolic and inflammatory pathways associated with psychiatric vulnerability, primarily as a peripheral marker. Although PCSK9 is implicated in neuroinflammation and may intersect with pathways relevant to brain insulin resistance, its role within the CNS remains incompletely characterized in relation to psychiatric disorders, highlighting an important area for future mechanistic and translational research.

Keywords:  Cholesterol homeostasis; Dyslipidemia; Immunometabolism; Neuroinflammation; PCSK9; Psychiatric disorders

DOI:  https://doi.org/10.1016/j.bbih.2026.101289
Brain Res Bull. 2026 Jun 29. pii: S0361-9230(26)00314-X. [Epub ahead of print]243 112027

GLUT1-driven glycolytic reprogramming in microglia promotes neuroinflammation and cognitive deficits in sepsis-associated encephalopathy.

Hui Guo, Hongling Li, Hu Han, Yubo Wei, Shuaikang Liu, Keke Han, Hexin Zhai, Shimin Dong.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is a severe neurological complication driven by microglial neuroinflammation. Proinflammatory microglial activation requires glycolytic reprogramming, but whether GLUT1 governs this process in SAE remains unclear.
METHODS: In vitro, LPS-stimulated BV2 microglia were transfected with siRNA targeting GLUT1 or GLUT3. Glucose uptake (2-NBDG), glycolytic flux (ECAR, lactate), mitochondrial respiration (OCR), glycolytic enzyme expression (HK2, PFKFB3, PKM2, LDHA), and inflammatory cytokine release were assessed. In vivo, SAE was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Hippocampal GLUT1 knockdown was achieved via stereotactic lentivirus injection. Cognitive function, neuronal damage, neuroinflammation, cerebral lactate/ATP levels, and glycolytic protein expression were evaluated.
RESULTS: LPS significantly upregulated GLUT1, but not GLUT3, in BV2 cells. GLUT1 knockdown markedly suppressed LPS-enhanced glucose uptake, ECAR, lactate production, and expression of HK2, PFKFB3, PKM2, and LDHA, while restoring OCR and reducing TNF-α, IL-1β, and IL-6 secretion. GLUT3 knockdown showed no such effects. In SAE mice, hippocampal GLUT1 expression was increased. Hippocampal GLUT1 knockdown ameliorated cognitive deficits, attenuated hippocampal neuronal loss and Nissl body damage, reduced cerebral inflammatory cytokines and lactate, restored ATP content, and abrogated CLP-induced upregulation of glycolytic enzymes.
CONCLUSIONS: GLUT1 is a critical metabolic checkpoint driving microglial glycolytic reprogramming and proinflammatory activation in SAE. Targeted GLUT1 knockdown in microglia alleviates neuroinflammation and cognitive impairment in experimental SAE models. These findings provide a proof-of-concept that metabolic checkpoint targeting may counteract microglial pro-inflammatory activation.

Keywords:  GLUT1; Glycolysis; Microglia; Neuroinflammation; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.brainresbull.2026.112027
Diabetes. 2026 Jul 01. pii: db260293. [Epub ahead of print]

Ketone Bodies Derived From Medium-Chain Triglycerides Support Brain Metabolism and Function Under Hypoglycemia in Type 1 Diabetes Mellitus.

Domenico Tricò, Lihong Jiang, Daniel Spicer, Kathleen Page, Renata Belfort de Aguiar, Sarita Naik, Mary Savoye, Donna M Caseria, Jagriti Arora, Graeme F Mason, Todd Constable, Douglas L Rothman, Raimund I Herzog.

Impaired cognitive function caused by insulin-induced hypoglycemia is a complication of type 1 diabetes mellitus (T1DM) for which no protective strategies are currently available. In this first-in-human mechanistic study using magnetic resonance spectroscopy, the direct contribution of the infused ketone β-hydroxybutyrate (BHB) to brain metabolism during clamped hypoglycemia was greater in participants with T1DM than healthy participants. In a randomized dietary intervention trial of participants with T1DM and recurrent hypoglycemia, receiving medium-chain triglycerides (MCTs) as a dietary ketone precursor was associated with higher working memory performance and greater regional brain activation during clamped hypoglycemia compared with an isocaloric standard diet. Counterregulatory hormone responses to hypoglycemia were not affected by MCT supplementation. We conclude that ketone bodies are well suited to support brain metabolism in persons with T1DM experiencing insulin-induced hypoglycemia. Dietary MCT supplementation raising BHB may represent a novel strategy to prevent hypoglycemia-induced brain injury in this vulnerable patient population.
ARTICLE HIGHLIGHTS: There are currently no strategies to prevent cognitive impairment caused by insulin-induced hypoglycemia in type 1 diabetes mellitus (T1DM). We examined whether β-hydroxybutyrate (BHB) supports brain metabolism during clamped hypoglycemia and whether dietary medium-chain triglycerides (MCTs), by raising BHB availability, elicit this protective effect. BHB contributed more to brain metabolism in participants with T1DM than in healthy control participants, and long-term MCT supplementation improved working memory and brain activation during hypoglycemia. Dietary MCT supplementation may protect against hypoglycemia-related cognitive deficits in T1DM.

DOI: https://doi.org/10.2337/db26-0293
Nat Commun. 2026 Jul 01.

Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming.

Chun-Hui Duan, Pei-Pei Liu, Xin Sun, Wen-Hui Ma, Jia-Ying Pang, Zi-Han Zhang, Xiao Li, Lin-Fei Jiao, Hong-Zhen Du, Zhao-Qian Teng, Hou-Zao Chen, Chang-Mei Liu.

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.

DOI: https://doi.org/10.1038/s41467-026-75063-z
J Vis Exp. 2026 Jun 12.

Standardized Immunofluorescence Imaging of Tunneling Nanotubes and Mitochondrial Transfer Between Astrocytes and Neurons.

Xiaoyan Du, Yang Deng.

Mitochondria are essential organelles that regulate energy production, cellular signaling, and metabolic homeostasis in neural cells. Tunneling nanotubes (TNTs) are thin membranous structures that mediate long-distance intercellular communication and facilitate the transfer of cellular components, including mitochondria, between connected cells. Reliable visualization of TNTs and mitochondrial transfer requires careful sample handling because these structures are highly fragile and sensitive to fixation, washing, and imaging conditions. This protocol describes standardized procedures for the fixation, staining, and confocal imaging of TNTs in astrocytes and astrocyte-neuron coculture systems. The workflow includes membrane and cytoskeletal staining for TNT visualization, mitochondrial labeling for tracking mitochondrial localization, and immunofluorescence staining for Miro1 colocalization analysis. Critical steps for preserving TNT morphology, including gentle washing and light-protected handling, are emphasized throughout the procedure. The protocol also outlines imaging approaches for the characterization of TNTs and mitochondria in fixed-cell preparations. These methods provide a reproducible experimental framework for studying TNT formation and mitochondrial transfer between neural cells in vitro.

DOI: https://doi.org/10.3791/71670
Br J Pharmacol. 2026 Jul 02.

Therapeutic potential of liver X receptor agonist GW3965 in preserving myelin integrity following traumatic brain injury.

Yongfang Zhou, Zhenyu Zhang, Yulan Zhang, Tao Yuan, Roberta M Lassance-Soares, Srinivas Tipparaju, Celeste Yin-Chieh Wu, Reggie Hui-Chao Lee.

   BACKGROUND: Myelin, a multilamellar sheath produced by oligodendrocytes, ensures rapid electrical impulse conduction and maintains axonal integrity in the central nervous system (CNS). Demyelination, the loss or disruption of this protective sheath, is a key pathological consequence of traumatic brain injury (TBI) that exacerbates axonal injury and ultimately contributes to persistent cognitive and motor deficits. Currently, no therapies specifically target demyelination after TBI. Liver X receptors (LXRs) regulate lipid metabolism, cholesterol homeostasis, and inflammation in CNS cells. Activation of LXRs promotes oligodendrocyte maturation, enhances myelin gene expression, and facilitates remyelination. We hypothesized that GW3965, a synthetic LXR agonist, would enhance myelination and improved cognitive outcomes after TBI.
APPROACHES: C57BL/6 mice were subjected to mild TBI using a closed-head injury model and treated orally with GW3965 (10 mg·kg-1·day-1) starting 1 day post-injury for 3 weeks. Cognitive and behavioural performance was assessed using the modified Neurological Severity Score, open-field, novel object recognition, and Y-maze tests. On day 28 post-TBI, cortical tissues were analysed by immunofluorescence and a ProteinSimple® capillary-based immunoassay.
RESULTS: TBI caused sustained neurological and cognitive impairments characterized by demyelination, axonal injury, and neuronal loss. GW3965 treatment significantly preserved mature oligodendrocytes and myelin, reduced axonal degeneration, and improved behavioural performance.
CONCLUSIONS: This study provides novel insights into the role of LXR activation via GW3965 in mitigating TBI-induced demyelination and axonal injury, while preserving mature oligodendrocytes and cognitive and behavioural outcomes. These findings advance our understanding of brain repair mechanisms and highlight LXR activation as a promising therapeutic strategy for TBI-related neurological damage.

Keywords:  GW3965; cardiovascular disease; liver X receptor; myelination; neuroprotection; traumatic brain injury; vascular pharmacology

DOI:  https://doi.org/10.1111/bph.70575
Mult Scler Relat Disord. 2026 Jun 23. pii: S2211-0348(26)00375-5. [Epub ahead of print]112 107339

Metabolic dysfunction in multiple sclerosis: Elevated lactate and impaired post-exercise creatine response in the anterior cingulate cortex.

Gemma Brownbill, Jeanne Dekerle, Mara Cercignani, Itamar Ronen, James Stone.

   BACKGROUND: Multiple Sclerosis (MS) is characterised by altered brain metabolism and increased chronic perceived fatigue. However, the relationship between brain metabolites, fatigue, and physical task effects in MS remains unclear. This study investigated brain metabolite concentrations (glutamate + glutamine (Glx), lactate, and total creatine (tCr)) in the anterior cingulate cortex (ACC), a region involved in interoceptive processing and fatigue perception, before and after a physical task.
METHODS: Twenty-two people with MS (pwMS) and 22 matched controls underwent Magnetic Resonance Spectroscopy before and after fatiguing isometric wrist extension tasks. Perceptual measures of state fatigue and effort were recorded. Linear mixed models analysed group differences and task-induced metabolite changes.
RESULTS: PwMS showed higher ACC lactate concentrations than controls at rest and post-exercise (F = 7.08, p = 0.011, 95% CI[0.033, 0.228]). No significant Glx differences were observed. A significant group × exercise interaction for tCr occurred (F = 4.63, p = 0.037, 95% CI[0.027, 0.581]), with tCr decreasing post-exercise in controls (t = 3.09, p = 0.02) but remaining stable in pwMS. Metabolite concentrations did not correlate with baseline fatigue measures in either group. Changes in lactate correlated moderately with perceived effort in pwMS only (r = 0.51, p = 0.04).
CONCLUSIONS: This study provides novel evidence of metabolic differences in pwMS, characterised by elevated lactate and stable post-exercise tCr, suggesting altered energy metabolism potentially linked to mitochondrial dysfunction. While these metabolic alterations did not directly correlate with perceived fatigue, they may contribute to the complex pathophysiology of MS-related fatigue.

Keywords:  Anterior cingulate cortex; Brain metabolism; Fatigue; Magnetic resonance spectroscopy; Multiple sclerosis

DOI:  https://doi.org/10.1016/j.msard.2026.107339
bioRxiv. 2026 Jun 22. pii: 2026.06.17.732817. [Epub ahead of print]

Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics.

Jian Qiu, Martha A Bosch, Mya Wolfe, Ksenija Korac, Stefano Rizzo, Todd L Stincic, Scotland E Farley, Wendy Fitzgerald, Megha Rajendran, Aurélien Laguerre, Frank Stein, Philip F Copenhaver, Oline K Rønnekleiv, Sean M Rønnekleiv-Kelly, Tatiana K Rostovtseva, Sergey M Bezrukov, Carsten Schultz, Martin J Kelly.

Loss of estrogens at menopause is linked to impaired brain metabolism and increased risk of Alzheimer's disease (AD). However, estrogen replacement therapies are limited due to the deleterious effects of estrogen on peripheral organs and increased risk of vascular dementia. We have developed a non-steroidal estrogenic compound, STX, which does not bind to the classical estrogen receptors α and β, but mimics estrogenic signaling in the central nervous system (CNS) without the peripheral reproductive actions. STX is protective against neurodegeneration in stroke and AD models, but its molecular targets are unknown. Here, we identified and validated STX neural targets using chemoproteomic, molecular biological, electrophysiological and metabolic assays of hypothalamic proopiomelanocortin (POMC) neurons. Chemoproteomic profiling identified voltage dependent anion channels (VDAC1-3) as major intracellular binding partners in mHypo43 (POMC) cells. Based on quantitative single-cell PCR, Vdac2 was identified as the dominant isoform in female hypothalamic POMC neurons. Seahorse metabolic flux analyses showed that STX potently increased glycolysis, oxidative respiration and mitochondrial ATP production in mHypo43 cells. Nanomolar concentrations of STX enhanced VDAC2 voltage-dependent gating in reconstituted lipid membranes and shifted the low-conductance states toward anion selectivity, consistent with increased ATP flux. Together, these findings reveal a mechanism for the neuroprotective effects of STX through enhancing mitochondrial bioenergetics and modulating VDAC channel properties, potentially increasing cellular energy stores. Therefore, this work identifies previously unrecognized estrogenic mitochondrial targets and provides a mechanistic basis for the neuroprotective actions of STX relevant to menopause-associated brain vulnerability.

DOI: https://doi.org/10.64898/2026.06.17.732817
Brain Res. 2026 Jul 01. pii: S0006-8993(26)00311-2. [Epub ahead of print]1889 150451

Transcriptome-guided modeling reveals insulin-related metabolic dysfunction in SCA3 mouse cerebellum.

Shin-Hung Pan, Jui-Chih Chang, Wen-Ling Cheng, An-Chi Wei, Chin-San Liu.

  Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disorder in which metabolic involvement may extend beyond proteotoxicity alone. We integrated cerebellar RNA sequencing with transcriptome-constrained genome-scale metabolic modeling to characterize metabolic dysregulation in transgenic SCA3 (84Q) versus control (15Q) mice and to relate cerebellar changes to circulating insulin-related measures. Differential expression and preranked gene set enrichment analyses revealed coordinated suppression of insulin/glucose-homeostasis modules and lipid/sterol programs in the SCA3 cerebellum. Context-specific metabolic models derived from iMM1865 and analyzed using parsimonious flux balance analysis, flux variability analysis, and flux sampling indicated reduced oxidative metabolism together with increased nucleotide salvage, one-carbon metabolism, and proteostasis-associated remodeling. Distribution-level comparisons of sampled fluxes detected widespread network reorganization despite modest median shifts. Plasma insulin was elevated in 84Q mice, whereas cerebellar Ins2 and Igf1 transcripts were reduced, consistent with an insulin-related dysregulation signature. Together, these data support broad metabolic reprogramming in the SCA3 cerebellum, including insulin/IGF-related alterations, and nominate pathway-level candidates for future mechanistic validation.

Keywords:  Cerebellum; Genome-scale metabolic modeling; Insulin/IGF signaling; Metabolic reprogramming; Spinocerebellar ataxia type 3; Transcriptomics

DOI:  https://doi.org/10.1016/j.brainres.2026.150451
J Psychiatr Res. 2026 Jun 26. pii: S0022-3956(26)00350-X. [Epub ahead of print]201 328-337

Region-specific dysregulation of proline metabolic enzymes underlying mitochondrial dysfunction in the postmortem brains of patients with schizophrenia.

Atsuko Nagaoka, Mizuki Hino, Risa Shishido, Masataka Hatano, Yuto Hosogai, Akimu Kano, Hideomi Hamasaki, Akiyoshi Kakita, Hiroaki Tomita, Yasuto Kunii.

  Proline metabolism has been associated with schizophrenia pathophysiology; however, the underlying molecular mechanisms remain elusive. This study aimed to investigate the changes in the entire proline metabolic pathway in postmortem brains of patients with schizophrenia. Herein, enzyme-linked immunosorbent assay was performed to determine the protein levels of proline metabolism-associated key enzymes (prolidase [PEPD], proline dehydrogenase [PRODH], pyrroline-5-carboxylate synthetase [ALDH18A1], ornithine aminotransferase [OAT], and pyrroline-5-carboxylate reductase 1 [PYCR1]). Additionally, amino acids metabolized through the proline pathway, including proline, ornithine, and glutamic acid, were quantitatively analyzed through liquid chromatography-tandem mass spectrometry. The alterations in the expression of proline metabolism-associated enzymes and associated amino acid levels were analyzed in the postmortem brains of individuals with schizophrenia, and their associations with premortem clinical symptom scores were examined. Notably, in patients with schizophrenia, PRODH and PYCR1 expression significantly decreased in the superior temporal gyrus and prefrontal cortex, respectively, whereas amino acid levels showed no significant differences. Overall, the findings of this study show that dysregulation in proline metabolism may contribute to mitochondrial dysfunction owing to its close association with energy production and redox regulation. These results suggest the underlying pathophysiology of schizophrenia and provide insights for developing novel therapeutic strategies for managing schizophrenia.

Keywords:  Mitochondrial dysfunction; Postmortem brains; Proline dehydrogenase; Proline metabolism; Pyrroline-5-carboxylate reductase 1; Schizophrenia

DOI:  https://doi.org/10.1016/j.jpsychires.2026.06.042
J Transl Med. 2026 Jun 30. pii: 837. [Epub ahead of print]24(1):

CTSS regulates macrophage lipid metabolic reprogramming and white matter repair after intracerebral hemorrhage.

Xian Yu, Huaping Huang, Dandan Mao, Jianan Wu, Jiahe Pan, Yirui Kuang, Yiwen Wu, Huaijun Chen, Linfeng Fan, Yonghe Zheng, Jiayin Zhou, Shandong Jiang, Xinyan Wu, Hang Zhou, Wei Yan, Haiyan Zheng, Jingyin Chen, Gao Chen, Chi Gu.

   BACKGROUND: Intracerebral hemorrhage (ICH) causes secondary white matter injury, which contributes substantially to long-term neurological disability. Although macrophages accumulate in the perihematomal region and participate in tissue remodeling after ICH, the molecular programs that link macrophage responses to white matter repair remain poorly understood, and no current strategies specifically target macrophage‑mediated white matter restoration. Cathepsin S (CTSS), a lysosomal cysteine protease involved in immune regulation and tissue remodeling, is strongly induced after brain injury; however, its role in post‑ICH white matter pathology has not been defined.
METHODS: A collagenase-induced mouse model of intracerebral hemorrhage (ICH) was established, followed by pharmacological inhibition of Cathepsin S (CTSS) using LY3000328. Single-cell RNA sequencing was performed on perihematomal tissues from Vehicle- and CTSS inhibitor-treated mice to explore CTSS-responsive cell populations and transcriptional programs. Macrophage lipid handling was assessed using flow cytometry, immunofluorescence, and fluorescent myelin debris-based uptake and lipid-transfer assays. A bone marrow-derived macrophage (BMDM)-oligodendrocyte precursor cell (OPC) co-culture system was used to determine whether CTSS inhibition alters macrophage-derived lipid support for OPC differentiation. The LXR agonist GW3965 was applied as a rescue intervention. White matter repair and neurological recovery were evaluated by myelin-associated protein analysis, immunofluorescence, behavioral testing, and transmission electron microscopy.
RESULTS: Single-cell analysis identified infiltrating macrophages, particularly adaptive lipid-associated macrophages (aLAMs), as a major CTSS-expressing population after ICH, displaying a transcriptional state related to lipid metabolism and tissue repair. CTSS inhibition attenuated this lipid-associated macrophage program and reduced ApoE, ABCA1, and ABCG1 expression. Mechanistically, CTSS inhibition reduced Npc1/Npc2 expression and disrupted lysosomal cholesterol trafficking, leading to lysosomal cholesterol retention. These changes suggest impaired Npc1/Npc2-associated cholesterol mobilization and attenuation of the LXR-associated macrophage lipid efflux program. In BMDM-OPC co-cultures, CTSS inhibition reduced the transfer of fluorescent macrophage-processed myelin-derived lipids to OPCs and limited OPC differentiation, whereas GW3965 partially restored Npc1/Npc2 expression, macrophage-derived lipid support, and OPC differentiation. Consistently, in vivo CTSS inhibition reduced MBP expression and MBP⁺ axonal wrapping, increased g-ratio values, aggravated myelin ultrastructural abnormalities, and delayed neurological recovery after ICH.
CONCLUSIONS: CTSS in macrophages supports white matter repair after ICH by maintaining lysosomal cholesterol trafficking and macrophage lipid efflux. CTSS inhibition limits macrophage-derived lipid support for OPCs and impairs remyelination, whereas LXR activation partially restores these reparative responses.

Keywords:  Cathepsin S; Intracerebral hemorrhage; Lipid metabolism; Macrophage; Single-cell transcriptomics; White matter injury

DOI:  https://doi.org/10.1186/s12967-026-08523-1
Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2521642123

Tau protein as a regulator of mitochondrial function and dynamics.

Eleni Tsakiri, Carlos Campos-Marques, Christina Ploumi, Kalliopi Skourti, Antonis Roussos, Eirini Mytilinaiou, Anastasia Vamvaka Iakovou, Ildete Luísa Ferreira, Chrysoula Dioli, Despoina D Gianniou, Martina Samiotaki, Jonas Campos, Clarissa Waites, Nuno Sousa, Ioannis P Trougakos, Joana M Silva, A Cristina Rego, Ioannis Sotiropoulos, Konstantinos Palikaras.

  Mitochondrial damage is a shared hallmark of brain aging and neurodegeneration. While pathological Tau mutations disrupt mitochondrial dynamics and function, the physiological role of wild-type (WT) Tau in the maintenance of mitochondrial homeostasis remains poorly understood. Here, using Caenorhabditis elegans and mice lacking PTL-1, the nematode Tau-like homolog, and Tau respectively, we demonstrate that Tau deficiency promotes a shift toward a pro-fusion mitochondrial state associated with enhanced mitochondrial function and stress resistance. In both models, loss of Tau leads to increased mitochondrial activity and altered redox homeostasis, while it enhances resistance to heat and mitochondrial stress in C. elegans. Strikingly, loss of FZO-1, the mitofusin homolog, abolishes the beneficial phenotypes, whereas its overexpression phenocopies key aspects of Tau/PTL-1 deficiency. Together, our findings uncover a conserved role for WT Tau in restraining mitochondrial fusion and functional adaptation, highlighting its contribution to mitochondrial homeostasis and cellular stress responses.

Keywords:  Tau; mitochondria; mitochondrial dynamics; neurodegeneration; neuron

DOI:  https://doi.org/10.1073/pnas.2521642123
Neurol Clin. 2026 Aug;pii: S0733-8619(26)00023-X. [Epub ahead of print]44(3): 393-414

Evolution of the Neurometabolic Cascade of Traumatic Brain Injury.

William P Flavin, Kevin C Bickart, Janel E Le Belle, Talin Babikian, Madison B Harris, Joshua Kamins, Jose A Pineda, Meeryo C Choe, Christopher C Giza, Mayumi L Prins.

  Since the original descriptions by Giza and Hovda of the acute neurometabolic cascade of concussion 25 years ago, there has been a broad evolution in the understanding of concussion and other types of traumatic brain injuries (TBI) to include not only acute, neuro, and metabolic aspects of pathophysiology but also the impact and risk of TBI on numerous molecular and cellular processes, neural networks and physiologic systems. This review summarizes research and clinical advancements in the neurometabolic cascade of TBI, recognizing that evolution beyond this postinjury neuronal perspective is key to unlocking improved therapies and reduction of long-term risk.

Keywords:  Chronic traumatic encephalopathy; Concussion; Neurometabolic cascade; Persisting post-concussion symptoms; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.ncl.2026.05.001
ACS Chem Biol. 2026 Jul 03.

Lipid Metabolic Labeling to Study Site- and Lipid-Specific Long-Chain S-Acylation Dynamics.

Samiksha Sardana, Carla Busquets-Hernández, Andrea Trezza, Alexandra Tsiotsia, Francine Rodrigues Ianiski, Peter Uljee, Anneroos E Nederstigt, Gemma Triola, Marc P Baggelaar.

Long-chain S-acylation is a post-translational modification that regulates key cellular processes, including signal transduction and metabolic regulation. However, the dynamic nature and site- and lipid-specific patterns of long-chain protein acylation remain poorly understood. Site- and lipid-specific metabolic labeling with various ω-alkynyl fatty acids uncovered the site-specific heterogeneity of long-chain protein S-acylation. Cells use various fatty acids for long-chain S-acylation, including C16:0, C18:0, and C18:1 on cysteines, while N-myristoylation preferentially incorporates C14:0 on N-terminal glycine residues. Our results demonstrate that long-chain S-acylation sites can exhibit both lipid heterogeneity and specificity and reveal that both enzymatic specificity and metabolic context can influence fatty acid incorporation. Exploration of dynamic protein long-chain S-acylation uncovered that acyl-protein thioesterases targeted by Palmostatin B regulate long-chain S-acylation involving various lipids, including C16:0, C18:0, and C18:1. Moreover, the site- and lipid-specific strategy uncovered dynamic long-chain S-acylation in a hydrophobic loop of ABHD17B that requires insertion into the lipid bilayer for efficient catalytic activity, suggesting tunability of ABHD17B enzyme activity through long-chain S-acylation. Our approach represents a significant advancement in lipid metabolic labeling methodologies, offering enhanced efficiency and sensitivity for studying S-acylation dynamics with lipid and site specificity.

DOI: https://doi.org/10.1021/acschembio.6c00517