bims-medebr 2025-06-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–06–22
34 papers selected by
Regina F. Fernández, Johns Hopkins University

Lactate and lactylation modifications in neurological disorders.
Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.
Preserving Neuronal Chemical Messengers: Heat Stabilization Versus Snap Freezing for Improved MALDI Mass Spectrometry Imaging of Brain Tissues.
Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors.
Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.
Low-Glucose Culture Conditions Bias Neuronal Energetics Towards Oxidative Phosphorylation.
Brain Adenylosuccinate Is Dramatically Increased Under Global Ischemia Without Evidence for Purine Nucleotide Cycle Activation.
Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.
Synaptic mitochondria in aging and neurodegenerative diseases: unraveling their functional decline and vulnerability.
Metabolic breakdown: Linking insulin resistance and mitochondrial dysfunction to neurodegeneration in Alzheimer's disease.
Dysregulated lipid metabolism in late preterm low birth weight neonates: A case-control study on maternal lipid levels and early metabolic programming implications.
Omega-3 fatty acids: multi-target mechanisms and therapeutic applications in neurodevelopmental disorders and epilepsy.
Treatment with Efavirenz extends survival in Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.
Modelling mitochondrial diseases in neurons In Vitro: A systematic review.
Subcellular Analysis of Fatty Acid Metabolism Using Organelle-Selective Click Chemistry.
APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.
Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.
Maternal exercise and neonatal overfeeding induces sex-specific peripheral and brain alterations in the offspring.
Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.
Blood Phenylalanine lowering partially reverses white matter changes in a mouse model of Phenylketonuria.
Fatty Acid Synthase Regulates Glucose and Energy Homeostasis via POMC neurons and Adrenergic Signals.
Consensus recommendations for hyperpolarized [1-13C]pyruvate MRI multi-center human studies.
The Regulatory Roles of REST in the Synaptic Development, Function and Related Neurological Disorders.
Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.
Lactate flux dysfunction in patients with bipolar disorder: preliminary insights from ultra-high field 7T MRSI during task and rest.
Brain pericytes upregulate glutamate uptake by astrocytes in vitro through sodium-dependent transporter.
Choline transporters are required for oligodendrocyte differentiation and myelin sheath formation in mouse postnatal brain.
Advances in Circulating Biomarkers for Neurodegenerative Diseases, Traumatic Brain Injuries, and Central Nervous System Tumors.
Differentiation of neonatal and infantile onset ECHS1 deficiency using SCEH enzyme activity and plasma acylcarnitine analysis.
Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss.
PKM2 alleviates mitochondrial oxidative stress and neuronal apoptosis through metabolic and non-metabolic pathways to protect SOD1G93A mice.
ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.
Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.
Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.

Neural Regen Res. 2025 Jun 19.

Lactate and lactylation modifications in neurological disorders.

Yu Gu, Keyang Chen, Chunyan Lei, Xinglong Yang, Lu Wang, Linhu Zhao, Wen Jiang, Qionghua Deng.

   ABSTRACT: Research into lactylation modifications across various target organs in both health and disease has gained significant attention. Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications. Lactate, once considered merely a byproduct of anaerobic metabolism, has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system. Furthermore, recent studies have emphasized the significant role of lactate in numerous neurological diseases, including Alzheimer's disease, Parkinson's disease, acute cerebral ischemic stroke, multiple sclerosis, Huntington's disease, and myasthenia gravis. The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases, aiming to clarify their mechanisms of action and identify potential therapeutic targets. As such, this work provides an overview of the metabolic regulatory roles of lactate in various disorders, emphasizing its involvement in the regulation of brain function. Additionally, the specific mechanisms of brain lactate metabolism are discussed, suggesting the unique roles of lactate in modulating brain function. As a critical aspect of lactate function, lactylation modifications, including both histone and non-histone lactylation, are explored, with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications, such as lactylation writers and erasers. The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized, revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders. Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.

Keywords:  astrocyte-neuron lactate shuttle theory; brain functions; brain lactate metabolism; central nervous system; histone lysine lactylation; monocarboxylate transporters; nervous system; neurodegenerative diseases; non-histone lysine lactylation; post-translational modifications

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01344
Front Neurosci. 2025 ;19 1602149

Fasting the mitochondria to prevent neurodegeneration: the role of ceramides.

Luis Armando Valenzuela-Ahumada, Octavio Fabián Mercado-Gómez, Rubi Viveros-Contreras, Rosalinda Guevara-Guzmán, Alberto Camacho-Morales.

  Neurodegenerative diseases affect up to 349.2 million individuals worldwide. Preclinical and clinical advances have documented that altered energy homeostasis and mitochondria dysfunction is a hallmark of neurological disorders. Diet-derived ceramides species might target and disrupt mitochondria function leading to defective energy balance and neurodegeneration. Ceramides as bioactive lipid species affect mitochondria function by several mechanism including changes in membrane chemical composition, inhibition of the respiratory chain, ROS overproduction and oxidative stress, and also by activating mitophagy. Promising avenues of intervention has documented that intermittent fasting (IF) is able to benefit and set proper energy metabolism. IF is an eating protocol that involves alternating periods of fasting with periods of eating which modulate ceramide metabolism and mitochondria function in neurons. This review will address the detrimental effect of ceramides on mitochondria membrane composition, respiratory chain, ROS dynamics and mitophagy in brain contributing to neurodegeneration. We will focus on effect of IF on ceramide metabolism as a potential avenue to improve mitochondria function and prevention of neurodegeneration.

Keywords:  ceramides; intermittent fasting; microglia; mitophagy; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2025.1602149
J Neurochem. 2025 Jun;169(6): e70122

Preserving Neuronal Chemical Messengers: Heat Stabilization Versus Snap Freezing for Improved MALDI Mass Spectrometry Imaging of Brain Tissues.

Emanuela Salviati, Dominika Luptáková, Anna Nilsson, Reza Shariatgorji, Pietro Campiglia, Nikita Tjernström, Erika Roman, Per E Andrén.

  One of the main challenges in analyzing chemical messengers in the brain is the optimization of tissue sampling and preparation protocols. Limiting postmortem time and terminating enzyme activity is critical to identify low-abundance neurotransmitters and neuropeptides. Here, we used a rapid and uniform conductive heat transfer stabilization method that was compared with a conventional fresh freezing protocol. Together with a selective chemical derivatization method and an optimized quantitation approach using deuterated internal standards, we spatially mapped neurotransmitters and their related metabolites by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in rat brain tissue sections. Although the heat stabilization did not show differences in the levels of dopamine, norepinephrine, and serotonin, their related metabolites 3,4-dihydroxyphenylacetaldehyde, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylacetaldehyde, dihydroxyphenylethyleneglycol, and 5-hydroxyindoleacetic acid were all significantly lower, indicating reduced neurotransmitter postmortem turnover ratios. Heat stabilization enabled detection of an increased number and higher levels of prodynorphin, proenkephalin, and tachykinin-derived bioactive neuropeptides. The low-abundant C-terminal flanking peptide, neuropeptide-γ, and nociceptin remained intact and were exclusively imaged in heat-stabilized brains. Without heat stabilization, degradation fragments of full-length peptides occurred in the fresh frozen tissues. The sample preparation protocols were furthermore tested on rat brains affected by acute anesthesia induced by isoflurane and medetomidine, showing comparable results to non-anesthetized animals on the neurotransmitters level without significant changes. Our data provide evidence for the potential use of heat stabilization prior to MALDI-MSI analyses to improve the examination of the in vivo state of neuronal chemical messengers in brain tissues not impacted by prior acute anesthesia.

Keywords:  brain; mass spectrometry imaging; metabolites; neuropeptide; neurotransmitter; postmortem degradation

DOI:  https://doi.org/10.1111/jnc.70122
EMBO J. 2025 Jun 17.

Lysine myristoylation mediates long-term potentiation via membrane enrichment of synaptic plasticity effectors.

Benjamin Matthews, Sevannah A Steeves, Isaac O Akefe, Noorya Yasmin Ahmed, Rachel S Gormal, Nathalie Dehorter, Tristan P Wallis, Frédéric A Meunier.

  Synaptic plasticity underlying long-term memory is associated with the generation of saturated free fatty acids (sFFAs) -particularly myristic acid- from membrane phospholipids by the phospholipase A1 isoform DDHD2. However, the mechanism through which myristic acid contributes to synaptic plasticity remains elusive. Here we demonstrate that DDHD2-derived myristic acid is rapidly converted to myristoyl CoA, which serves as the substrate for N-myristoyl transferases (NMT1/2), to promote post-translational lysine myristoylation of synaptic proteins. Chemically-induced long-term potentiation (cLTP) in cortical neurons increases both sFFAs and their CoA-conjugates, predominantly myristoyl CoA, and this response is blocked by the DDHD2 inhibitor KLH-45. KLH-45-mediated inhibition of DDHD2 or IMP-1088-mediated inhibition of NMT1/2 also disrupts cLTP-induced proteomic changes, impairs dendritic spine remodeling, and prevents LTP in hippocampal slices. Instrumental conditioning further induces proteomic changes in the hippocampus, which are abolished in learning-deficient DDHD2-/- knockout mice. In these mice, key synaptic proteins such as NMDA receptor subunit GluN1, MAP2, and GAS7 fail to undergo learning-induced changes, effectively linking DDHD2 function to learning-dependent proteome remodeling. Our findings reveal that de novo lysine myristoylation promotes synaptic plasticity and memory formation.

Keywords:   N-Myristoyl Transferase; DDHD2; Long-Term Potentiation; Lysine Myristoylation; Myristic Acid

DOI:  https://doi.org/10.1038/s44318-025-00484-3
Front Comput Neurosci. 2025 ;19 1594330

Constraint-based modeling of bioenergetic differences between synaptic and non-synaptic components of dopaminergic neurons in Parkinson's disease.

Xi Luo, Diana C El Assal, Yanjun Liu, Samira Ranjbar, Ronan M T Fleming.

   Introduction: Emerging evidence suggests that different metabolic characteristics, particularly bioenergetic differences, between the synaptic terminal and soma may contribute to the selective vulnerability of dopaminergic neurons in patients with Parkinson's disease (PD).
Method: To investigate the metabolic differences, we generated four thermodynamically flux-consistent metabolic models representing the synaptic and non-synaptic (somatic) components under both control and PD conditions. Differences in bioenergetic features and metabolite exchanges were analyzed between these models to explore potential mechanisms underlying the selective vulnerability of dopaminergic neurons. Bioenergetic rescue analyses were performed to identify potential therapeutic targets for mitigating observed energy failure and metabolic dysfunction in PD models.
Results: All models predicted that oxidative phosphorylation plays a significant role under lower energy demand, while glycolysis predominates when energy demand exceeds mitochondrial constraints. The synaptic PD model predicted a lower mitochondrial energy contribution and higher sensitivity to Complex I inhibition compared to the non-synaptic PD model. Both PD models predicted reduced uptake of lysine and lactate, indicating coordinated metabolic processes between these components. In contrast, decreased methionine and urea uptake was exclusively predicted in the synaptic PD model, while decreased histidine and glyceric acid uptake was exclusive to the non-synaptic PD model. Furthermore, increased flux of the mitochondrial ornithine transaminase reaction (ORNTArm), which converts oxoglutaric acid and ornithine into glutamate-5-semialdehyde and glutamate, was predicted to rescue bioenergetic failure and improve metabolite exchanges for both the synaptic and non-synaptic PD models.
Discussion: The predicted differences in ATP contribution between models highlight the bioenergetic differences between these neuronal components, thereby contributing to the selective vulnerability observed in PD. The observed differences in metabolite exchanges reflect distinct metabolic patterns between these neuronal components. Additionally, mitochondrial ornithine transaminase was predicted to be the potential bioenergetic rescue target for both the synaptic and non-synaptic PD models. Further research is needed to validate these dysfunction mechanisms across different components of dopaminergic neurons and to explore targeted therapeutic strategies for PD patients.

Keywords:  Parkinson’s disease; bioenergetics; modeling; non-synaptic; synaptic

DOI:  https://doi.org/10.3389/fncom.2025.1594330
J Neurochem. 2025 Jun;169(6): e70125

Low-Glucose Culture Conditions Bias Neuronal Energetics Towards Oxidative Phosphorylation.

Sarpras Swain, David M Roberts, Saad Chowdhry, Ryan Durbin, Reece Boyd, Juli Petereit, Robert Renden.

  Neurons are almost exclusively cultured in media containing glucose at much higher concentrations than found in the brain. To test whether these "standard" hyperglycemic culture conditions affect neuronal respiration relative to near-euglycemic conditions, we compared neuronal cultures grown with minimal glial contamination from the hippocampus and cortex of neonatal C57BL/6NCrl mice in standard commercially available media (25 mM Glucose) and in identical media with 5 mM glucose. Neuronal growth in both glucose concentrations proceeded until at least 14 days in vitro, with similar morphology and synaptogenesis. Neurons grown in high glucose were highly dependent on glycolysis as their primary source of ATP, measured using ATP luminescence and cellular respirometry assays. In contrast, neurons grown in 5 mM glucose showed a more balanced dependence on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), greater reserve mitochondrial respiration capacity, and increased mitochondrial population relative to standard media. Our results show that neurons cultured in artificially high glucose-containing media preferentially use glycolysis, opposite to what is known for neurons in vivo as the primary pathway for ATP maintenance. Changes in gene and protein expression levels corroborate these changes in function and additionally suggest that high glucose culture media increases neuronal inflammation. We suggest using neuronal culture systems in 5 mM glucose to better represent physiologically relevant neuronal respiration.

Keywords:  cell culture; glucose; mitochondrial respiration; neurobasal media; neuronal bioenergetics; primary mouse neuron

DOI:  https://doi.org/10.1111/jnc.70125
J Neurochem. 2025 Jun;169(6): e70121

Brain Adenylosuccinate Is Dramatically Increased Under Global Ischemia Without Evidence for Purine Nucleotide Cycle Activation.

Drew R Seeger, Brennon Schofield, Derek Besch, Svetlana A Golovko, Peddanna Kotha, Mikhail Y Golovko.

  It is well documented that adenosine and adenine nucleotides, such as ATP, ADP, and AMP, undergo significant alterations within seconds upon brain ischemia. For their accurate quantification, in situ deactivation of enzymes involved in their metabolism is required to prevent postmortem alterations. Thus, techniques such as high energy head-focused microwave irradiation (MW) or freeze-blowing are often used prior to metabolome analysis. However, alterations of another important purine nucleotide, adenylosuccinate (AdSucc), under brain ischemia have not been previously addressed. AdSucc is an intermediate in purine nucleotide de novo synthesis. Over 50 years ago, it was also proposed to have a role in brain energy metabolism through the purine nucleotide cycle (PNC) similar to that in muscle, with, to the best of our knowledge, no follow-up studies. In the present study, we applied MW and LC-MS analysis for mouse brain AdSucc quantification in situ at baseline and upon 30 s, 2 min, and 10 min of global ischemia. Our data indicate that in situ enzyme deactivation is required for brain AdSucc quantification. We report, for the first time, that brain AdSucc is dramatically increased 19-fold at 30 s ischemia and 77-fold at 2 min, from 0.007 ± 0.001 to 0.136 ± 0.026 and 0.555 ± 0.036 nmol/mg of brain wet weight (ww), respectively, without further increase at 10 min, positioning it as one of the major brain metabolites under ischemia (~0.56 mM). Quantification of PNC and tricarboxylic acid cycle (TCA) metabolites did not support the role of AdSucc induction in the activation of these pathways under ischemia. Importantly, a significant AdSucc increase up to ~0.56 mM did not affect its precursor aspartate (Asp), which remained at ~1 mM (0.923 ± 0.036 nmol/mg ww) during ischemia, indicating that AdSucc is not produced by the condensation reaction between Asp and IMP in the PNC catalyzed by adenylosuccinate synthase (ADSS). Further studies are required to elucidate the mechanisms for AdSucc increase and its role under brain ischemia.

Keywords:  adenylosuccinate; brain; ischemia; microwave irradiation; purine nucleotide cycle; tricarboxylic acid cycle

DOI:  https://doi.org/10.1111/jnc.70121
Genet Med. 2025 Jun 11. pii: S1098-3600(25)00131-5. [Epub ahead of print] 101484

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.

Sarah C Grünert, Matthias R Baumgartner, Juliette Bouchereau, Alberto Burlina, Peter T Clayton, Javier de Las Heras, Carlo Dionisi-Vici, Corinne Gemperle-Britschgi, Claudia Haase, Stanley H Korman, Johannes Krämer, Eva Kühlwein, Esther M Maier, Arianna Maiorana, Manuel Schiff, Carl Ulrich Schmid, Trine Tangeraas, Raina Yamamoto, Johannes Zschocke, Jörn Oliver Sass.

   PURPOSE: Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far.
PATIENTS AND METHODS: We performed a comprehensive literature search to identify all published cases of HMGCS2D (n=59). Additionally, data of 16 yet undescribed patients with this disorder were collected. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided.
RESULTS: Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life, but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only one variant was identified to be common, (HMGCS2) NM_005518.4: c.634G>A, p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established.
DISCUSSION: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D including a list of HMGCS2 variants identified in affected individuals.

Keywords:  HMGCS2; fatty acid catabolism; ketogenesis; ketone body metabolism; ketone body synthesis; mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency

DOI:  https://doi.org/10.1016/j.gim.2025.101484
Neural Regen Res. 2025 Jun 19.

Synaptic mitochondria in aging and neurodegenerative diseases: unraveling their functional decline and vulnerability.

Karina A Cicali, Angie K Torres, Cheril Tapia-Rojas.

   ABSTRACT: Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.

Keywords:  aging; hippocampus; memory; mitochondria; synaptic mitochondria

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01571
Neural Regen Res. 2025 Jun 19.

Metabolic breakdown: Linking insulin resistance and mitochondrial dysfunction to neurodegeneration in Alzheimer's disease.

Simona Lanzillotta, Lucrezia Romana Rolfi, Barbara Zulli, Eugenio Barone.

   ABSTRACT: The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer's disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer's disease and accelerated aging. Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer's disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagonlike peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative distress and neuroinflammation. This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative distress regulation, as these are pivotal in both Alzheimer's disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Down syndrome; aging; brain insulin resistance; energy metabolism; glucagon-like peptide 1; incretins; insulin; mitochondria; neurodegeneration

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00144
PeerJ. 2025 ;13 e19542

Dysregulated lipid metabolism in late preterm low birth weight neonates: A case-control study on maternal lipid levels and early metabolic programming implications.

Jing Liu, Lijuan Tang, Qi Sun, Di Lv, Yuanmei Chen, Fang Ye, Die Liu, Qin Hui, Haixiao Liang, Chao Wang, Qi Zhang.

   Objectives: While low birth weight (LBW) is a recognized risk factor for adult metabolic syndrome, the unique lipid metabolic phenotype of late preterm low birth weight (LPTB-LBW) neonates-who experience dual exposures to shortened gestation and intrauterine growth restriction-remains uncharacterized. This study specifically examines whether the convergence of prematurity and growth restriction synergistically disrupts lipid metabolic programming.
Methods: Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we compared lipidomic profiles of 88 plasma samples: 45 LPTB-LBW (340/7-366/7 weeks, <2,500 g) and 43 later preterm birth-normal birth weight (LPTB-NBW, 340/7-366/7 weeks, 2,500-4,000 g) controls. Multivariate orthogonal partial least squares-discriminant analysis and univariate modeling identified discriminant lipids. Maternal-neonatal lipid continuity was assessed through Spearman's correlation analysis.
Result: A total of 1,173 lipids were identified, categorized into five major lipid classes, with 349 significantly different lipids detected (324 upregulated and 25 downregulated) in the LPTB-LBW group. All glycerolipids were upregulated, accounting for 50% (162/324) of the upregulated lipids. Long-chain polyunsaturated triglycerides (TG) showed extreme elevations, such as TG (18:2_18:3_18:4) and TG (18:2_20:4_20:5). Monoglycerides, including MG (18:2) and MG (18:1), were also significantly elevated. Among glycerophospholipids (GP), 76 species were upregulated, with notable increases in phosphatidylethanolamines such as PE (O-18:0_22:3) and PE (18:2_22:1), while PG (20:4_22:6) was significantly reduced. All differentially expressed ceramides, including Cer (d26:3/33:1(2OH)), Cer (d29:2/30:2(2OH)), and Cer (d28:3/31:1(2OH)), were upregulated, whereas sphingosines were downregulated. Cholesterol esters were decreased, while bile acids, free fatty acids and acylcarnitines were elevated. KEGG pathway enrichment analysis highlighted significant perturbations in cholesterol, glycerolipid, and sphingolipid metabolism. Maternal high-density lipoprotein cholesterol (HDLC) levels during early pregnancy showed exclusive negative correlations with neonatal lipids, particularly triacylglycerol TG (16:0_18:2_18:2) (r =  - 0.33, p = 0.002), diacylglycerols, and ceramides, whereas no associations were observed for maternal low density lipoprotein (LDLC), TC, or TG.
Conclusions: LPTB-LBW neonates exhibit a unique lipidomic phenotype marked by hyperaccumulation of glycerolipids (e.g., long-chain polyunsaturated TGs), elevated ceramides, and altered phospholipid species (increased PE, decreased PG). Maternal HDLC levels negatively correlated with specific neonatal lipids. These findings highlight early-life lipid alterations in LPTB-LBW infants and the need for further investigation into their clinical implications.

Keywords:  Ceramide; Glycerolipids; LPTB-LBW; Later preterm birth-low birth weight; Lipidomics; UPLC-MS/MS

DOI:  https://doi.org/10.7717/peerj.19542
Front Nutr. 2025 ;12 1598588

Omega-3 fatty acids: multi-target mechanisms and therapeutic applications in neurodevelopmental disorders and epilepsy.

Miao Li, Zhiqiang Li, Yuying Fan.

  Neurodevelopmental disorders (NDDs), including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette's syndrome (TS), impair brain development and function, primarily affecting cognition, behavior, and social skills in children. Epilepsy, characterized by recurrent seizures due to neuronal hyperexcitability, shares pathological mechanisms with NDDs, such as neuroinflammation, synaptic dysfunction, and oxidative stress. Omega-3 fatty acids-primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-exert neuroprotective and neuromodulatory effects in these conditions through multifaceted mechanisms. Omega-3 fatty acids play a role in activating the Nrf2/ARE pathway, protecting neurons from oxidative damage, regulating the gut-brain axis, and regulating the balance of microflora. Although Omega-3 fatty acids have a natural safety advantage in improving NDDs and epilepsy symptoms, the bioavailability is limited by the source, formulation form, and dietary environment. Current studies point out that monotherapy has a limited effect and requires a combination of vitamin D, probiotics, or drugs, as well as the development of innovative functional foods to improve intake efficiency. This review summarizes the multi-pathway roles of Omega-3 fatty acids in NDDs and epilepsy, emphasizing the potential as a core component of integrated treatment strategies. Future studies should prioritize precision nutrition approaches and functional food development to optimize patient outcomes in neuropsychiatric care.

Keywords:  Omega-3 fatty acid; autism spectrum disorder; epilepsy; hyperactivity disorder; tic disorder

DOI:  https://doi.org/10.3389/fnut.2025.1598588
JCI Insight. 2025 Jun 19. pii: e190296. [Epub ahead of print]

Treatment with Efavirenz extends survival in Creutzfeldt-Jakob disease model by regulating brain cholesterol metabolism.

Tahir Ali, Jessica Cashion, Samia Hannaoui, Hanaa Ahmed-Hassan, Hermann M Schatzl, Sabine Gilch.

  Prion diseases are fatal, infectious and incurable neurodegenerative conditions affecting humans and animals, caused by the misfolding of the cellular prion protein (PrPC) into its pathogenic isoform, PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form. Recently, we demonstrated that treatment with the FDA-approved anti-HIV drug Efavirenz (EFV) significantly reduced PrPSc and extended survival of scrapie prion-infected mice. Among other effects, EFV activates the brain cholesterol metabolizing enzyme, CYP46A1, which converts cholesterol into 24S-hydroxycholesterol (24S-HC). However, drugs effective against scrapie prions often fail in human prion diseases, and a relation of the anti-prion effects of EFV to CYP46A1 activation is not established. Thus, we evaluated EFV treatment in mice overexpressing human PrPC infected with human sCJD prions. Oral, low-dose EFV treatment starting at 30- or 130-days post-infection significantly slowed disease progression and extended their survival. At early clinical stage, we observed reduced PrPSc accumulation, decreased cholesterol and lipid droplet content, and elevated CYP46A1 and 24S-HC levels in EFV-treated mice. Overexpression of CYP46A1 in prion-infected neuronal cells reduced PrPSc levels and increased 24S-HC, indicating that anti-prion effects of EFV correlate with CYP46A1 activation. These findings highlight EFV as a safe and efficacious therapeutic candidate for human prion diseases.

Keywords:  Cholesterol; Infectious disease; Neurodegeneration; Prions; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.190296
J Neuromuscul Dis. 2025 Jun 19. 22143602241307198

Modelling mitochondrial diseases in neurons In Vitro: A systematic review.

Mariana Zarate-Mendez, Nihal A Basha, Oliver Podmanicky, Natalia Malig, Denisa Hathazi, Rita Horvath.

  Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.

Keywords:  induced pluripotent stem cells; neuronal models; primary mitochondrial diseases

DOI:  https://doi.org/10.1177/22143602241307198
J Am Chem Soc. 2025 Jun 17.

Subcellular Analysis of Fatty Acid Metabolism Using Organelle-Selective Click Chemistry.

Takami Kimura, Seita Kawamoto, Alma Fujisawa, Mao Yoshida, Yuying Shen, Masaki Tsuchiya, Tomonori Tamura, Itaru Hamachi.

The structural diversity of the fatty acids esterified in organellar membrane lipids is thought to confer the characteristic physiological properties of the membranes. However, the abundance profiles of fatty acid derivatives are still poorly characterized at organelle-level spatial resolution. Here, we have developed a technology for organelle-specific labeling and quantitative analysis of fatty acid derivatives involving the metabolic incorporation of azide fatty acids and organelle-localizing clickable dyes. This approach was used to investigate palmitate- and oleate-derived lipids in different organelle membranes. The relative abundances of fatty acid-containing lipids were found to differ depending on the organelle and the structure of the fatty acid. In addition, organelle-specific temporal variations in fatty acid derivatives were revealed that are difficult to detect using conventional lipid analysis.

DOI: https://doi.org/10.1021/jacs.5c02871
Stem Cell Reports. 2025 Jun 06. pii: S2213-6711(25)00141-9. [Epub ahead of print] 102537

APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.

Karina K Meyer-Acosta, Eva Diaz-Guerra, Parul Varma, Adyasha Aruk, Sara Mirsadeghi, Aranis Muniz-Perez, Yousef Rafati, Ali Hosseini, Vanesa Nieto-Estevez, Michele Giugliano, Christopher Navara, Jenny Hsieh.

  Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, APOE4 causes persistent changes in brain structure as early as infancy and is associated with altered functional connectivity that extends beyond adolescence. Here, we used human induced pluripotent stem cell-derived cortical and ganglionic eminence organoids (COs and GEOs) to examine APOE4's influence during the development of cortical excitatory and inhibitory neurons. We show that APOE4 reduces cortical neurons and increases glia by promoting gliogenic transcriptional programs. In contrast, APOE4 increases proliferation and differentiation of GABAergic progenitors resulting in early and persistent increases in GABAergic neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupts neural network function resulting in heightened excitability and synchronicity. Together, our data provide new insights on how APOE4 influences cortical neurodevelopmental processes and the establishment of functional networks.

Keywords:  APOE4; Alzheimer's disease; cortical development; differentiation; disease modeling; gliogenesis; iPSC; network excitability; neurodevelopment; neurogenesis

DOI:  https://doi.org/10.1016/j.stemcr.2025.102537
Commun Biol. 2025 Jun 17. 8(1): 936

Membrane lipid composition modulates the organization of VDAC1, a mitochondrial gatekeeper.

Elodie Lafargue, Jean-Pierre Duneau, Nicolas Buzhinsky, Pamela Ornelas, Alexandre Ortega, Varun Ravishankar, James Sturgis, Ignacio Casuso, Lucie Bergdoll.

VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.

DOI: https://doi.org/10.1038/s42003-025-08311-5
Brain Res. 2025 Jun 12. pii: S0006-8993(25)00339-7. [Epub ahead of print]1864 149778

Maternal exercise and neonatal overfeeding induces sex-specific peripheral and brain alterations in the offspring.

Pauline Maciel August, Bernardo Gindri Dos Santos, Ismael Mesquita, Alessandra Gonçalves Machado, Débora Santos Rocha, Eduardo Z B de Assis, Luisa Soares Pedroso, Vinicius Stone, Manuela Menegotto Zeferino, Carla Dalmaz, Cristiane Matté.

  Childhood obesity is rapidly increasing, resulting in long-term negative health consequences. The impact of early-life factors on adulthood health is described through the Developmental Origin of Health and Disease (DOHaD) concept, which links the metabolic effects of prenatal interventions to an increased risk of chronic non-communicable diseases later in life. Our study aimed to evaluate the influence of prenatal exercise and neonatal overfeeding on pup development, and peripheral metabolic parameters, as well as mitochondrial function and oxidative stress in the hypothalamus and hippocampus. Female Wistar rats were divided into two groups before and during pregnancy: (1) sedentary, and (2) swimming exercise. One day after birth, the litter size was adjusted to 8 pups or 3 pups per dam, leading to control and overfed subgroups within each maternal group. Maternal exercise and neonatal overfeeding resulted in an accelerated eye opening in the pups. Overfeeding-induced increased mesenteric fat in females was decreased by maternal exercise. In male pups, maternal exercise was able to prevent overfeeding-induced increased blood glucose. In the hippocampus we also found a sex-specific effect, with male pups born from exercised dams and raised in an overfeed environment showing impaired mitochondrial function. Overall, our data demonstrates a positive effect of maternal exercise in well-known overweight effects, such as body fat and blood glucose levels. In the male pup hippocampus, maternal exercise could not prevent the sex-specific effects caused by neonatal overfeeding.

Keywords:  Brain redox status; DOHaD; Maternal exercise; Metabolic programming; Obesity

DOI:  https://doi.org/10.1016/j.brainres.2025.149778
Nat Neurosci. 2025 Jun 13.

Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.

Yifei Cai, Iguaracy Pinheiro-de-Sousa, Mykhaylo Slobodyanyuk, Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas A Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet T Lam, Evangelia Petsalaki, Jüri Reimand, Angus C Nairn, Jaime Grutzendler.

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions, including those linked to amyloid-β processing, axonal outgrowth and lipid metabolism. Expansion microscopy confirmed the subcellular localization of top proteomic hits and revealed amyloid-β aggregation within the internodal periaxonal space and paranodal/juxtaparanodal channels. Although overall myelin coverage is preserved, we found reduced paranode density, aberrant myelination and altered paranode positioning around amyloid-plaque-associated dystrophic axons. These findings suggest that the myelin-axon interface is a critical site of protein aggregation and disrupted neuro-glial signaling in AD.

DOI: https://doi.org/10.1038/s41593-025-01973-8
Mol Ther. 2025 Jun 14. pii: S1525-0016(25)00471-X. [Epub ahead of print]

Blood Phenylalanine lowering partially reverses white matter changes in a mouse model of Phenylketonuria.

Rachna Manek, Weixiao Huang, Yinyin Huang, Lilu Guo, Cathleen S Cornell, Mohammed Salman Shazeeb, Alexander Verbitsky, Robert Jackson, Jennifer Johnson, Patricia Berthelette, Dan Yu, Edith L Pfister, Dinesh Bangari, Xiaoyou Ying, Dinesh Kumar, Christian Mueller, Sirkka Kyostio-Moore.

Phenylketonuria (PKU) is a genetic defect caused by lack of liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood Phenylalanine (Phe) levels and neurotoxicity which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering by analyzing the corpus callosum (CC) of adult Pahenu2 (PAH-deficient) mice. MRI and immunostaining demonstrated a significant reduction in CC volume in Pahenu2 mice. Treatment with an adeno-associated vector (AAV) encoding mouse PAH for 3.5 months improved but did not completely normalize CC volume. Total cholesterol, a major component of myelin, was unchanged in the CC of Pahenu2 mouse while some sterol intermediates were significantly reduced by treatment. Single nuclei transcriptomics showed upregulation of oxidative stress-related pathways, and increased expression of transthyretin, ApoE, Cst3, and Cd81 in CC in Pahenu2 mice. Normalization of blood Phe restored gene expression to levels comparable to heterozygous mice and was associated with generation of differentiated myelin-producing oligodendrocyte subtypes and neuroprotective astrocytes. In summary, Pahenu2 mice showed white matter abnormalities and changes in transcriptome and sterol profiles, which were partially corrected by normalization of blood Phe.

DOI: https://doi.org/10.1016/j.ymthe.2025.06.020
Mol Metab. 2025 Jun 18. pii: S2212-8778(25)00084-5. [Epub ahead of print] 102177

Fatty Acid Synthase Regulates Glucose and Energy Homeostasis via POMC neurons and Adrenergic Signals.

Luis Leon-Mercado, Yanbin Dong, Bandy Chen, Arely Tinajero, Caleb C Lord, Syann Lee, Chen Liu, Kevin W Williams, Joel K Elmquist.

OBJECTIVE: Hypothalamic Fatty Acid Synthase (FASN) plays a critical role in regulating energy balance by influencing food intake and body weight. This study aimed to investigate the neuronal mechanisms by which FASN impacts metabolism, focusing on its role in Pro-Opiomelanocortin (POMC) neurons.
METHODS: We used transgenic mouse models with pre- or postnatal deletion of FASN specifically in POMC neurons in male mice. We evaluated changes in adiposity, glucose metabolism and metabolic parameters including food intake, energy expenditure and substrate utilization using metabolic chambers. Changes in neuronal activity were assessed using electrophysiology and further validated by optogenetic stimulation of POMC neurons. Additionally, the role of adrenergic signaling was examined using pharmacological approaches and gene expression analyses.
RESULTS: FASN deletion in POMC neurons reduced food intake, decreased adiposity, and altered glucose metabolism. FASN-deficient POMC neurons exhibited increased baseline activity. The developmental stage of FASN deletion influenced its effects on energy expenditure and body weight regulation. Additionally, FASN in POMC neurons was found to be essential for maintaining glucose homeostasis and insulin release via adrenergic signaling.
CONCLUSIONS: FASN in POMC neurons plays an age- and neuron-specific role in regulating feeding, energy expenditure, and glucose homeostasis through mechanisms including the sympathetic nervous system. These findings highlight FASN as a potential therapeutic target for metabolic diseases by improving energy expenditure and insulinemia. Given the developmental programming of metabolic outcomes, interventions aimed at modulating FASN activity may have long-lasting benefits in managing metabolic diseases.

DOI: https://doi.org/10.1016/j.molmet.2025.102177
Magn Reson Med. 2025 Jun 16.

Consensus recommendations for hyperpolarized [1-13C]pyruvate MRI multi-center human studies.

HP 13C MRI Consensus Group

MRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.

DOI: https://doi.org/10.1002/mrm.30570
J Neurochem. 2025 Jun;169(6): e70132

The Regulatory Roles of REST in the Synaptic Development, Function and Related Neurological Disorders.

Chong Teik Lim, Cheng Wei Lim, Tan Huang, Elysha Nur Ismail, Parham Reisi, Pike See Cheah, King Hwa Ling.

  The synaptic system is the core of the nervous system, coordinating neural communication. Synaptic dysfunctions, including deficits in synaptogenesis, neurotransmission and plasticity, underlie various neurological diseases. Repressor element-1 silencing transcription factor (REST), an epigenetic transcription factor, plays a crucial role in neurodevelopment and neuroprotection by fine-tuning the expression of neuronal genes. REST binds to the RE-1 motif on target genes and recruits cofactors to exert transcriptional regulation. Dysregulation of REST, affecting thousands of downstream neuronal genes, is characteristic of neurological diseases with synaptic dysfunctions, including Huntington's disease, Alzheimer's disease, epilepsy, cerebral ischaemia, bipolar disorder and Kleefstra syndrome. Research on REST-targeted synaptic genes has been ongoing since 1993, using various fundamental and disease neuronal models. However, there has been no comprehensive review to consolidate the scattered knowledge of the regulatory role of REST in the synaptic system. Therefore, we reviewed and identified a list of REST-targeted and -regulated synaptic genes to address this gap. We found that REST plays significant roles in synapse development and function, particularly in the synaptic vesicle cycle, chemical neurotransmission systems and homeostasis of synaptic plasticity. Importantly, approaches to restore REST level in various neurological diseases have successfully rescued REST-targeted synaptic gene expression and ameliorated their synaptic and neuronal functions. This review serves as a foundation for future research on REST and neurological diseases. It aims to delineate the regulatory role of REST in the synaptic system and explore the potential of targeting REST restoration to improve synaptic functions in various neurological conditions.

Keywords:  REST; RE‐1; synapse; synaptic dysfunction; transcription factor

DOI:  https://doi.org/10.1111/jnc.70132
J Neurol Sci. 2025 Jun 16. pii: S0022-510X(25)00202-3. [Epub ahead of print]475 123585

Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.

Qing-Lin Wu, Xiong Yang, Jia-Xin Luo, Li Liu, Ya Zhou, Mei-Hong Lu.

  Alzheimer's disease (AD) is a progressive age-associated neurodegenerative disorder characterized by systemic cerebral metabolic disturbances. Neuroimaging and biochemical analyses reveal three hallmark features: decreased glucose utilization, mitochondrial bioenergetic deficits, and impaired energy homeostasis within hippocampal circuits. Emerging evidence highlights the pivotal role of microglia, the brain's specialized immune guardians, whose metabolic plasticity forms a self-reinforcing pathological cycle with AD progression. During early disease stages, oxidative phosphorylation (OXPHOS)-dependent M2 microglia mediate neuroprotective functions through efficient β-amyloid (Aβ) phagocytosis. However, progressive metabolic reprogramming drives a pathological shift toward glycolysis-dominant M1, characterized by heightened proinflammatory cytokine secretion and compromised clearance capacity. Notably, AD-associated pathological aggregates disrupt microglial metabolic adaptation, suppress mitophagy processes, and perpetuate sustained neuroinflammatory responses. The metabolic flexibility of microglia allows them to adapt to different energy demands. This study reviews the roles of major metabolic pathways and metabolic regulators of microglia in AD and the link between AD pathology and microglia energy metabolism, and describes the potential of relevant drugs and non-drug approaches in AD treatment, revealing metabolic regulation as a new target for AD therapy.

Keywords:  Alzheimer's disease; Energy metabolism; Inflammatory; Microglia; Mitochondrial; Treatment

DOI:  https://doi.org/10.1016/j.jns.2025.123585
Front Neurosci. 2025 ;19 1587011

Lactate flux dysfunction in patients with bipolar disorder: preliminary insights from ultra-high field 7T MRSI during task and rest.

Michele A Bertocci, Rasim S Diler.

   Introduction: The symptoms of bipolar disorder (BD) may be characterized as disruptions in energy metabolism, and neural energy availability may serve as a mechanistic marker of BD. Lactate, the end product of glycolysis, is a poorly understood neural energy source that may contribute to the neural dysfunction underlying BD.
Methods: We aimed to assess precuneus lactate availability during an emotion processing task and during rest in a sample of participants with well-characterized, pediatric-onset BD (n = 17) and healthy participants (n = 8), using 7-Tesla (7T) magnetic resonance spectroscopic imaging (MRSI). The mean age of the participants was 19.2 years (3.8).
Results: In this small sample, we observed that the difference in precuneus lactate availability between the emotion processing task and rest (e.g., lactate flux) was greater in participants with BD [mean = 0.014 (0.041)] than in healthy controls (HCs) [mean = -0.033 (0.028), t(17) = 2.64, p = 0.017, Cohen's d = 1.3, Bayes factor10 = 3.528]. In addition, we found that this greater difference in lactate availability (task-rest) in participants with BD, particularly those with lower precuneus lactate availability at rest, demonstrated a trend related to elevated depression scores (r = 0.459, p = 0.055, Bayes factor10 = 1.617).
Discussion: These results suggest, for the first time, using ultra-high-field strength MRSI with a high signal-to-noise ratio, that lactate flux is dysfunctional in well-characterized BD. Our findings highlight the importance of lactate as a mechanistic marker of BD, which may be used to develop novel treatment options.

Keywords:  bipolar disorder; depression; lactate; neural metabolism; precuneus

DOI:  https://doi.org/10.3389/fnins.2025.1587011
IBRO Neurosci Rep. 2025 Dec;19 54-61

Brain pericytes upregulate glutamate uptake by astrocytes in vitro through sodium-dependent transporter.

Kenta Sakai, Fuyuko Takata, Takuro Iwao, Miho Yasunaga, Gaku Yamanaka, Yasufumi Kataoka, Shinya Dohgu.

  Astrocytes maintain glutamate homeostasis in the central nervous system (CNS) via glutamate uptake through Na+-dependent excitatory amino acid transporters (EAAT1 and EAAT2), and this process is regulated by several CNS cell types. However, it is unclear whether brain pericytes regulate glutamate uptake by astrocytes. Therefore, in this study, we aimed to investigate the effects of pericytes on the uptake of extracellular glutamate by astrocytes using an in vitro co-culture model of human brain-derived pericytes and astrocytes (pericyte co-cultures). The [3H]-L-glutamate ([3H]-L-Glu) uptake rate of astrocytes in pericyte co-cultures was significantly higher than that in astrocyte monocultures. Under Na+-free conditions, [3H]-L-Glu uptake by astrocytes was significantly inhibited in astrocyte monocultures and pericyte co-cultures. The inhibitory effect of Na+ depletion on glutamate uptake by astrocytes was more pronounced in pericyte co-cultures than in astrocyte monocultures. These findings suggest that glutamate uptake by astrocytes through the Na+-dependent transporter EAATs is upregulated by pericytes. Treatment with dihydrokainic acid, a selective inhibitor of EAAT2, significantly inhibited [3H]-L-Glu uptake by astrocytes in pericyte co-cultures but not in astrocyte monocultures. Treatment with UCPH-101, a selective inhibitor of EAAT1, significantly inhibited [3H]-L-Glu uptake by astrocytes in both monocultures and pericyte co-cultures. The UCPH-101-induced reduction in [3H]-L-Glu uptake by astrocytes in pericyte co-cultures was similar to that observed in astrocyte monocultures. These results suggest that pericytes upregulate glutamate uptake via EAAT2 in astrocytes. Furthermore, [3H]-L-Glu uptake in astrocytes significantly increased when astrocytes were treated with pericyte-conditioned medium. This finding suggests that pericyte-derived soluble factors contribute to the upregulation of astrocytic glutamate uptake. To our knowledge, this is the first study to report that pericyte-released mediators upregulate the EAAT2-dependent uptake of extracellular glutamate in astrocytes.

Keywords:  Astrocytes; EAAT2; Glutamate uptake; Pericyte-derived soluble factor; Pericytes; Sodium-dependent glutamate transporter

DOI:  https://doi.org/10.1016/j.ibneur.2025.05.017
Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00623-0. [Epub ahead of print]44(7): 115852

Choline transporters are required for oligodendrocyte differentiation and myelin sheath formation in mouse postnatal brain.

Ming-Chen Liu, Bin Yu, Yu Xia, Qian Cheng, Yao Chen, Xing Gao, Shuang-Ling Wu, Fei Wang, Tao Li, Lan Xiao, Qi-Jing Lei, Feng Mei.

  Oligodendrocyte (OL) myelination is essential for neurological function in the brain. During OL differentiation, rapid membrane synthesis is required for myelin formation, but the mechanisms driving this process remain poorly understood. Choline, a critical component of membrane phospholipids, is transported into cells via choline transporters (ChTs). Here, we identify SLC44A1 and SLC44A5 as the predominant ChTs selectively expressed in oligodendroglia. Conditional knockout (cKO) of either SLC44A1 or SLC44A5 in oligodendroglia impairs OL differentiation and myelination in neonatal brains, with shortened myelin segment lengths. SLC44A1-cKO mice show persistent hypomyelination into adulthood whereas SLC44A5-cKO mice do not, a divergence likely attributable to age-related decline in SLC44A5 expression in oligodendroglia. Metabolomics profiling indicates disrupted lipid metabolism by SLC44A1 deletion, specifically inhibiting plasmalogen synthesis, a pathway vital for myelin biogenesis. Our findings show that SLC44A1/5 support white matter integrity by fueling lipid metabolism, underscoring their potential as therapeutic targets for demyelinating diseases.

Keywords:  CP: Cell biology; CP: Neuroscience; SLC44A1/SLC44A5; choline; choline transporters; lipid metabolism; myelination; oligodendrocyte

DOI:  https://doi.org/10.1016/j.celrep.2025.115852
Ann Lab Med. 2025 Jul 01. 45(4): 381-390

Advances in Circulating Biomarkers for Neurodegenerative Diseases, Traumatic Brain Injuries, and Central Nervous System Tumors.

Ming Yang, Allison Zhang, Meng Chen, Jing Cao.

  Neurological disorders, including neurodegenerative diseases, traumatic brain injuries (TBI), and central nervous system (CNS) tumors, are complex conditions that significantly impact patients globally. Timely diagnosis and monitoring are critical for improving outcomes, driving the need for reliable biomarkers. Specifically, biomarkers detectable in cerebrospinal fluid (CSF) and blood offer important insights into disease presence and progression. This review explores the evolution of circulating blood biomarkers for neurodegenerative diseases, TBI, and CNS tumors, highlighting advanced detection technologies from enzyme-linked immunosorbent assays (ELISAs) to electrochemiluminescence (ECL) assays, single-molecule arrays (Simoa), and mass spectrometry. Advanced technologies with enhanced sensitivity and specificity, particularly in detecting low-abundance analytes, facilitate the investigation of CSF biomarkers for various neurological disorders. We also describe the progress in blood-based biomarkers for , emerging as less invasive alternatives to CSF sampling. Clinically, the implementation of Alzheimer's disease (AD) blood biomarkers Aβ42/Aβ40 ratio and Apolipoprotein E isoform-specific peptide can aid the diagnosis, while p-tau181 and p-tau217 differentiates AD dementia from non-AD neurodegenerative diseases. Blood glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are used in ruling out mild TBI. Despite these innovations, challenges remain, including assay standardization, sensitivity/specificity trade-offs, and the requirement for longitudinal studies to understand biomarker utility over time. Future research should focus on addressing these challenges to fully realize the potential of blood-based biomarkers in neurological disorder diagnostics and patient care.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Blood-based marker; Central nervous system tumors; Multiple sclerosis; Parkinson’s disease; Traumatic brain injuries

DOI:  https://doi.org/10.3343/alm.2024.0611
Mol Genet Metab. 2025 Jun 08. pii: S1096-7192(25)00147-7. [Epub ahead of print]145(4): 109156

Differentiation of neonatal and infantile onset ECHS1 deficiency using SCEH enzyme activity and plasma acylcarnitine analysis.

Olivia D'Annibale, Whitney Phinney, Molly Crenshaw, Mary Kate LoPiccolo, Ibrahim Elsharkawi, Emily Shelkowitz, Daniel Pique, Rodrigo T Starosta, Austin Larson, Johan L K Van Hove, Tim Wood, Aaina Kochhar.

  Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is an autosomal recessive disorder that presents in the neonatal or infantile period with encephalopathy and lactic acidosis. Biomarkers are variable, with many ECHS1D patients having elevated plasma C4-carnitine and urine 2-methyl-2,3-dihydroxybutyric acid while others have none. Neonates often succumb prior to molecular sequencing results being returned. ECHS1D diagnosis may be faster if biomarkers are used in plasma and urine along with enzyme activity measurement. Short-chain enoyl-CoA hydratase activity was performed in six ECHS1D fibroblasts with neonatal or infantile onset. DBS cards were obtained from two patients and one carrier. Control fibroblasts (n = 11) activity was 229.62 ± 68.52 nmol/min/mg. Neonatal ECHS1D fibroblasts activity was 3.92 ± 0.62 nmol/min/mg. Infantile onset ECHS1D fibroblasts activity was 17.27 ± 2.14 nmol/min/mg. Control DBS SCEH activity was 141.18 ± 34.00 nmol/min/mg (n = 10) and one neonatal and infantile patient sample showed approximately 2 % and 27 % activity, respectively. One carrier had 45 % activity. We described five new cases of ECHS1D and analyzed seven total cases. We determined SCEH activity reference ranges in neonatal and infantile onset ECHS1D fibroblasts. For the first time, we demonstrated SCEH activity in DBS with separation between ECHS1D and controls. SCEH activity in DBS could allow for newborn screening for ECHS1D as new treatments are developed. SYNOPSIS: Neonatal and infantile onset ECHS1D can be differentiated via fibroblast and dried blood spot short-chain enoyl-CoA hydratase activity and detection of plasma S-(2-carboxypropyl)cysteine carnitine species to allow for faster diagnosis and prompt treatment.

Keywords:  Acylcarnitine profiling; ECHS1; Enzyme activity; SCEH; Screening,S-(2-carboxypropyl)cysteine carnitine (SCPCC); Valine catabolism

DOI:  https://doi.org/10.1016/j.ymgme.2025.109156
Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2421806122

Decreased mitochondrial activity in the demyelinating cerebellum of progressive multiple sclerosis and chronic EAE contributes to Purkinje cell loss.

Kelley C Atkinson, Shane Desfor, Micah Feri, Maria T Sekyi, Marvellous Osunde, Sandhya Sriram, Saima Noori, Wendy Rincón, Britany Bello, Seema K Tiwari-Woodruff.

  In multiple sclerosis (MS), cerebellar gray matter atrophy, white matter demyelination, and Purkinje cell (PC) loss have been linked to tremors, impaired motor control, and loss of coordination. Similar pathologies have been observed in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). This study hypothesized that inflammatory demyelination of the cerebellum alters overall mitochondrial function and is a contributor to axon degeneration and PC loss. Postmortem cerebellar tissue from MS patients, particularly those with secondary progressive MS, showed decreased mitochondrial complex IV (COXIV) activity and significant PC loss. Inflammation, PC axon demyelination, axon degeneration, and parallel fiber loss were also evident. These findings were mirrored in late-stage EAE mice, which also showed increased inflammation and demyelination, reduced PC COXIV activity, and overall PC loss. Further analysis of EAE mice revealed altered mitochondrial structure, modified mitochondrial respiration, and reduced levels of mitochondrial genes involved in energy production. These findings indicate that both human MS and mouse EAE share similar cerebellar changes linked to mitochondrial dysfunction. Thus, late-stage EAE is a valuable model for studying MS-related cerebellar pathology, and mitochondria may be a potential therapeutic target for MS treatment.

Keywords:  COXIV; axon damage; cerebellar pathology; experimental autoimmune encephalomyelitis; mitochondria respiration

DOI:  https://doi.org/10.1073/pnas.2421806122
Free Radic Biol Med. 2025 Jun 15. pii: S0891-5849(25)00761-0. [Epub ahead of print]238 1-16

PKM2 alleviates mitochondrial oxidative stress and neuronal apoptosis through metabolic and non-metabolic pathways to protect SOD1G93A mice.

Zhuo Zhang, Xia Guo, Yan Liu, Pingyang Ke, Yuan Meng, Juan Gu, Liqin Hu, Ziwei Yuan, Ran Duan, Jing Luo, Fei Xiao.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motor neuron death. Dysregulated energy metabolism is implicated in ALS pathogenesis, yet the role of pyruvate kinase M2 (PKM2), a key glycolytic enzyme, remains elusive. Here, we demonstrated that PKM2 expression was upregulated in the spinal neurons of SOD1G93A mice during early stages of disease. Pharmacological inhibition of PKM2 with compound 3k (C3k) shortened survival times, exacerbated motor deficits, and amplified mitochondrial oxidative stress and neuronal apoptosis in mice with ALS. Mechanistically, PKM2 mitigated mitochondrial dysfunction via its enzymatic activity, promoting lactate metabolism to reduce reactive oxygen species (ROS) accumulation. Concurrently, nuclear PKM2 directly bound to the Nrf2 promoter, enhancing Nrf2 transcription to strengthen antioxidant defenses. Our findings unveil PKM2 as a multifunctional neuroprotectant in ALS, offering novel therapeutic directions through metabolic and transcriptional modulation.

Keywords:  ALS; Apoptosis; Nrf2; Oxidative stress; PKM2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.012
Nat Struct Mol Biol. 2025 Jun 19.

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.

Edrees H Rashan, Abigail K Bartlett, Daven B Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A Abriata, Andrew J Smith, Zakery N Baker, Taylor Cook, Alana Caldwell, Autumn R Chevalier, Patrick Forny, Brian F Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A Simcox, David J Pagliarini.

Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.

DOI: https://doi.org/10.1038/s41594-025-01596-4
Arch Pharm Res. 2025 Jun 19.

Oleanolic acid activates the JNK-Sp1-DJ-1 axis to promote mitophagy-mediated neuroprotection in dopaminergic neurons for Parkinson's disease treatment.

Han-Bin Yang, Chien-Hsing Lee, Nguyen Thao Nhung, Shih-Ya Hung.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by mitochondrial dysfunction and oxidative stress. Although levodopa remains the gold standard for managing PD motor symptoms, it lacks neuroprotective and disease-modifying effects, highlighting the need for new neuroprotective therapies. Mitophagy, the selective mitochondrial degradation by autophagy, is critical for neuronal health. Oleanolic acid, a natural hepatoprotective compound, shows uncertain efficacy in PD treatment. This study investigated the neuroprotective effects and underlying mechanisms of oleanolic acid using the 1-methyl-4-phenylpyridinium (MPP⁺)-induced cellular model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. In vitro, oleanolic acid demonstrated dopaminergic neuroprotection by reducing mitochondrial dysfunction and reactive oxygen species accumulation in PD cells. It upregulated the mitophagic protein DJ-1, enhancing the sequestration of damaged mitochondria into autophagosomes by mitophagy. DJ-1 knockdown attenuated oleanolic acid's neuroprotection, confirming DJ-1's role in oleanolic acid's action. In vivo, pre-treatment with oleanolic acid in MPTP-induced PD mice prevented PD-like motor symptoms, reduced neuronal death in the substantia nigra, and mitigated striatal neurodegeneration. Post-treatment with oleanolic acid not only reduced these effects but also increased Bcl-2 and DJ-1 levels in the substantia nigra and striatum. In vitro, oleanolic acid activated JNK for Sp1 upregulation and nuclear translocation, which induced DJ-1 expression. Computational modeling predicted that oleanolic acid likely interacts with JNK, suggesting this binding might be necessary for JNK-Sp1-DJ-1 axis activation for mitophagy-driven neuroprotection. These results highlight oleanolic acid's potential as a therapeutic agent in PD prevention and treatment via the JNK-Sp1-DJ-1 pathway. Further studies are required to validate its efficacy.

Keywords:  DJ-1; JNK-Sp1 pathway; Mitophagy; Neuroprotection; Oleanolic acid; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12272-025-01550-4
Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809

Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.

Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.

  Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.

Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1016/j.celrep.2025.115809