bims-medebr 2026-04-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–04–05
33 papers selected by
Regina F. Fernández, Johns Hopkins University

Glial lactate metabolism and transport in Alzheimer's disease.
Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.
Lipid Metabolism and Neurodegeneration: Mechanistic Insights and Therapeutic Targets.
Spatial Lipidomics Reveals Region-Specific Lipid Remodeling in Scn2a-Deficient Mouse Brain.
Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.
Spatial lipidomics identifies α-synuclein-induced lipid changes in an AAV-induced Parkinsonian mouse model.
Neuron-derived mitochondrial DNA (mtDNA) activates microglia via the Z-DNA binding protein 1 (ZBP1)-mediated pathway in mild traumatic brain injury.
Preclinical 1H MRS Study of a Porcine Model Shows Evidence and Mechanisms for Acute Neuronal Injury in Neonatal Cardiopulmonary Bypass (CPB) Surgery.
Multiplexed Tandem Mass Spectrometry Imaging Enables Large-Scale Isomer Mapping and Annotation in Tissues.
The Microglial Lactate-Lactylation Axis as a Metabolic-Epigenetic Driver of Alzheimer's Disease.
Transporters for Creatine and Related Guanidino Compounds: Their Relevance to Brain Health and Disorders.
Sex-specific effect of cortisol on cerebral glucose metabolism across Alzheimer's disease spectrum: a neuroimaging study.
Metabolism Controls the Timing of Human Brain Development and Maturation.
Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.
UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.
Glut1 Acts in Corazonin-Producing Neurons to Regulate Glycogen Storage in Drosophila.
Knockout of Low-Density Lipoprotein Receptor-Related Protein 1 From Astrocytes in Adult Mice Accelerates Long-Term Functional Recovery After Ischemic Stroke.
Neuroimaging confirms selective cerebral involvement in primary lateral sclerosis and predilection to brain regions with high metabolic activity.
Metabolic reprogramming is critical to microglial activation in Huntington's disease.
Cross-species evidence for cardiolipin remodeling in neonatal hypoxic-ischemic encephalopathy.
Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.
Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.
Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.
The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.
The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.
Developmental Profiling of Structural and Functional Maturation in Mouse Corpus Callosum.
Implantable microelectrode biosensors for monitoring neurometabolic markers.
Altered glucose metabolic pattern in basal ganglia: 18F-FDG PET/CT semi-quantitative analysis of metabolic signatures in neonatal bilirubin encephalopathy.
Real-World Evidence on Statin Use for Traumatic Brain Injury Associated Degenerative Neurological Disorders.
The extracellular matrix as a dynamic regulator of brain function and plasticity.
Neuron-specific expression of murine thyroid hormone transporters Mct8 and Oatp1c1 is dispensable for hippocampus-dependent neuronal functions.
Disrupted lipid homeostasis as a pathogenic mechanism in ABCA7-associated Alzheimer's disease risk.

Front Aging Neurosci. 2026 ;18 1731089

Glial lactate metabolism and transport in Alzheimer's disease.

Yaxin Wang, Boxiang Feng, Ruiwei Hong, Dan Qiu, Jinfeng Zhao, Li Zhao.

  Emerging evidence suggests that lactate, once considered merely a metabolic byproduct, plays vital roles in brain energy metabolism, signaling, and neuroprotection. In Alzheimer's disease (AD), increasing research has implicated disruptions in glial lactate metabolism and transport as key contributors to neurodegenerative progression. This review synthesizes recent findings on the dynamic metabolic profiles of astrocytes, oligodendrocytes, and microglia, with emphasis on their stage-specific glycolytic activities and their roles in neuronal energy support. We detail how these cellular metabolic behaviors and the intercellular lactate shuttle systems-mediated by monocarboxylate transporters (MCTs) and gap junctions-are altered in AD pathology. We highlight how these changes lead to a state of neuronal energetic crisis and, paradoxically, contribute to neuroinflammation. A clearer understanding of these complex glial lactate dynamics offers a promising perspective for novel AD biomarkers and therapeutic strategies.

Keywords:  Alzheimer’s disease; aerobic glycolysis; glial cells; lactate metabolism; lactate shuttle

DOI:  https://doi.org/10.3389/fnagi.2026.1731089
bioRxiv. 2026 Mar 27. pii: 2026.03.24.712448. [Epub ahead of print]

Requirement for oxidation of neuronal ketone bodies in aging and neurodegeneration.

Joyce Yang, Mitsunori Nomura, Jonathan X Meng, Thelma Y Garcia, Timothy R Matsuura, Daniel P Kelly, Ken Nakamura, John C Newman.

Glucose is the brain's primary fuel, but the brain can also use alternative energy substrates, especially during development or starvation. Emerging evidence suggests ketone metabolism may help the brain adapt to energy stress in neurodegenerative diseases such as Alzheimer's disease, although its role in constitutive brain function in normal aging is poorly understood. Using iPSC-derived human neurons and adult-inducible, neuron-specific Bdh1 knockout mice, we show that ketone body metabolism is essential for maximum energy production, neuronal function, and mouse survival-even under normal nutritional conditions. Mechanistically, phenotypes of Bdh1 knockout neurons are mitigated by provision of acetoacetate, a downstream energy metabolite. Moreover, loss of neuronal ketone oxidation markedly increases mortality and memory deficits in Alzheimer's disease model mice. These findings identify ketones as critical neuronal fuels, with particular importance during neurodegeneration. While non-energetic activities of ketone bodies are increasingly appreciated, oxidation for energy provision is an essential mechanism for normal function in neurons and mice. Targeting the energetic function of ketones may thus offer new therapeutic strategies for both aging and neurodegenerative diseases such as Alzheimer's.

DOI: https://doi.org/10.64898/2026.03.24.712448
Ageing Res Rev. 2026 Mar 26. pii: S1568-1637(26)00106-6. [Epub ahead of print] 103114

Lipid Metabolism and Neurodegeneration: Mechanistic Insights and Therapeutic Targets.

Yessenia Marroquin Salas, Kevin M Kemper, Santhanam Shanmughapriya, Dianne Langford, Kalimuthusamy Natarajaseenivasan.

  Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and signaling, thereby increasing oxidative stress and inflammatory responses. Advanced techniques such as single-cell RNA sequencing (scRNA-seq) and single-nucleus transcriptomics have revealed specific alterations in lipid metabolism across different cell types, indicating a metabolic shift that enhances microglial activation and astrocytic reactivity. This lipid dysregulation contributes to a cycle that heightens neuronal vulnerability. Lipid rafts also facilitate receptor-mediated signaling, tying lipid imbalances to immune activation. Consequently, therapeutic strategies targeting lipid pathways are gaining traction, including modulating apolipoprotein E, inhibiting ceramide synthesis, and supplementing fatty acids to enhance membrane fluidity. Moreover, lipidomics helps identify unique lipid signatures that could serve as biomarkers for early diagnosis and treatment monitoring. Understanding the connection between lipid metabolism, neuroinflammation, and neurodegeneration offers valuable insights for developing targeted interventions in neurodegenerative diseases.

Keywords:  Aging; Alzheimer's disease; Lipid metabolism; Lipid rafts; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1016/j.arr.2026.103114
ACS Chem Neurosci. 2026 Mar 30.

Spatial Lipidomics Reveals Region-Specific Lipid Remodeling in Scn2a-Deficient Mouse Brain.

Alyssa Moore, Xiaoling Chen, Emerson Hernly, Jingliang Zhang, Yang Yang, Julia Laskin.

  Mass spectrometry imaging (MSI) is a powerful tool for mapping the spatial distribution of biomolecules in biological samples. Among the various MSI techniques, nanospray desorption electrospray ionization (nano-DESI) is ideally suited for quantitative imaging of a wide range of biomolecules in biological tissues due to its capabilities as an ambient, liquid extraction-based technique. In this study, we used nano-DESI MSI to investigate the effects of Scn2a gene deficiency in the mouse brain. Scn2a, which encodes the voltage-gated sodium channel NaV1.2, is critical to neuronal excitability, and its dysfunction is linked to epilepsy and neurodevelopmental disorders such as autism. Despite its importance, the molecular alterations associated with Scn2a dysfunction are still poorly understood. Herein, we present the first comprehensive study of regional lipid and metabolite alterations associated with Scn2a deficiency, achieved by comparing brain tissues from wild-type (WT) and Scn2a homozygous gene-trap (HOM) mice. Nano-DESI MSI experiments were performed on an Orbitrap mass spectrometer in both positive and negative ionization modes, with three biological replicates per group to ensure reproducible detection and broad coverage of biomolecules. Region-of-interest (ROI) analysis revealed multiple species with altered abundance in the HOM mouse brain. Notably, several phosphatidylethanolamine (PE) lipids were observed at higher abundance in different regions of the brain. For example, PE(O-36:5) is more abundant in both the cortex and hippocampus of the HOM brains, while PE(40:4) is more abundant in the hippocampus. Meanwhile, several lipid species, including phosphatidylserine, PS(38:1), were at lower abundance in the cortex. In contrast, abundant structural lipids, including phosphatidylinositol, PI(38:4), and phosphatidylcholine, PC(34:1), showed no significant differences between WT and HOM brains. Our findings offer new insights into the lipid alterations underlying epilepsy and related neurodevelopmental disorders associated with Scn2a deficiency.

Keywords:  epilepsy; lipidomics; mass spectrometry imaging; nano-DESI; neurodevelopmental disorders; spatial neurobiology

DOI:  https://doi.org/10.1021/acschemneuro.6c00199
FEBS Lett. 2026 Mar 30.

Linking neurogenesis, oligodendrogenesis, and myelination defects to neurodevelopmental disruption in primary mitochondrial disorders.

Sahitya Ranjan Biswas, Porter L Tomsick, Alicia M Pickrell, Paul D Morton.

  Primary mitochondrial disorders (PMDs) are inherited metabolic diseases that most often present with neurological symptoms in infancy or adolescence, underscoring the central importance of mitochondrial function to brain health. Historically, the field has emphasized neurodegeneration-consistent with the high energetic demands of postmitotic neurons. However, neurodevelopmental manifestations are now recognized as common early phenotypes, frequently preceding clinical regression in many PMDs. Given the pivotal role of mitochondria in neural stem/progenitor cell maintenance and cell fate decisions, defects in the respiratory chain are poised to disrupt neurogenesis and gliogenesis. Evidence for such developmental vulnerabilities is reviewed here. Likewise, because mitochondrial metabolism and dynamics shift across the oligodendrocyte lineage-from oligodendrocyte precursor cell expansion to differentiation and the energetically intensive phase of myelin synthesis-callosal atrophy in mitochondrial leukoencephalopathies may, at least in part, reflect developmental shortcomings in oligodendrogenesis and myelination. This possibility warrants focused investigation in cellular and in vivo models.

Keywords:  mitochondria; mitochondria disorders; neural stem cells; oligodendrocytes; white matter

DOI:  https://doi.org/10.1002/1873-3468.70335
Neurobiol Dis. 2026 Mar 31. pii: S0969-9961(26)00117-8. [Epub ahead of print] 107372

Spatial lipidomics identifies α-synuclein-induced lipid changes in an AAV-induced Parkinsonian mouse model.

Yachao He, Ibrahim Kaya, Xiaoqun Zhang, Anna Nilsson, Li Cao, Per E Andren, Per Svenningsson.

  Parkinson's disease (PD) is characterized by Lewy body pathology, mainly consisting of accumulation of aggregated α-synuclein and lipid contents. Lipid dyshomeostasis has frequently been observed in PD, and compelling evidences indicate that lipids play critical roles in modulating α-synuclein toxicity. However, how α-synuclein regulates brain lipid composition remains poorly understood. Here, we used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to spatially profile brain lipids in a unilateral adeno-associated virus (AAV)-α-synuclein mouse model of Parkinsonism. We identified region-specific alterations in sphingolipids and glycerophospholipids in the substantia nigra and striatum of these mice. In sphingolipids, α-synuclein overexpression altered certain monosialotetrahexosylgangliosides (GM1s), sphingomyelins (SMs), and sulfated hexosyl ceramides (SHexCers; a.k.a. sulfatides). Glycerophospholipid changes followed a desaturation pattern: polyunsaturated fatty acid (PUFA)-containing species were decreased, while saturated and mono-unsaturated species were increased. Additionally, oxidized phosphatidylcholine (PC) lipids, such as SAzPC (1-stearoyl-2-azelaoyl-sn-PC) and PAzPC(1-palmitoyl-2-azelaoyl-sn-PC), were elevated in the substantia nigra, and ether phosphatidylethanolamines (PEs) were reduced in the substantia nigra but increased in the striatum. Our study provides a comprehensive, spatially resolved lipidomic landscape of α-synuclein-induced pathology in the nigrostriatal pathway, offering new insights into lipid dysregulation in experimental PD and a framework for future therapeutic exploration.

Keywords:  Adeno-associated virus; Gangliosides; Glycerophospholipids; Mass spectrometry imaging; Parkinson's disease; Spatial lipidomics; Sphingolipids; α-Synuclein

DOI:  https://doi.org/10.1016/j.nbd.2026.107372
Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2527009123

Neuron-derived mitochondrial DNA (mtDNA) activates microglia via the Z-DNA binding protein 1 (ZBP1)-mediated pathway in mild traumatic brain injury.

Michela Marcatti, Javier Allende Labastida, Tony Zifeng Tang, Akbar Ahmad, Christina Payne, Nora Schwartz, Paula Villarreal, Olivia D Solomon, Gracie Vargas, Ping Wu, Bartosz Szczesny.

  Traumatic brain injury (TBI) is a leading cause of morbidity and mortality, with closed-head mild TBI (mTBI) accounting for nearly 90% of all cases. Early pathological events include microglial activation and neuronal mitochondrial dysfunction; however, their interconnection in mTBI remains poorly understood. Using a clinically relevant closed-head weight-drop mouse model, we identified mitochondrial DNA (mtDNA)-specific damage and increased expression of innate inflammatory markers (IL-1α/β, IL-6, TNFα, and CXCL1) in the cerebral cortex during the acute mTBI phase. Mechanistically, neurons subjected to in vitro injury model of mTBI exhibited early mtDNA-specific damage followed by mtDNA release via extracellular vesicles (EVs) together with the neuronal and exosomal markers. The released neuronal mtDNA induced a robust microglial activation mediated by binding to the cytoplasmic DNA/RNA sensor Z-DNA-binding protein 1 (ZBP1), triggering activation of the ZBP1-TBK1-IRF3 pathway resulted IL-6 and TNFα expression. An early, enhanced amounts of mtDNA, neuronal and exosomal markers were measured in EVs circulating in the blood of mice subjected to mTBI. ZBP1 knockout (KO) mice displayed suppressed microglial-but not astrocytic-activation in the cortex during the acute mTBI phase. We also measured accumulation of mtDNA-specific damage in the hippocampus during the postacute mTBI phase. The absence of microglial activation in ZBP1 KO mice exacerbated hippocampal-related memory deficits in the postacute mTBI phase. Collectively, our findings identify mtDNA-ZBP1 signaling as a key mechanism regulating microglial activation in mTBI.

Keywords:  Z DNA binding protein 1; microglia; mild traumatic brain injury; mitochondrial DNA; neuroinflammation

DOI:  https://doi.org/10.1073/pnas.2527009123
Magn Reson Med. 2026 Apr 01.

Preclinical 1H MRS Study of a Porcine Model Shows Evidence and Mechanisms for Acute Neuronal Injury in Neonatal Cardiopulmonary Bypass (CPB) Surgery.

Aaron Omon, Meng Gu, Ralph Hurd, Kirk Riemer, Frank Hanley, Daniel Spielman.

   PURPOSE: Congenital heart disease affects 1% of US births, with some infants requiring cardiothoracic surgery under cardiopulmonary bypass (CPB). Optimal surgical parameters to minimize neuronal injury are unknown. We used serial 1H MRS in a neonatal CPB porcine model to assess acute neuronal damage and associated injury mechanisms.
METHODS: 2-week-old piglets (N = 26) were placed in a 3 T MRI to study brain metabolism during CPB. Dynamic single-voxel 1H MRS brain data were acquired while animals underwent CPB via antegrade cerebral perfusion (ACP) or complete circulatory arrest (CA) with findings quantified via ratios to the average total creatine (tCrave). Hypothermic temperatures ranged between 18°C-37°C, and blood glucose (Glc) levels immediately prior to CA ranged from 54 to 700 mg/dL. Acute neuronal injury at ∼1 h post-CA was assessed by decreased N-acetyl aspartate (NAA) and correlated with three potential injury mechanisms: (1) energy failure via pre-CA Glc and phosphocreatine (PCr) loss during CA, (2) reperfusion injury via elevated succinate (Suc) at end of CA, and (3) ammonia toxicity via post-CA glutamine/glutamate (Gln/Glu) levels.
RESULTS: A temperature-dependent NAA/tCrave decrease was observed for the CA studies, whereas no decreases were seen in the ACP animals. Multiple linear regression analysis revealed that NAA/tCrave loss was significantly associated with pre-CA brain Glc/tCr (p = 0.001) and average PCr/tCrave levels during CA (p = 0.024). NAA/tCrave losses were not significantly associated with Suc/tCrave or Gln/Glu changes.
CONCLUSIONS: 1H-MRS in a CPB model identified neuronal injury ∼1 h post CA, with injury severity correlating with pre-CA Glc/tCrave levels and loss of PCr/tCrave during CA.

Keywords:  antegrade cerebral perfusion; blood glucose; brain metabolism; cardiopulmonary bypass; circulatory arrest; deep hypothermic circulatory arrest; magnetic resonance spectroscopy; neonatal

DOI:  https://doi.org/10.1002/mrm.70364
Angew Chem Int Ed Engl. 2026 Mar 30. e22119

Multiplexed Tandem Mass Spectrometry Imaging Enables Large-Scale Isomer Mapping and Annotation in Tissues.

Varun V Sharma, Gabor Toth, Robert Martinis, Cathrin E Hansen, Gijs Kooij, Ingela Lanekoff.

  Accurate molecular annotation is essential for deciphering biochemical processes in spatial biology. Here, we present a scalable and broadly applicable molecular annotation tool for tandem mass spectrometry imaging (MS2I). Our workflow includes parallel image acquisition (PIA) for parallel MS2I and an open-access computational framework for spatial similarity networking (SSN) that enables molecular annotation of MS2I data with isomeric specificity. The PIA enables simultaneous untargeted MSI and targeted MS2I ensuring structure-specific imaging of hundreds of molecules in a single experiment. The SSN increases annotation confidence through graph-based spatial correlation of product ion distributions, opening up new avenues for data investigation and annotation from both MSI and MS2I data. By integrating PIA and SSN into a single workflow, we visualize and annotate 134 phospholipid isomers and isobars in mouse brain tissue. Furthermore, we demonstrate the biological utility of the platform by mapping cholesterol metabolism in human multiple sclerosis brain tissue, revealing lesion-associated cholesterol oxidation pathways. Finally, we propose annotation confidence levels for structural annotation in MSI. Overall, PIA and SSN together provide large-scale, structure-specific MSI, expanding the scope for spatial metabolomics, lipidomics, and chemical pathology through molecular annotation beyond current capabilities.

Keywords:  annotation; isomers; lipids; mass spectrometry imaging; multiple sclerosis

DOI:  https://doi.org/10.1002/anie.202522119
Aging Dis. 2026 Mar 21.

The Microglial Lactate-Lactylation Axis as a Metabolic-Epigenetic Driver of Alzheimer's Disease.

Zhaoxie Yu, Hanzhang Li, Yao Wang, Yanan Li, Feng Shen, Yanchun Wang.

The idea of amyloid-β (Aβ) plaques and tau neurofibrillary tangles has long been central to framing an understanding of Alzheimer disease (AD), but emerging and growing evidence now points to bioenergetic failure and metabolic-epigenetic crosstalk as central to AD progression. Hai et al. summarize animal and human biofluid and neuroimaging data to carve out the pathophysiology of AD in relation to the role of disrupted glucose metabolism, lactate build-up and protein lactylation in glucose metabolism, in their comprehensive review "Lactate, Lactylation and Alzheimer Disease". Building on Hai et al.'s key contributions, we offer a complementary perspective. The microglial lactate-lactylation axis may be remodeled across disease stages during chronic neuroinflammation, potentially serving compensatory functions early but shifting toward maladaptive, pro-inflammatory amplification at later stages. In light of emerging evidence for tau lactylation in human AD brain tissue, we propose a testable hypothesis of intercellular metabolic crosstalk: lactate exported from highly glycolytic microglia may alter local lactate availability and provide an additional substrate for neuronal tau lactylation. Although the causal contribution of lactate from distinct cellular sources remains to be established, this framework provides a useful lens for interpreting coupled metabolic and epigenetic mechanisms in AD. Our future efforts should focus particularly on glycolytic flux, lactate, epigenetic writers/erasers, therapeutic approaches, and non-pharmacological approaches to stage- and cell-specific lactylation profiling, biomarker development, and the incorporation of metabolic and epigenetic endpoints into interventional studies.

DOI: https://doi.org/10.14336/AD.2025.1487
Biol Pharm Bull. 2026 ;49(4): 601-617

Transporters for Creatine and Related Guanidino Compounds: Their Relevance to Brain Health and Disorders.

Masanori Tachikawa.

  Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.

Keywords:  blood–brain barrier; brain barrier; cerebral creatine deficiency syndrome; creatine; guanidino compound; transporter

DOI:  https://doi.org/10.1248/bpb.b25-00796
Front Neurol. 2026 ;17 1680116

Sex-specific effect of cortisol on cerebral glucose metabolism across Alzheimer's disease spectrum: a neuroimaging study.

Alzheimer's Disease Metabolomics Consortium

  Higher levels of cortisol can disrupt the normal patterns of cerebral glucose metabolism in the human brain. This study aims to investigate the effects of elevated cortisol levels on cerebral glucose metabolism in men and women across Alzheimer's disease spectrum. The data was derived from the publicly available Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Eight hundred and twenty-two participants across varying diagnostic cognition status were included: 469 men (mean age of 74.14 ± 7.19 years) and 353 women (mean age of 72.31 ± 7.34 years). Main effect and interaction terms were used in generalized linear models to examine the association between elevated cortisol levels and cerebral glucose metabolism as measured by Fluorodeoxyglucose positron emission tomography (FDG-PET) in men and women across Alzheimer's disease spectrum. Sex-stratified analysis was conducted a priori based on established biological differences in HPA axis function between sexes. Elevated cortisol levels were negatively associated with brain glucose consumption in women, but not in men. Women with APOE4 alleles were at greater risk of brain hypometabolism. Diastolic blood pressure in men, but not women, was negatively associated with brain glucose consumption, an indication of higher vascular vulnerability in men. Notably, while sex-stratified analyses revealed these differential patterns, the formal cortisol*sex interaction term did not reach statistical significance (p = 0.157), potentially due to limited statistical power for detecting interactions. Larger studies are warranted to confirm these sex-specific findings. These findings suggest that cortisol may represent a modifiable risk factor warranting further investigation, particularly in postmenopausal women who experience estrogen decline, a known neuroprotective mediator.

Keywords:  Alzheimer's disease; FDG-PET; MCI; brain hypometabolism; cerebral glucose metabolism; cortisol; healthy aging; sex differences

DOI:  https://doi.org/10.3389/fneur.2026.1680116
J Inherit Metab Dis. 2026 May;49(3): e70180

Metabolism Controls the Timing of Human Brain Development and Maturation.

Valentina Rava, Erica Cannone, Maura Francolini, Elena Taverna.

Among primates the human brain is the largest in size, exhibiting a higher neuronal density and connectivity. The prolonged expansion and subsequent connectome reorganization of the human brain have been suggested to promote higher cognitive and behavioral abilities. The notable variations in cognitive functions between human and nonhuman primates do not exclusively reside in neuronal abundance and connectivity but are also linked to a higher complexity in glial cells' morphology and functions at earlier time points, during embryonic brain development. Here we discuss two features of the human brain and their reciprocal connection. One feature is the high metabolic need of the developing and adult human brain. The other is its prolonged maturation, also known as neoteny. Even though the human brain occupies only a small percentage of the body mass, it is the highest consumer of glucose and oxygen. Among all brain cells, neurons have a great energy demand. Comparative studies suggest that increased glucose consumption and energy metabolism are positively correlated with higher cognitive abilities in humans. In line with the essential role of metabolism as a regulator of brain functions, recent breakthrough works have uncovered the correlation between metabolism and the timing of brain and neuron maturation during evolution. In this review, we specifically focus on the role of time in the evolution of the human brain and its synapses, focusing on the involvement of tissue, cellular, and subcellular metabolism.

DOI: https://doi.org/10.1002/jimd.70180
Free Radic Biol Med. 2026 Mar 26. pii: S0891-5849(26)00250-9. [Epub ahead of print]

Lonp1 Inhibition Disrupts Mitochondrial Function in the hippocampus and Drives an Aging-Like Synaptic and Cognitive Phenotype in adult SAMP8 mice.

Daniela Cortés-Díaz, Claudia Jara, Ítalo Fuentes, Jesús Llanquinao, Matías Lira, Micaela Ricca, Sebastián Valenzuela, Carolina A Oliva, Cheril Tapia-Rojas.

  Lonp1 is the main mitochondrial matrix protease responsible for maintaining mitochondrial proteostasis through the degradation of damaged or misfolded proteins. Although impaired Lonp1 expression or activity has been linked to mitochondrial dysfunction and oxidative stress in peripheral tissues and non-neuronal cells, its role in the brain, and particularly in hippocampal function, remains unexplored. Here, we provide the first in vivo evidence that Lonp1 activity is a critical regulator of mitochondrial redox homeostasis, synaptic integrity, and learning in the hippocampus. We administered the Lonp1 inhibitor Sesamin intranasally to 4-month-old adult Senescent-Acelerated Mouse Prone 8 (SAMP8) mice for 6 weeks. Subsequently, we conducted cognitive tests to assess hippocampal-dependent learning and memory. We also examined Lonp1 proteolytic activity using the FITC-Casein assay, performed Golgi staining to evaluate dendritic spines, and used fluorescent and luminescent probes to investigate mitochondrial function. Interestingly, we selectively impaired Lonp1 function at an early stage of age-related brain vulnerability. Lonp1 inhibition led to the accumulation of mitochondrial Lonp1 substrates and a marked reduction in mitochondrial bioenergetic capacity, as reflected by decreased ATP production and a robust increase in mitochondrial reactive oxygen species (ROS). These redox alterations were accompanied by selective synaptic remodeling, characterized by a reduction in thin dendritic spines without changes in total spine density, and by impaired hippocampus-dependent learning, while memory retention remained preserved. Thus, our findings identify Lonp1 as a previously unrecognized regulator of mitochondrial redox balance and synaptic structure in the hippocampus. Importantly, Lonp1 inhibition recapitulates key features of brain aging, linking defective mitochondrial proteostasis to ROS-driven synaptic vulnerability and cognitive dysfunction. This study establishes Lonp1-dependent mitochondrial quality control as a central node connecting redox dysregulation to synaptic failure and highlights Lonp1 as a novel target for strategies aimed at preserving mitochondrial and cognitive function during aging.

Keywords:  Lonp1; Mitochondrial dysfunction; SAMP8 mice; hippocampal-dependent learning

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.059
Nat Neurosci. 2026 Mar 30.

UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration.

Yang Liu, Zhiyuan Huang, Yu-Wen Hsu, Pragney Deme, Ashley M Frankenfield, Suheng Wu, Xiaofeng Zhao, Honghe Liu, Tao Zhang, Elizabeth J Alexander, Mingming Liu, Yanjun Zhang, Haocheng Wang, Yixin Zhou, Mervyn J Monteiro, Ling Hao, Norman J Haughey, Jiou Wang.

Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2-ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41593-026-02226-y
Front Biosci (Schol Ed). 2026 Mar 19. 18(1): 47458

Glut1 Acts in Corazonin-Producing Neurons to Regulate Glycogen Storage in Drosophila.

Prem Patel, Justin R DiAngelo.

   BACKGROUND: Metabolic homeostasis is regulated by numerous genes, whose dysregulation leads to metabolic diseases such as obesity and diabetes. Several genes important for lipid storage were identified in a buoyancy-based screen in Drosophila larvae, including Glucose transporter 1 (Glut1), which encodes a glucose uniporter. Previous studies have identified metabolic functions of Glut1 in the whole fly brain; however, the specific neurons in which Glut1 acts to regulate nutrient storage remain unknown.
METHODS: To determine the neuronal populations in which Glut1 regulates lipid and carbohydrate storage, Glut1 levels were decreased in specific neurons, and triglycerides (TAGs) and glycogen levels were measured. We specifically decreased Glut1 expression in corazonin (Crz)-expressing neurons, a neuronal population that expresses the corazonin gene (Crz), which encodes a neuropeptide involved in carbohydrate metabolism.
RESULTS: Targeting RNAi against Glut1 in Crz neurons reduced glycogen levels in males but did not alter TAG levels. To further characterize this nutrient storage phenotype, we measured the expression of two genes involved in glycogen storage, glycogen phosphorylase (Glyp) and glycogen synthase (Glys) as well as the Crz transcript. Notably, knocking down Glut1 in Crz-expressing neurons increased Glys and Crz transcript levels.
CONCLUSIONS: These data suggest that Glut1 acts in the Crz-expressing neurons to regulate Crz levels and organismal glycogen metabolism.

Keywords:   Drosophila ; carbohydrate metabolism; corazonin (Crz); glycogen; glycogen phosphorylase; glycogen synthase; neuropeptides

DOI:  https://doi.org/10.31083/FBS47458
Brain Behav. 2026 Apr;16(4): e71300

Knockout of Low-Density Lipoprotein Receptor-Related Protein 1 From Astrocytes in Adult Mice Accelerates Long-Term Functional Recovery After Ischemic Stroke.

Meng Wang, Sadiya N Ahmad, Pamela Reed, Shane Sprague, Naomi L Sayre.

   PURPOSE: Ischemic stroke is a primary cause of death and disability worldwide; however, therapeutic opportunities are limited. Astrocytes, a major class of caretaker glia in the brain, can significantly alter outcomes after stroke through multiple pathways. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor that can modulate cellular signaling through its interaction with a diverse array of signaling mediators; however, its role in astrocyte function is not well elucidated. We tested whether LRP1 in astrocytes could alter outcomes in both the acute phase (24 h) and chronic phase (3-9 months) after middle cerebral artery occlusion in mice.
METHODS: Astrocyte-specific Lrp1 knockout mice were generated by crossing Cx30-CreERT2 mice with Lrp1-floxed mice. As controls, mice were compared to Cx30-CreERT2 mice with wild-type Lrp1. Cre activation was induced by tamoxifen treatment at 2 months of age in all mice. At 3 months of age, male and female mice were subjected to either middle cerebral artery occlusion for 1 h or sham surgery. Mice underwent motor coordination testing, and tissues were harvested at 24 h, 7 days, 3 months, or 9 months post-surgery for subsequent histological analysis.
FINDINGS: We found that genetic knockout of Lrp1 in astrocytes worsened motor coordination in mice acutely after middle cerebral artery occlusion, but paradoxically improved long-term outcomes by 3 months after stroke. Notably, at 3 months post-stroke, loss of astrocyte LRP1 was associated with improved motor outcomes and reduced gliosis.
CONCLUSION: Our results suggest that loss of astrocyte LRP1 accelerates recovery after ischemic stroke.

Keywords:  LRP1; astrocyte; gliosis; middle cerebral artery occlusion; recovery; stroke

DOI:  https://doi.org/10.1002/brb3.71300
Rev Neurol (Paris). 2026 Mar 31. pii: S0035-3787(26)00495-9. [Epub ahead of print]

Neuroimaging confirms selective cerebral involvement in primary lateral sclerosis and predilection to brain regions with high metabolic activity.

J Kleinerova, M Tahedl, E Finegan, W F Siah, J C Hengeveld, M A Doherty, O Hardiman, R L McLaughlin, S Hutchinson, E L Tan, P Bede.

   BACKGROUND: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease manifesting in progressive limb spasticity, gait impairment, bulbar dysfunction and often in pseudobulbar affect. Varying degree of frontotemporal involvement has also been recently confirmed. Postmortem data is scarce in PLS and disease burden patterns are best characterised in vivo by purpose-designed neuroimaging protocols.
METHODS: A large prospective neuroimaging study has been undertaken to explore cerebral involvement patterns in PLS using a both structural T1-weighted data and diffusion MRI data. Neuroimaging data were complemented by genetic screening and comprehensive clinical profiling. Brain involvement patterns have been first characterised by standard morphometric and diffusivity analyses. Resulting disease burden maps were then correlated to physiological mitochondrial density (MitoD) maps. In an additional, region-of-interest analysis, brain regions with significant topological associations between neurodegeneration and MitoD were ranked based on their r-values.
RESULTS: Grey matter degeneration in PLS is not limited to the motor cortex, but also encompasses frontotemporal, caudate, thalamic, cerebellar and cingulate regions. Voxelwise statistics confirm topological associations between atrophy and physiological mitochondrial density. The most significant associations between neurodegeneration and MitoD were detected in the cerebellum, superior temporal lobe, precentral gyrus, inferior operculum, and orbitofrontal gyrus. Similarly, white matter degeneration is not limited to the corticospinal tracts, but includes the corpus callosum, frontotemporal association fibres, the cingulum, cerebellar peduncles, and the fornix. Anatomical associations were also detected between diffusivity alterations and focal MitoD.
DISCUSSION: PLS is associated with a selective disease burden pattern, and our data suggest that brain regions with high baseline metabolic activity are more likely to succumb to neurodegeneration. Cerebral areas showing the most significant anatomical associations between atrophy and mitochondrial density (precentral gyrus, cerebellum, frontotemporal regions) are pathognomonic brain regions of PLS driving its core clinical manifestations.

Keywords:  ALS; Amyotrophic lateral sclerosis; MRI; Mitochondria; Motor Neuron Disease; Neuroimaging; PLS; Primary lateral sclerosis

DOI:  https://doi.org/10.1016/j.neurol.2026.03.003
JCI Insight. 2026 Apr 02. pii: e201466. [Epub ahead of print]

Metabolic reprogramming is critical to microglial activation in Huntington's disease.

Abhishek Jauhari, Adam C Monek, Olena S Abakumova, Tanisha Singh, Sukhman Singh, Xiaomin Wang, Carley S Clise, Diane L Carlisle, Robert M Friedlander.

  Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (CAG) repeat in the N-terminal of the Huntingtin protein (HTT). Microglial activation and elevated pro-inflammatory cytokines are observed in HD brains, but the mechanisms regulating neuroinflammation and microglial activation are poorly understood. Metformin-mediated neuroprotection has been demonstrated in experimental models of neurodegeneration, including HD. We found that metformin inhibits mitochondrial DNA (mtDNA) release and subsequent neuroinflammation in the cortex and striatum of a mouse model of HD. Moreover, elevated pro-inflammatory cytokines and microglial activation are inhibited by metformin in HD transgenic mice brain. Metformin reduced pathological microglial clusters and shifted towards a quiescent, homeostatic phenotype. Metformin improved aberrant immunometabolism in HD mouse brain and primary microglia. Mechanistically found that metformin regulates mitochondrial fission, reprograms deregulated metabolism in HD microglia, and controls microglial activation and inflammation in HD transgenic mice.

Keywords:  Glucose metabolism; Metabolism; Neurodegeneration; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.201466
J Cereb Blood Flow Metab. 2026 Mar 31. 271678X261435368

Cross-species evidence for cardiolipin remodeling in neonatal hypoxic-ischemic encephalopathy.

Katlynn J Emaus, Garrett M Fogo, Sarita Raghunayakula, Erin Gruley, Liam McCracken, Caroline Dubs, Reagan L Speas, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.

  Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of infant mortality and long-term neurological disability. Current treatments offer limited efficacy, especially in premature or severely affected infants. The pathology of HIE involves a cascade of cellular damage initiated by oxygen and nutrient deprivation, followed by reperfusion injury characterized by excessive reactive oxygen species (ROS) production and mitochondrial dysfunction. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a critical role in maintaining mitochondrial integrity, dynamics, and quality control through mitophagy and programmed cell death. In this study, we examined changes in CL subspecies in an in vitro ischemia/reperfusion model and small and large animal models of neonatal HIE. We observed a significant increase in the ratio of monolysocardiolipin (MLCL) to CL and significant increase in saturated CL species following injury. Genetic ablation of Tafazzin protein using conditional Taz knockout mice resulted in accumulation of MLCL and demonstrated larger brain infarct size following HIE in mice, but without affecting mitochondrial respiration or mitochondrial dynamics under basal conditions. These findings suggest that CL remodeling and MLCL accumulation contribute to the progression of neonatal HIE pathology. This study highlights an underexplored mechanism linking cardiolipin remodeling to brain injury severity, offering potential therapeutic targets for neonatal HIE.

Keywords:  Animal models; cardiolipin; ischemia–reperfusion injury; mitochondrial dysfunction; neonatal hypoxia–ischemia encephalopathy

DOI:  https://doi.org/10.1177/0271678X261435368
Trends Endocrinol Metab. 2026 Apr 02. pii: S1043-2760(26)00068-8. [Epub ahead of print]

Flip the fuel, and the heat is on! Carnitine synthesis as a physiological mediator of fuel adaptation.

Nicolai R Hathiramani, Alexandra E Jerrett, Jessica B Spinelli.

  To what extent does de novo carnitine synthesis in tissues dictate their fuel preference? Recently, Auger et al. identified Solute Carrier 25A45 (SLC25A45) as a mitochondrial trimethyllysine importer for carnitine biosynthesis. SLC25A45 enables certain tissues to constitutively utilize fatty acids as fuel and, upon bioenergetic crisis, mediates a fuel switch that restores homeostasis.

Keywords:  GLP-1RA; TML transporter; carnitine biosynthesis; cold adaptation; fuel switching; mitochondria

DOI:  https://doi.org/10.1016/j.tem.2026.03.007
Am J Hum Genet. 2026 Mar 30. pii: S0002-9297(26)00113-8. [Epub ahead of print]

Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.

Natalie B Tan, Matthias Gautschi, Michael Raum, Daniella H Hock, Robert Kopajtich, Jia Wang, Xiao Qian, Tanavi Sharma, Timothy E Green, Jean-Marc Nuoffer, Katrina M Bell, Katarzyna Pospieszny, Tegan Stait, Chloe Pike, Michelle Cao, Susan M White, David R Thorburn, Theresa Brunet, Matias Wagner, Wolfgang Müller-Felber, Leopold Zeng, Thomas Klopstock, André Schaller, Jing Liu, David A Stroud, Holger Prokisch.

  NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.

Keywords:  CI deficiency; NDUFA5; complex I deficiency; mitochondrial disease; mitochondriopathy

DOI:  https://doi.org/10.1016/j.ajhg.2026.03.003
Brain Commun. 2026 ;8(2): fcag095

Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.

Alessandra Torraco, Charlotte L Alston, Giulia Barcia, Daniela Verrigni, Teresa Rizza, Michela Di Nottia, Anastasia Altobelli, Diego Martinelli, Daria Diodato, Stephanie Efthymiou, Melis Kose, Yamna Kriouile, Albert Z Lim, Silvia Morlino, Barbara Siri, Nebal Waill Saadi, Antonio Novelli, Henry Houlden, Carlo Dionisi-Vici, Robert McFarland, Agnès Rötig, Enrico Bertini, Robert W Taylor, Rosalba Carrozzo.

  NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)-ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function. Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient's mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies. Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability. To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics-including age of symptom onset, phenotypic variability, and patient outcomes-aiming to improve prognostic information and facilitate genetic counselling in clinical practice.

Keywords:  Assembly factors; Leigh syndrome; Mitochondrial disease; NADH–ubiquinone oxidoreductase; Respiratory chain complexes

DOI:  https://doi.org/10.1093/braincomms/fcag095
Exp Neurol. 2026 Mar 31. pii: S0014-4886(26)00115-9. [Epub ahead of print] 115752

Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.

Shuhong Wang, Lili Shi, Yin Tian, Jin Wu, Fujian Guo, Anyong Yu.

  Traumatic brain injury (TBI) initiates a complex secondary injury cascade, within which the bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation forms a self-amplifying vicious cycle, termed the "mitochondria-inflammation axis." This axis is increasingly recognized as a core mechanism driving progressive neural damage. Following TBI, impaired mitochondria not only cause bioenergetic failure but also release copious damage-associated molecular patterns (mtDNA, etc.) and reactive oxygen species (ROS), which potently activate innate immune platforms such as the NLRP3 inflammasome and NF-κB signaling. Conversely, the ensuing inflammatory milieu further aggravates mitochondrial damage through oxidative stress and disruption of quality control, creating a feed-forward loop. This review systematically synthesizes recent advances in understanding this axis, highlighting novel concepts like immunometabolic reprogramming of microglia and intercellular mitochondrial transfer. Furthermore, we critically evaluate emerging therapeutic strategies aimed at breaking this cycle, including mitochondria-targeted antioxidants, precise immunomodulators, and pioneering mitochondrial transplantation. By integrating evidence from multi-omics studies and diverse models, this review provides a unified conceptual framework for understanding TBI pathophysiology and illuminates promising avenues for future translational research.

Keywords:  Immunometabolism; Mitochondria-inflammation axis; Mitochondrial dysfunction; Neuroinflammation; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.expneurol.2026.115752
J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00283-8. [Epub ahead of print] 111413

The inositol pyrophosphate 5-InsP7 regulates mitochondrial polyphosphate synthesis and bioenergetic function.

Jayashree S Ladke, Azmi Khan, Anshit Singh, Henning J Jessen, Ullas Kolthur-Seetharam, Manish Jaiswal, Rashna Bhandari.

  Inorganic polyphosphate (polyP) is a linear polymer of phosphate residues linked by phosphoanhydride bonds. PolyP remains poorly understood in mammals due to its low abundance and lack of information on its metabolism. We developed a DAPI fluorescence-based assay to quantify the low levels of polyP present in mammalian cell lines and tissues, detecting an enrichment of polyP in the mitochondria compared with the nucleus and post-mitochondrial fraction. Mitochondrial polyP synthesis was found to depend on active FoF1 ATP synthase and an intact proton gradient across the inner mitochondrial membrane. Additionally, orthophosphate (Pi) is essential for mitochondrial polyP production, and ATP enhances Pi-driven polyP synthesis in isolated mitochondria. We discovered that the inositol pyrophosphate 5-InsP7, synthesized by IP6K1, regulates mitochondrial polyP levels. Mice and cells deficient in IP6K1 showed a significant reduction in mitochondrial polyP synthesis compared with wild type controls. Cells lacking IP6K1 also showed impaired mitochondrial respiration. The expression of active IP6K1, but not its catalytically inactive form, restored mitochondrial polyP synthesis in IP6K1 deficient cells, but mitochondrial respiration was rescued by expression of either active or inactive IP6K1. These data show that IP6K1 regulates mitochondrial function and polyP production both through the synthesis of 5-InsP7 and via a catalytic activity-independent mechanism. Our findings uncover a link between 5-InsP7, an energy sensor, and polyP, an energy store, in the regulation of mammalian mitochondrial homeostasis.

Keywords:  ATP synthase; cell metabolism; inorganic polyphosphate; inositol phosphate; inositol pyrophosphates; mitochondria; mitochondrial membrane potential; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.jbc.2026.111413
Mol Metab. 2026 Apr 01. pii: S2212-8778(26)00044-X. [Epub ahead of print] 102360

The hypothalamus is an early site of mitochondrial failure and neuro-immune circuit disruption in amyotrophic lateral sclerosis.

Silvia Scaricamazza, Valentina Nesci, Gianmarco Fenili, Marta Tiberi, Anna Percio, Marco Rosina, Illari Salvatori, Flaminia Riggio, Niccolò Candelise, Luisa Pieroni, Viviana Greco, Valerio Chiurchiù, Alberto Ferri, Cristiana Valle.

   BACKGROUND: Metabolic dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), emerging early and strongly associated with disease progression and prognosis. While systemic hypermetabolism is well documented, the central mechanisms underlying energy imbalance remain poorly understood. The hypothalamus, a key regulator of whole-body energy homeostasis, has recently been implicated in ALS, but its mechanistic contribution to metabolic failure and disease progression remains unclear.
METHODS: We analyzed the hypothalamus SOD1-G93A mouse model using proteomics (ProteomeXchange ID: PXD070931), mitochondrial bioenergetic assays, immunofluorescence, flow cytometry, and gene expression to assess hypothalamic mitochondrial function, glial activation, and melanocortin system integrity. Limited analyses in the hFUS model confirmed the presence of key hypothalamic alterations, supporting a shared vulnerability across ALS models. In SOD1-G93A mice, the metabolic modulator trimetazidine (TMZ) was administered presymptomatically to evaluate effects on hypothalamic pathology, metabolic regulation, disease onset, and survival.
FINDINGS: We provide the first evidence that mitochondrial bioenergetic defects arise specifically in the hypothalamus of ALS models before symptom onset. Proteomic profiling revealed dysregulation of mitochondrial pathways, while functional assays confirmed impaired bioenergetics in the hypothalamus. These deficits were accompanied by local pro-inflammatory activation of astrocytes and microglia, mitochondrial dysfunction in glial cells, and early disruption of the arcuate nucleus melanocortin system. Limited analyses in hFUS mice confirmed selective hypothalamic vulnerability. Early TMZ treatment in SOD1-G93A mice specifically restored hypothalamic bioenergetics, normalized local glial activation and melanocortin signaling, delayed disease onset, and extended survival.
INTERPRETATION: These findings establish the hypothalamus as an early and selectively vulnerable site in ALS, where region-specific mitochondrial dysfunction contributes to metabolic and neuroinflammatory alterations. Targeting hypothalamic bioenergetics represents a promising therapeutic strategy.

Keywords:  Energy Metabolism in ALS; Hypothalamic Mitochondrial Dysfunction; Melanocortin System Alterations; Neuroinflammation; Therapeutic Modulation

DOI:  https://doi.org/10.1016/j.molmet.2026.102360
Glia. 2026 Jun;74(6): e70152

Developmental Profiling of Structural and Functional Maturation in Mouse Corpus Callosum.

Hayes Johnson, Maren Beall, Sophia Latifi, Juan Peng, Wenjing Sun.

  As the largest white matter tract within the central nervous system (CNS) to connect two cerebral hemispheres, the corpus callosum axon bundle consists of a mixture of myelinated and unmyelinated axons and plays a crucial role in executing sensory, motor and cognitive functions within the CNS. In this study, we comprehensively characterized progressive alterations in myelination and oligodendrocyte lineage cell densities during the postnatal myelin development and then correlated these structural dynamics to the maturation of axonal impulse conduction within the mouse corpus callosum. In addition, we found that the extracellular spaces between callosal axons were significantly reduced during the first three postnatal weeks in mice, while micron-scale diffusion of small molecule within this region remained largely unaffected and displayed isotropy. However, the glutamate transporter GLT-1 was markedly upregulated within the first 3 postnatal weeks, and its expression was found not only in astrocytes but also in oligodendrocyte lineage cells. Finally, we showed that the ectopic callosal axonal vesicle machinery were not fully matured until the later state of myelin development. In summary, our study provided a dynamic profile of the structural and functional maturation of mouse corpus callosum during postnatal myelin development.

Keywords:  compound action potential; corpus callosum; extracellular space; glutamate signaling; myelin development

DOI:  https://doi.org/10.1002/glia.70152
Bioelectrochemistry. 2026 Mar 24. pii: S1567-5394(26)00072-1. [Epub ahead of print]171 109286

Implantable microelectrode biosensors for monitoring neurometabolic markers.

Eliana Fernandes, Ana Ledo, Rui M Barbosa.

  Implantable microelectrode biosensors enable the monitoring of neurometabolic markers with high spatial and temporal resolution. This review provides an overview of the designs, surface modifications, and electrochemical principles of enzyme-based biosensors that can continuously monitor glucose, lactate, and pyruvate in vivo. It includes the evolution of single-channel and multi-channel microelectrode architectures alongside with advances in surface functionalization strategies that enhance sensitivity, selectivity, and biocompatibility. Critical challenges including foreign body responses, enzymatic stability, and sensor drift are addressed through innovations in soft materials, antifouling chemistries, and enzyme immobilization approaches. Recent findings demonstrate that simultaneous monitoring of multiple neurometabolic markers reveals astrocyte-neuron metabolic coupling, metabolic-vascular coordination, and metabolic stress signatures under physiological and pathological conditions. Integrating wireless telemetry, on-chip signal processing, and machine learning-enabled calibration enables chronic implantation in freely moving animals, supporting fundamental neuroscience and translational neurometabolic research. Emerging developments in multimodal integration that combine chemical sensing, electrophysiology, and neuromodulation promises a new generation of implantable devices for personalized neurological monitoring and adaptive therapeutic interventions. This review highlights the interdisciplinary advances driving implantable biosensors toward clinical translation, as well as the opportunities and challenges remaining for enabling next-generation in vivo brain monitoring technologies.

Keywords:  Electrochemical biosensors; Glucose biosensors; Implantable biosensors; Lactate biosensors; Microelectrode arrays; Neurometabolic monitoring

DOI:  https://doi.org/10.1016/j.bioelechem.2026.109286
Exp Neurol. 2026 Mar 31. pii: S0014-4886(26)00117-2. [Epub ahead of print] 115754

Altered glucose metabolic pattern in basal ganglia: 18F-FDG PET/CT semi-quantitative analysis of metabolic signatures in neonatal bilirubin encephalopathy.

Jiapei Lei, Jie Yu, Xiaotao Zheng, Xiangguo Lai, Junlin Chen, Min Yang, Meng Yu, Yin Wang, Ning Tan.

  Neonatal bilirubin encephalopathy arises from unconjugated bilirubin deposition in the brain. Conventional tests are limited: serum bilirubin does not reflect intracerebral load, and MRI T1 changes are late and confounded by myelination. We evaluated whether 18F-FDG PET detects early metabolic abnormalities and monitor progression. Twelve Sprague-Dawley rat were randomly assigned to bilirubin-exposed or control groups. The bilirubin-exposed group received intraperitoneal bilirubin from postnatal day 3. 18F-FDG PET/CT was performed on days 7 and 21, and regional standardized uptake values and cerebellum-normalized SUV ratios were quantified. Serum bilirubin, histology, immunohistochemistry and qRT-PCR were assessed in parallel. The model showed elevated serum bilirubin (p < 0.001) and neuronal injury. On day 7, PET revealed regional hypermetabolism in hippocampus and thalamus (p < 0.01), coinciding with increased IL-6 (cortex, thalamus) and TNF-α (thalamus). By day 21, widespread hypometabolism involved cortex, basal ganglia, hippocampus, thalamus, and brainstem (p < 0.001), with only residual thalamic IL-6. GFAP indicated persistent astrocytic activation, whereas MAP2 and NeuN were largely preserved. The SUV ratio analysis showed a pattern consistent with the SUV-based findings.18F-FDG PET detected age-dependent metabolic alterations in bilirubin encephalopathy and may be useful for early detection and longitudinal monitoring.

Keywords:  (18)F-FDG PET; Bilirubin encephalopathy; Glucose metabolism; Inflammatory response; Neonates

DOI:  https://doi.org/10.1016/j.expneurol.2026.115754
Ther Clin Risk Manag. 2026 ;22 591742

Real-World Evidence on Statin Use for Traumatic Brain Injury Associated Degenerative Neurological Disorders.

Yu-Hui Lin, I-Ju Tsai, Yu-Ang Chang, Ching-Hui Huang, Chia-Chu Chang.

   Background: Traumatic brain injury (TBI) is a major risk factor for subsequent neurodegenerative disorders. Emerging evidence suggests that statins may mitigate neuroinflammation and lipid dysregulation after TBI. This study aimed to evaluate the association between statin use and the risk of post-TBI degenerative neurological disorders in a global, real-world population.
Methods: We conducted a retrospective cohort study using the TriNetX global research network and a 1:1 propensity score matching procedure to balance demographic, clinical, and medication covariates. Patients with the first TBI diagnosis from 2000 onward were included. Individuals with continuous statin use every year from 1 year before to 5 years after the index date were classified as the statin treated group, whereas those with no statin prescriptions during the same period were categorized as the untreated group. Patients younger than 18 years and those with pre-index dementia, stroke, or CNS infection were excluded. A 1:1 propensity score matching procedure was applied to balance demographic, clinical, and medication covariates. Cox proportional hazards models estimated hazard ratios (HRs) for vascular dementia, non-vascular dementia, stroke, depression, and Parkinson's disease during the 5-year follow-up.
Results: After matching, 21,427 patients were included in each group. Statin-treated patients demonstrated higher risks of all neurologic outcomes compared with untreated individuals, including vascular dementia (HR 2.47; 95% CI, 1.83-3.34), non-vascular dementia (HR 1.45; 95% CI, 1.30-1.61), stroke (HR 1.80; 95% CI, 1.70-1.89), depression (HR 1.91; 95% CI, 1.79-2.04), and Parkinson's disease (HR 1.63; 95% CI, 1.34-1.98). Subgroup analyses showed consistent risk elevations across sex and age categories.
Conclusion: The current Real-World data do not provide evidence supporting the use of statins primarily for neuroprotection after TBI. These findings underscore the importance of pursuing alternative therapeutic strategies that directly target TBI-associated neurodegenerative mechanisms.

Keywords:  TBI; TriNetX; neurodegenerative disease; real-world data; statins; traumatic brain injury

DOI:  https://doi.org/10.2147/TCRM.S591742
Neurobiol Dis. 2026 Apr 01. pii: S0969-9961(26)00119-1. [Epub ahead of print] 107374

The extracellular matrix as a dynamic regulator of brain function and plasticity.

Chuang Ge, Maral Tajerian.

The brain extracellular matrix (ECM) is a dynamic and complex scaffold that not only provides structural support but also plays a key role in regulating synaptic plasticity, axonal regeneration, and cell signaling throughout development and into adulthood. This review focuses on the major components of the brain ECM-including structural proteins (e.g., collagen, elastin), adhesion glycoproteins (e.g., laminin, fibronectin, tenascin), and proteoglycans (e.g., aggrecan, brevican), with an emphasis on their region-specific expression patterns and dynamic changes during development and disease. We explore the role of the ECM in neurodegenerative diseases, psychiatric disorders, and chronic pain, and examine its interactions with glial cells (particularly astrocytes and microglia), which actively remodel the ECM through secretion of matrix-degrading enzymes such as matrix metalloproteinases (MMPs). This review also explores the unique challenges of studying the brain ECM, including its specialized composition and the technical limitations of existing methods. We discuss how recent advances in imaging, mass spectrometry, and omics technologies may provide new insights into ECM dynamics. Finally, we consider future directions, highlighting the potential of AI-based modeling and multi-omics integration to reveal the role of the ECM in brain function and dysfunction and inform a novel therapeutic strategy for neurological and psychiatric diseases.

DOI: https://doi.org/10.1016/j.nbd.2026.107374
Front Endocrinol (Lausanne). 2026 ;17 1781214

Neuron-specific expression of murine thyroid hormone transporters Mct8 and Oatp1c1 is dispensable for hippocampus-dependent neuronal functions.

Andrea Alcaide-Martin, Rim Jaber, Anita Boelen, Heike Heuer, Steffen Mayerl.

   Introduction: Global absence of the thyroid hormone (TH) transporters monocarboxylate transporter 8 (Mct8) and organic anion transporting polypeptide 1c1 (Oatp1c1) in Mct8/Oatp1c1 double knockout (M/O dKO) mice results in a severe central TH deficit due to impaired TH transport across brain barriers. This deficit is accompanied by pronounced abnormalities in inhibitory and excitatory neuronal systems in the brain. However, it remains unclear whether these alterations arise solely from central TH deficiency or whether Mct8 and Oatp1c1 also exert cell-autonomous functions in neurons.
Methods: Immunofluorescence and fluorescent in situ hybridization (FISH) were used to first characterize the expression of Mct8 and Oatp1c1 in GABAergic interneuron subpopulations. Two conditional mouse lines with deletion of both transporters either in all GABAergic (GABA del mice) or glutamatergic neurons (Glut del mice) were then generated. Serum TH concentrations and TH-dependent gene expression were assessed by LC-MS/MS and FISH, respectively. Using immunofluorescence and qPCR, components of the GABAergic and glutamatergic systems as well as adult hippocampal neurogenesis were evaluated. Functional analyses were performed including pilocarpine-induced seizure susceptibility, novel object recognition and elevated plus maze tests.
Results: Serum TH concentrations and TH-regulated gene expression in the brain were unaltered in both conditional mouse lines. No differences in GABAergic markers and expression of glutamatergic ionotropic receptor subunits were found in the hippocampus of GABA del and Glut del mice alongside a normal seizure susceptibility and an unaltered neurogenic program in the adult dentate gyrus. Finally, evaluation of hippocampus-dependent behaviors did not reveal alterations upon neuronal Mct8/Oatp1c1 deficiency, whereas M/O dKO mice exhibit abnormal anxiety-related behavior.
Conclusions: Together, these data point to the central hypothyroid state of M/O dKO mice as the main cause of the neuronal alterations present in these animals and rule out a major cell-autonomous function of Mct8/Oatp1c1 in GABAergic or glutamatergic neurons.

Keywords:  GABAergic interneurons; Mct8; Oatp1c1; glutamatergic neurons; thyroid hormones

DOI:  https://doi.org/10.3389/fendo.2026.1781214
Alzheimers Dement. 2026 Apr;22(4): e71312

Disrupted lipid homeostasis as a pathogenic mechanism in ABCA7-associated Alzheimer's disease risk.

Younji Nam, Brooke A DeRosa, Aura M Ramirez, Biniyam A Ayele, Patrice Whitehead-Gay, Larry D Adams, Charles G Golightly, Takiyah D Starks, Mayra Juliana Laverde-Paz, Holly N Cukier, Rufus Akinyemi, Fred Sarfo, Albert Akpalu, Michael L Cuccaro, Scott M Williams, Allison Caban-Holt, Christiane Reitz, Jonathan L Haines, Goldie S Byrd, Farid Rajabli, Derek M Dykxhoorn, Juan I Young, Jeffery M Vance, Margaret A Pericak-Vance.

   INTRODUCTION: ABCA7 (ATP binding cassette subfamily A member 7) encodes a lipid transporter associated with increasing risk for Alzheimer's disease (AD). A 44-base pair deletion in ABCA7 (rs142076058; p.Arg578Alafs) is a strong risk factor in individuals of African ancestry (AA). However, the biological consequences of this deletion are poorly understood.
METHODS: We expressed the truncated ABCA7 protein in HEK and HepG2 cells to assess cellular localization and impact on lipid metabolism, respectively. Additionally, induced pluripotent stem cell (iPSC)-derived neurons carrying the deletion were functionally assessed compared to isogenic controls.
RESULTS: Truncated ABCA7 localized to endoplasmic reticulum and plasma membranes similarly to the wild type in HEK cells but induced significant lipid droplet accumulation in HepG2 cells and iPSC-derived neurons while reducing mitochondrial membrane potential in iPSC-derived neurons.
DISCUSSION: These findings show that the AA-specific ABCA7 deletion disrupts lipid and mitochondrial homeostasis, supporting a mechanistic link between the ABCA7 deletion and increased AD risk.

Keywords:  ATP binding cassette subfamily A member 7; African ancestry; Alzheimer's disease; frameshift deletion; lipid droplet

DOI:  https://doi.org/10.1002/alz.71312