bims-medebr 2025-03-30 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–03–30
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Neuroglia and brain energy metabolism.
The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
Regulation of CNS Lipids by Protease Activated Receptor 1.
Lipid Composition Diversity of the Human Brain White Matter Tracts.
Comprehensive characterization of metabolic consumption and production by the human brain.
A map of mitochondrial biology reveals the energy landscape of the human brain.
Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
Neuroprotection vs. Neurotoxicity: The Dual Impact of Brain Lipids in Depression.
A human brain map of mitochondrial respiratory capacity and diversity.
Reversible reduction in brain myelin content after endurance exercise.
MFSD2A in focus: the molecular mechanism of omega-3 fatty acid transport.
Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.
Ex-vivo Imaging of Glial Energy Metabolism in the Neonatal Mouse Brain during Convulsive Seizures with Intranasal Radiotracer Administration.
Ceramide: a central regulator in Alzheimer's disease pathogenesis.
Astrocyte glucose-6-phosphatase-Beta regulates ventromedial hypothalamic nucleus glucose counterregulatory neurotransmission and systemic hormone profiles
Reversible reduction in brain myelin content upon marathon running.
Lipidomic and sterolomic profiles of different brain regions in the mouse model of Alzheimer's disease.
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.
Hypoxic Neuroinflammation in the Pathogenesis of Multiple Sclerosis.
On-Tissue Chemical Derivatization for Mass Spectrometry Imaging of Fatty Acids with Enhanced Detection Sensitivity.
Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5.
Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2.
Effect of chronic intermittent hypoxia on hippocampal lipid metabolism in mice: A Targeted Lipidomics Study.
Metabolic Pattern of Brain Death-NMR-Based Metabolomics of Cerebrospinal Fluid.
Age-related differences in resting glutamate levels and glutamate uptake in the hippocampus and frontal cortex of C57BL/6 mice.

Handb Clin Neurol. 2025 ;pii: B978-0-443-19104-6.00007-3. [Epub ahead of print]209 117-126

Neuroglia and brain energy metabolism.

Uchenna Peter-Okaka, Detlev Boison.

  The glial control of energy homeostasis is of crucial importance for health and disease. Astrocytes in particular play a major role in controlling the equilibrium among adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), and adenosine. Any energy crisis leads to a drop in ATP, and the resulting increase in adenosine is an evolutionary ancient mechanism to suppress energy-consuming activities. The maintenance of brain energy homeostasis, in turn, requires the availability of energy sources, such as glucose and ketones. Astrocytes have assumed an important role in enabling efficient energy utilization by neurons. In addition, neurons are under the metabolic control of astrocytes through regulation of glutamate and GABA levels. The intricate interplay between glial brain energy metabolism and brain function can be best understood once the homeostatic system of energy metabolism is brought out of control. This has best been studied within the context of epilepsy where metabolic treatments provide unprecedented opportunities for the control of seizures that are refractory to conventional antiseizure medications. This chapter will discuss astroglial energy metabolism in the healthy brain and will use epilepsy as a model condition in which glial brain energy homeostasis is disrupted. We will conclude with an outlook on how those principles can be applied to other conditions such as Alzheimer disease.

Keywords:  Adenosine; Astrocyte; DNA methylation; Epigenetics; Epilepsy; Metabolism

DOI:  https://doi.org/10.1016/B978-0-443-19104-6.00007-3
Biomolecules. 2025 Mar 14. pii: 416. [Epub ahead of print]15(3):

The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.

Shashwat Sharma, Matthew McKenzie.

  Living systems require energy to maintain their existence and perform tasks such as cell division. This energy is stored in several molecular forms in nature, specifically lipids, carbohydrates, and amino acids. At a cellular level, energy is extracted from these complex molecules and transferred to adenosine triphosphate (ATP) in the cytoplasm and mitochondria. Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease. Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000. Similar to other mitochondrial disorders, there is no cure for VLCADD, with symptomatic treatment comprising dietary management and supplementation with medium-chain fatty acids to bypass the enzyme deficiency. While this addresses the primary defect in VLCADD, there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function. Here, we review our current understanding of VLCADD with a focus on the associated biochemical and molecular defects that can disrupt multiple aspects of mitochondrial function. We describe the interactions between FAO proteins and the OXPHOS complexes and how these interactions are critical for maintaining the activity of both metabolic pathways. In particular, we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis.

Keywords:  FAO; FAOD; OXPHOS; VLCAD; VLCADD; fatty acid oxidation disorder; fatty acid β-oxidation; oxidative phosphorylation; very long-chain acyl-CoA dehydrogenase; very long-chain acyl-CoA dehydrogenase deficiency

DOI:  https://doi.org/10.3390/biom15030416
J Neurochem. 2025 Mar;169(3): e70047

Regulation of CNS Lipids by Protease Activated Receptor 1.

Hyesook Yoon, Erin M Triplet, Lincoln Wurtz, Whitney L Simon, Chan-Il Choi, Isobel A Scarisbrick.

  Disruptions in the metabolism of cholesterol and other lipids are strongly implicated in the pathogenesis of neurological disease. The CNS is highly enriched in cholesterol, which is primarily synthesized de novo. Cholesterol synthesis is also rate limiting for myelin regeneration. Given that knockout of the thrombin receptor (Protease Activated Receptor 1 (PAR1)) accelerates myelin regeneration, here we sought to determine the potential regulatory actions of PAR1 in CNS cholesterol and lipid metabolism in the intact adult CNS and during myelin regeneration. We present quantitative PCR and RNAseq evidence from murine spinal cords at the peak of myelination and in adulthood showing PAR1 knockout is associated with increased gene expression for cholesterol biosynthesis (Hmgcs1, Hmgcr, Sqle, and Dhcr7), lipid transport (ApoE, Abca1, and Ldlr), and intracellular processing (Lcat, Npc1, and Npc2) at one or more time points examined. An upregulation of genes involved in the synthesis of other lipids enriched in the myelin membrane, specifically Fa2h, Ugt8a, and Gal3st1, was also observed in PAR1 knockouts. Transcription factors essential for lipid and cholesterol production (Srebf1 and Srebf2) were also increased in PAR1 knockout spinal cords at the postnatal day 21 peak of myelination and at day 45. GC-MS and LC-MS quantification of lipids demonstrated coordinate increases in the abundance of select cholesterol and lipid species in the spinal cords of PAR1 knockout mice, including enrichment of esterified cholesterol, together with sphingomyelins and sphingolipids. Co-localization of the SREBP1 and SREBP2 transcription factors, as well as HMGCS1, a rate-limiting enzyme in cholesterol biosynthesis, to glia during remyelination post-lysolecithin or cuprizone-mediated demyelination showed a prominent regulatory role for PAR1 in Olig2+ oligodendrocytes. PAR1 knockouts also demonstrated elevated levels of SREBP2 in more mature GST3+ oligodendrocytes and SREBP1 in GFAP+ astrocytes during remyelination post-lysolecithin. These findings demonstrate novel roles for PAR1 as a regulator of CNS cholesterol and lipid metabolism and its potential as a therapeutic target to increase cholesterol availability to improve myelin regeneration.

Keywords:  GPCR; astrocyte; cholesterol; development; myelin; oligodendrocyte; regeneration

DOI:  https://doi.org/10.1111/jnc.70047
J Neurochem. 2025 Mar;169(3): e70042

Lipid Composition Diversity of the Human Brain White Matter Tracts.

Marina Zavolskova, Dmitry Senko, Maria Osetrova, Olga Efimova, Elena Stekolshchikova, Gleb Vladimirov, Evgeny Nikolaev, Philipp Khaitovich.

  Understanding the molecular basis of the structural organization of the human brain may shed light on its functional mechanism. We present spatial lipidomics analysis of human brain sections containing neocortical gray matter and two white matter regions representing two axonal tracks: the cingulum bundle and the corpus callosum. Using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) we identify lipid composition differences not only between gray and white matter but also between two axonal tracks. Results, obtained with the MALDI-MSI method, correlated with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis of these brain regions, with Spearman's correlation coefficient equal to 0.48 (the cingulum bundle vs. gray matter), 0.47 (the corpus callosum vs. gray matter), 0.33 (the cingulum bundle vs. the corpos callosum) on 75 lipids annotated in both experiments. Using UPLC-MS/MS analysis, we further identified specific lipid classes that distinguished the two white matter regions (CL, PG, LPE), while gray and white matter comparison yielded well-established differences in lipid composition between myelin-rich and myelin poor regions (CL, DG, Cholesterol). Our findings highlight the significance of in-depth molecular analysis of brain regions and enhance our comprehension of the brain's molecular composition.

Keywords:  MALDI‐MSI; UPLC‐MS/MS; brain; human; lipidome; myelin

DOI:  https://doi.org/10.1111/jnc.70042
Neuron. 2025 Mar 24. pii: S0896-6273(25)00175-8. [Epub ahead of print]

Comprehensive characterization of metabolic consumption and production by the human brain.

Yilong Wang, Lebo Zhou, Nan Wang, Baoshan Qiu, Di Yao, Jie Yu, Miaoqing He, Tong Li, Yufeng Xie, Xiaoqian Yu, Zhanying Bi, Xiangli Sun, Xunming Ji, Zhen Li, Dapeng Mo, Woo-Ping Ge.

  Metabolism is vital for brain function. However, a systematic investigation to understand the metabolic exchange between the human brain and circulatory system has been lacking. Here, we compared metabolomes and lipidomes of blood samples from the cerebral venous sinus and femoral artery to profile the brain's uptake and release of metabolites and lipids (1,365 metabolites and 140 lipids). We observed a high net uptake of glucose, taurine, and hypoxanthine and identified glutamine and pyruvate as significantly released metabolites by the brain. Triacylglycerols are the most prominent class of lipid consumed by the brain. The brain with cerebral venous sinus stenosis (CVSS) consumed more glucose and lactate and released more glucose metabolism byproducts than the brain with cerebral venous sinus thrombosis (CVST). Our data also showed age-related alterations in the uptake and release of metabolites. These results provide a comprehensive view of metabolic consumption and production processes within the human brain.

Keywords:  arteriovenous comparison; blood circulation; brain metabolism; cerebral venous stenosis; cerebral venous thrombosis; lipid; metabolite; metabolomics; release; uptake

DOI:  https://doi.org/10.1016/j.neuron.2025.03.003
Nature. 2025 Mar 26.

A map of mitochondrial biology reveals the energy landscape of the human brain.



Keywords:  Brain; Metabolism; Neuroscience

DOI:  https://doi.org/10.1038/d41586-025-00872-z
Diabetes Res Clin Pract. 2025 Mar 23. pii: S0168-8227(25)00143-3. [Epub ahead of print] 112129

Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.

Amna Aqeel, Areeba Akram, Minahil Ali, Maryam Iqbal, Mehral Aslam, Rukhma Sattar, Fatima Iftikhar Shah.

  Mitochondria, also known as the powerhouse of cells, have an important role in cellular metabolism and energy production. However, during Mitochondrial Dysfunction (MD), it is known to generate reactive oxidative species and induce cellular apoptosis. A number of research findings have linked MD to various diseases, highlighting its critical role in maintaining health and contributing to disease development. In this regard, recent research has revealed that disruptions in lipid metabolism, especially in fatty acid oxidation, are significant contributors to MD. However, the precise mechanisms by which these defects lead to disease remain poorly understood. This review explores how disruptions in lipid metabolism are responsible for triggering oxidative stress, inflammation, and cellular damage, leading to impaired mitochondrial function. By examining specific fatty acid oxidation disorders, such as carnitine palmitoyltransferase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency, this review aims to uncover the underlying molecular pathways connecting lipid metabolism to mitochondrial dysfunction. Furthermore, MD is a common underlying mechanism in a wide array of diseases, including neurodegenerative disorders, and metabolic syndromes. Understanding the mechanisms behind mitochondrial malfunction may aid in the development of tailored therapies to restore mitochondrial health and treat intricate health conditions.

Keywords:  Fatty acid oxidation disorders (FAODs); Lipid metabolism; Mitochondrial dysfunction; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.diabres.2025.112129
Int J Mol Sci. 2025 Mar 18. pii: 2722. [Epub ahead of print]26(6):

Neuroprotection vs. Neurotoxicity: The Dual Impact of Brain Lipids in Depression.

Yuting Yan, Yan Zhang, Mengting Liu, Lingjie Li, Yanrong Zheng.

  Growing neurochemical evidence highlights cerebral lipid dysregulation as a key factor in the pathophysiology of major depressive disorder (MDD). This review systematically explores the dual roles of lipid species in both normal behavioral regulation and MDD development. By critically examining the recent literature, we classify these lipid species into two functional categories based on their functional neuroactivity: (1) neuroprotective lipids (sphingomyelin, cholesterol, cardiolipin, sphingosine, phosphatidic acid, and phosphatidylserine), which exert neuroprotective effects by modulating membrane fluidity and supporting synaptic vesicle trafficking; and (2) neurotoxic lipids (ceramides, phosphatidylinositol, phosphocholine, and phosphatidylethanolamine), which promote apoptotic signaling cascades and disrupt mitochondrial bioenergetics. An unresolved but critical question pertains to the maintenance of homeostatic equilibrium between these opposing lipid classes. This balance is essential, given their significant impact on membrane protein localization and function, monoaminergic neurotransmitter metabolism, energy homeostasis, and redox balance in neural circuits involved in mood regulation. This emerging framework positions cerebral lipidomics as a promising avenue for identifying novel therapeutic targets and developing biomarker-based diagnostic approaches for MDD treatment.

Keywords:  depression; fatty acyls; glycerophospholipids; lipid; sphingolipids; sterol lipids

DOI:  https://doi.org/10.3390/ijms26062722
Nature. 2025 Mar 26.

A human brain map of mitochondrial respiratory capacity and diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .

DOI: https://doi.org/10.1038/s41586-025-08740-6
Nat Metab. 2025 Mar 24.

Reversible reduction in brain myelin content after endurance exercise.

DOI: https://doi.org/10.1038/s42255-025-01251-8
Physiology (Bethesda). 2025 Mar 24.

MFSD2A in focus: the molecular mechanism of omega-3 fatty acid transport.

Farrah Blades, Aysenur Torun Yazici, Rosemary Jane Cater, Filippo Mancia.

  Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients required to support growth, maintenance, and function of the central nervous system (CNS). While the brain has a high demand for DHA, it cannot synthesize it de novo and thus relies on its uptake from the bloodstream. Circulating DHA is primarily obtained from dietary sources and is transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC-DHA) by the transmembrane transporter Major Facilitator Superfamily Domain containing 2A (MFSD2A), in a sodium-dependent manner. Here we provide a comprehensive analysis of recent insights gained from structural, functional and computational studies of MFSD2A. We focus on the mechanism by which this transporter mediates sodium-dependent uptake of LPC-DHA, and lysolipids more broadly, highlighting different conformational states, substrate entry and release pathways, and the ligand binding sites. This review presents a detailed overview of the molecular mechanism that enables MFSD2A to supply the brain with this essential nutrient, while simultaneously providing biophysical insights into how lysolipids are transported across biological membranes.

Keywords:  Docosahexaenoic acid; MFS transporters; blood-brain barrier; cryo-EM; lysolipid

DOI:  https://doi.org/10.1152/physiol.00068.2024
Alzheimers Dement. 2025 Mar;21(3): e70112

Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.

Ni Wang, Yining Pan, Skylar C Starling, Devon H Haskell, Astrid C Quintero, Keiji Kawatani, Yasuteru Inoue, Francis Shue, Xiaoye Ma, Tomonori Aikawa, Yuka A Martens, Aishe Kurti, Tammee M Parsons, Ralph B Perkerson, Bhaskar Roy, Ana-Caroline Raulin, Yingxue Ren, Michael DeTure, Dennis W Dickson, Hanmei Bao, Xianlin Han, Guojun Bu, Takahisa Kanekiyo.

   INTRODUCTION: Loss-of-function variants of the ABCA7 gene are associated with an increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown.
METHODS: Using neuron-specific Abca7 KO mice (nAbca7-/-) with or without 5×FAD amyloid model background and post mortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics.
RESULTS: Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7-/- mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7-/- mice showed diminished mitochondria respiration and reduced synaptic protein levels, which is further supported by results from human AD brains.
DISCUSSION: Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.
HIGHLIGHTS: Neuronal ABCA7 deficiency exacerbates Aβ pathology and neuronal damage in 5×FAD mice. Neuronal ABCA7 deficiency alters brain transcriptomes and lipidomes of 5×FAD mice. Neuronal ABCA7 deficiency disturbs mitochondria functions in synaptosomes from 5×FAD mice. Neuronal ABCA7 expression associates with genes and pathways related to mitochondrial homeostasis in AD brains.

Keywords:  ABCA7; Alzheimer's disease; lipid; mitochondria; neuron

DOI:  https://doi.org/10.1002/alz.70112
Mol Imaging Biol. 2025 Mar 25.

Ex-vivo Imaging of Glial Energy Metabolism in the Neonatal Mouse Brain during Convulsive Seizures with Intranasal Radiotracer Administration.

Rie Hosoi, Kenya Tada, Takahiro Hayakawa, Yuka Haga.

   PURPOSE: In this study, we examined changes in glial energy metabolism in neonatal mouse brain images obtained under pathological conditions following intranasal administration of the radiotracer [2-14C]acetate.
PROCEDURES: [2-14C]acetate was administered via the mouse nasal cavity, after which autoradiograms of the brain of 7-day-old mice were obtained. Radio thin-layer chromatography was applied for metabolite analysis of brain radioactivity. We also compared brain uptake of [2-14C]acetate when administrated intranasally and intravenously in 3-week-old mice. To confirm selective uptake by glial cells, [2-14C]acetate was injected into the nasal cavity of mice injected with a glial toxin in the brain. Pentylenetetrazole (PTZ) was applied to induce seizures.
RESULTS: Intranasally administered [2-14C]acetate was rapidly incorporated into the brains of 7-day-old mice, reaching its highest uptake level 20 min after administration. After 20 min of intranasal [2-14C]acetate administration, glutamate and glutamine accounted for 32 ± 2.5% and 30 ± 3.4% of total brain radioactivity, respectively. There was no difference in the radioactivity distribution in the brain between intranasal and intravenous administration, except in the ventral olfactory bulb in 3-week-old mice. Microinjection of the glial-specific toxin fluorocitrate reduced the accumulation of radioactivity in the brain by 60% following intranasal administration in 3-week-old mice. The uptake of [2-14C]acetate in the brains of 7-day-old mice significantly decreased 30 min after systemic PTZ administration, suggesting a decrease in energy metabolism in glial cells during seizures.
CONCLUSIONS: Quantitative images of biological functions in the neonatal mouse brain can be obtained by intranasal administration. This technique allowed the observation of a decrease in acetate uptake associated with convulsive seizures. The results of this study could be applied to the imaging of biological brain functions and research on neurological disorders using labeled probes in neonatal mice.

Keywords:  Glia; Intranasal administration; Neonatal mouse brain; Pentylenetetrazole; Seizure

DOI:  https://doi.org/10.1007/s11307-025-02000-9
Inflammopharmacology. 2025 Mar 27.

Ceramide: a central regulator in Alzheimer's disease pathogenesis.

Priyanka Choudhary, Shilpa Kumari, Kajal Bagri, Rahul Deshmukh.

  Ceramide is a key component of sphingolipid metabolism and functions as a lipid second messenger. Sphingolipids are crucial for maintaining the nervous system, particularly in differentiation and development. Ceramide supports hippocampal growth but, at elevated levels, can impair dendritic cell function. During aging and neurodegenerative diseases like Alzheimer's disease (AD), intracellular ceramide production and accumulation increase, negatively impacting cognitive functions. High ceramide levels are linked to the progression of AD pathology, significantly contributing to amyloid β (Aβ) accumulation, tau tangle formation, insulin resistance, oxidative stress, and neuroinflammation. Ceramide facilitates the production and aggregation of Aβ peptides, leading to neurotoxic plaque formation. Its dysregulation is associated with abnormal tau protein phosphorylation, resulting in neurofibrillary tangles (NFTs). In addition, elevated ceramide levels can trigger brain inflammation by promoting the release of pro-inflammatory cytokines and activating microglia. This accumulation also enhances oxidative stress in neurons, damaging cellular components such as proteins, lipids, and DNA. This review will help in deeper understanding of the molecular pathways altered via ceramide metabolism and accumulation involved in the AD pathology. The cellular and pathological mechanisms of ceramide and their impact on Alzheimer's disease pathophysiology. A deeper understanding of ceramide-mediated effects in aging and AD could pave the way for innovative therapeutic strategies targeting ceramide metabolism to treat neurodegenerative diseases and age-related cognitive decline.

Keywords:  Alzheimer’s disease; Ceramide; Neurodegeneration; Neuroinflammation; Oxidative stress; Sphingolipids

DOI:  https://doi.org/10.1007/s10787-025-01719-9
Neuropeptides. 2025 03 18. pii: S0143-4179(25)00019-8. [Epub ahead of print]111 102519

Astrocyte glucose-6-phosphatase-Beta regulates ventromedial hypothalamic nucleus glucose counterregulatory neurotransmission and systemic hormone profiles

Karen P Briski, Sushma Katakam, Subash Sapkota, Madhu Babu Pasula, Rami Shrestha, Rajesh Vadav.

  Brain astrocytes generate free glucose at the conclusion of glycogenolysis or gluconeogenesis by glucose-6-phosphatase-beta (Glc-6-Pase-β) hydrolytic action. Astrocytes shape ventromedial hypothalamic nucleus (VMN) control of glucose counterregulation via lactate provision, yet possible effects of astrocyte endogenous glucose production are unknown. Current research investigated eu- and hypoglycemic patterns of VMN neuron counterregulatory neurotransmitter marker protein expression and counterregulatory hormone secretion following in vivo VMN astrocyte Glc-6-Pase-β gene-knockdown. Gene-silencing caused reductions in VMN astrocyte Glc-6-Pase-β protein expression and tissue glycogen and glucose content. Hypoglycemic suppression (dorsomedial VMN; VMNdm) or augmentation (ventrolateral VMN; VMNvl) of glycogen involves Glc-6-Pase-β -independent versus -dependent mechanisms, respectively. siRNA pretreatment reversed hypoglycemic down-regulation of VMNdm glucose levels and intensified up-regulated VMNvl glucose accumulation. Glc-6-Pase-β gene-knockdown correspondingly suppressed or enhanced baseline expression of glutamate decarboxylase65/67 (GAD) and neuronal nitric oxide synthase (nNOS), protein markers for the counterregulation-inhibiting or -enhancing neurochemicals γ-aminobutyric acid and nitric oxide. Glc-6-Pase-β siRNA pretreatment did not alter hypoglycemic suppression of VMN GAD protein but reversed (VMNdm) or amplified (VMNvl) nNOS up-regulation. VMN Glc-6-Pase-β gene-silencing attenuated hypoglycemic patterns of corticosterone and growth hormone secretion and enhanced glucagon release. In summary, data provide unique evidence that VMN Glc-6-Pase-β activity affects glucose counterregulation. Outcomes document astrocyte Glc-6-Pase-β control of VMN glucose and glycogen accumulation as well as VMN neuron counterregulatory neurotransmission. Further research is warranted to identify Glc-6-Pase-β - mediated adjustments in astrocyte glucose metabolism that affect VMN GABAergic and/or nitrergic signaling within the brain glucostatic circuitry.

Keywords:  Glucose-6-phosphatase-beta; Glutamate decarboxylase(65/67); Insulin-induced hypoglycemia; Laser-catapult-microdissection; Ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.1016/j.npep.2025.102519
Nat Metab. 2025 Mar 24.

Reversible reduction in brain myelin content upon marathon running.

Pedro Ramos-Cabrer, Alberto Cabrera-Zubizarreta, Daniel Padro, Mario Matute-González, Alfredo Rodríguez-Antigüedad, Carlos Matute.

Here we use magnetic resonance imaging to study the impact of marathon running on brain structure in humans. We show that the signal for myelin water fraction-a surrogate of myelin content-is substantially reduced upon marathon running in specific brain regions involved in motor coordination and sensory and emotional integration, but recovers within two months. These findings suggest that brain myelin content is temporarily and reversibly diminished by severe exercise, a finding consistent with recent evidence from rodent studies that suggest that myelin lipids may act as glial energy reserves in extreme metabolic conditions.

DOI: https://doi.org/10.1038/s42255-025-01244-7
Neural Regen Res. 2025 Feb 24.

Lipidomic and sterolomic profiles of different brain regions in the mouse model of Alzheimer's disease.

Xingsen Zhao, Liqun Chen, Liangjian Ma, Xiaohui Liu, Zhongkai Cao, Xiangjun Chen, Lidan Hu.

ABSTRACT: Alzheimer's disease is the most common cause of dementia. Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease, the overall profile of lipid and sterol changes that occur in the brain during Alzheimer's disease remains unclear. In this study, we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer's disease model mice, which carry mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) genes. Using untargeted lipidomics and sterolomics techniques, we investigated the metabolic profiles of lipids, with a focus on sterols specifically, in three brain regions: cerebellum, hippocampus, and olfactory bulb. Our results revealed significant alterations in various lipids, particularly in the hippocampus and olfactory bulb, suggesting changes in energy levels in these regions. Further pathway analysis indicated notable disruptions in key metabolic processes, particularly those related to fatty acids and cell membrane components. Additionally, we observed decreased expression of 15 genes involved in lipid and sterol regulation. Collectively, these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer's disease, highlighting potential metabolic pathways involved in the development of this debilitating disease.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00975
Mol Neurodegener. 2025 Mar 27. 20(1): 37

Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research.

Eun Sun Jung, Hayoung Choi, Inhee Mook-Jung.

  Alzheimer's disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation and glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts as an energy sensor, coordinating lipid and glucose metabolism. TREM2 and APOE regulate microglial lipid homeostasis, influencing Aβ clearance and immune responses. LPL and ABCA7, both associated with AD risk, modulate lipid processing and cholesterol transport, linking lipid metabolism to neurodegeneration. PPARG further supports lipid metabolism by regulating microglial inflammatory responses. Amino acid metabolism also contributes to microglial function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked to AD pathology. Additionally, glucose-6-phosphate dehydrogenase regulates the pentose phosphate pathway, maintaining redox balance and immune activation. Dysregulated glucose and lipid metabolism, influenced by genetic variants such as APOE4, impair microglial responses and exacerbate AD progression. Recent findings highlight the interplay between metabolic regulators like REV-ERBα, which modulates lipid metabolism and inflammation, and Syk, which influences immune responses and Aβ clearance. These insights offer promising therapeutic targets, including strategies aimed at HIF-1α modulation, which could restore microglial function depending on disease stage. By integrating metabolic, immune, and genetic factors, this review underscores the importance of microglial immunometabolism in AD. Targeting key metabolic pathways could provide novel therapeutic strategies for mitigating neuroinflammation and restoring microglial function, ultimately paving the way for innovative treatments in neurodegenerative diseases.

Keywords:  APOE; Aβ; HIF; Hexokinase; Immunometabolism; Metabolic reprogramming; Microglia; Neuroinflammation; TREM2; Tau

DOI:  https://doi.org/10.1186/s13024-025-00825-0
Brain Sci. 2025 Feb 26. pii: 248. [Epub ahead of print]15(3):

Hypoxic Neuroinflammation in the Pathogenesis of Multiple Sclerosis.

Bethany Y A Hollingworth, Patrick N Pallier, Stuart I Jenkins, Ruoli Chen.

  Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheath around the central nervous system axons, leading to neurological dysfunction. Although the initial damage is driven by inflammation, hypoxia has been reported in several brain regions of MS patients, but the significance of this for prognosis and treatment remains unclear. Neuroinflammation can induce hypoxia, and hypoxia can induce and exacerbate neuroinflammation, forming a vicious cycle. Within MS lesions, demyelination is often followed by remyelination, which may restore neurological function. However, demyelinated axons are vulnerable to damage, which leads to the accumulation of the permanent neurological dysfunction typical in MS, with this vulnerability heightened during hypoxia. Clinically approved therapies for MS are immunomodulatory, which can reduce relapse frequency/severity, but there is a lack of pro-regenerative therapies for MS, for example promoting remyelination. All tissues have protective responses to hypoxia, which may be relevant to MS lesions, especially during remyelinating episodes. When oxygen levels are reduced in the brain, constitutively expressed hypoxia-inducible factors (HIF) are stabilised, upregulating hundreds of genes, including neuroprotective factors. Furthermore, astrocytes upregulate heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in the early stage of MS. HB-EGF promotes protective mechanisms and induces oligodendrocyte and neuron differentiation and survival. This review article outlines the neuroinflammation and hypoxia cycle in MS pathology and identifies potential therapeutic targets to limit neurodegeneration and/or promote regeneration. Both HIF and HB-EGF signalling pathways induce endogenous protection mechanisms in the CNS, promoting neuroprotection and remyelination directly, but also indirectly by modulating the immune response in MS. Promoting such endogenous protective signalling pathways could be an effective therapy for MS patients.

Keywords:  HB-EGF; HIF; demyelination; hypoxia; immunomodulation; multiple sclerosis; neurodegeneration; neuroinflammation; remyelination

DOI:  https://doi.org/10.3390/brainsci15030248
Biomolecules. 2025 Mar 03. pii: 366. [Epub ahead of print]15(3):

On-Tissue Chemical Derivatization for Mass Spectrometry Imaging of Fatty Acids with Enhanced Detection Sensitivity.

Malik Ebbini, Zicong Wang, Hua Zhang, Kelly H Lu, Penghsuan Huang, Cameron J Kaminsky, Luigi Puglielli, Lingjun Li.

  The dysregulation of fatty acid (FA) metabolism is linked to various brain diseases, including Alzheimer's disease (AD). Mass spectrometry imaging (MSI) allows for the visualization of FA distribution in brain tissues but is often limited by low detection sensitivity and high background interference. In this work, we introduce a novel on-tissue chemical derivatization method for FAs using Girard's Reagent T (GT) as a derivatization reagent combined with 2-chloro-1-methylpyridinium iodide (CMPI) as a coupling reagent and triethylamine (TEA) to provide a basic environment for the reaction. This method significantly enhances the detection sensitivity of FAs, achieving a 1000-fold improvement over traditional negative ion mode analysis. Our method enabled us to observe a notable depletion of oleic acid in the corpus callosum of AD mouse model brain tissue sections compared to wild-type control brain tissue sections. The reliability of our method was validated using LC-MS/MS, which confirmed the presence of eight distinct GT-labeled FAs across various tissue locations. This approach not only improves FA detection in brain tissues but also has the potential to provide a deeper understanding of FA dynamics associated with AD pathogenesis.

Keywords:  Alzheimer’s disease mouse model; MALDI; fatty acids; mass spectrometry imaging; on-tissue chemical derivatization

DOI:  https://doi.org/10.3390/biom15030366
Cell Mol Life Sci. 2025 Mar 26. 82(1): 131

Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5.

Alejandro Montilla, Alazne Zabala, Ibai Calvo, Marina Bosch-Juan, Irene Tomé-Velasco, Paloma Mata, Mirjam Koster, Amanda Sierra, Susanne M Kooistra, Federico N Soria, Bart J L Eggen, Olatz Fresnedo, José Andrés Fernández, Vanja Tepavcevic, Carlos Matute, María Domercq.

  Interferon regulatory factor 5 (IRF5) is a transcription factor that plays a role in orchestrating innate immune responses, particularly in response to viral infections. Notably, IRF5 has been identified as a microglia risk gene linked to multiple sclerosis (MS), but its specific role in MS pathogenesis remains unclear. Through the use of Irf5-/- mice, our study uncovers a non-canonical function of IRF5 in MS recovery. Irf5-/- mice exhibited increased damage in an experimental autoimmune encephalomyelitis (EAE) model and demonstrated impaired oligodendrocyte recruitment into the lesion core following lysolecithin-induced demyelination. Transcriptomic and lipidomic analyses revealed that IRF5 has a role in microglia-mediated myelin phagocytosis, lipid metabolism, and cholesterol homeostasis. Indeed, Irf5-/- microglia phagocytose myelin, but myelin debris is not adequately degraded, leading to an accumulation of lipid droplets, cholesterol esters, and cholesterol crystals within demyelinating lesions. This abnormal buildup can hinder remyelination processes. Importantly, treatments that promote cholesterol transport were found to reduce lipid droplet accumulation and mitigate the exacerbated damage in Irf5-/- mice with EAE. Altogether, our study identified the antiviral transcription factor IRF5 as a key transcriptional regulator of lipid degradation and cholesterol homeostasis and suggest that loss of IRF5 function leads to pathogenic lipid accumulation in microglia, thereby obstructing remyelination. These data and the fact that Irf5 polymorphisms are significantly associated with MS, highlight IRF5 as a potential therapeutic target to promote regenerative responses.

Keywords:  Demyelination; IRF5; Lipid homeostasis; Microglia; Multiple sclerosis; Remyelination

DOI:  https://doi.org/10.1007/s00018-025-05648-2
Mov Disord. 2025 Mar 28.

Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2.

Sarah D Neuman, Rajan S Thakur, Scott J Gratz, Kate M O'Connor-Giles, Arash Bashirullah.

   BACKGROUND: Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood.
OBJECTIVE: The objective of this study was to determine tissue-specific and aging-dependent roles for VPS13A and BLTP2 using Drosophila models.
METHODS: We generated tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function.
RESULTS: Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by aging-dependent movement deficits and reduced lifespan, whereas muscle-specific loss affected only lifespan. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, whereas muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction.
CONCLUSIONS: VPS13A maintains neuronal survival, whereas BLTP2 orchestrates synaptic development. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  VPS13A; lipid transfer proteins; lipids; membrane contact sites; parkinsonism

DOI:  https://doi.org/10.1002/mds.30178
Brain Res Bull. 2025 Mar 25. pii: S0361-9230(25)00131-5. [Epub ahead of print] 111319

Effect of chronic intermittent hypoxia on hippocampal lipid metabolism in mice: A Targeted Lipidomics Study.

Juan Li, Na Zhang, Wenjing Ren, Lan Li, Yi Sun, Yanyan Hou, Shuling Song, Lei Pan, Yunliang Sun, Kai Zhang, Dongze Li, Rongrong Guo, Changjun Lv, Fang Han, Yan Yu.

  Evidence suggests that cognitive impairments due to obstructive sleep apnea (OSA) are related to abnormal lipid metabolism. Abnormal lipid metabolism in the brain might be a potential cause of neurodegeneration. Nonetheless, there is limited clarity regarding the comprehensive lipid metabolism changes in the hippocampus induced by chronic intermittent hypoxia (CIH). Targeted lipidomic analysis of mouse hippocampus and HT22 cells was essential to exploring changes in lipid metabolism after CIH exposure. The approach was used to quantify 575 lipid species in mouse hippocampus and 1,285 lipid species in HT22 cells, belonging to 6 different classes. Among those lipid classes, glycerophospholipids (GP), fatty acyls (FA), sphingolipids (SP), glycerolipid (GL), and prenol lipids (PR) were not significantly changed in mouse hippocampus under CIH conditions, but steroid (ST) levels were significantly reduced. Based on in vitro results, CIH exposure significantly raises the levels of several lipids, including GP, PR, SP, and ST. However, GL and FA did not change significantly. Notably, in vivo as well as in vitro experiments showed down-regulation of LPI (16:0), LPI (18:0), PC (18:1/20:4), PE (O-18:0/16:0), PE (O-16:0/22:6), PI (18:0/18:0), and up-regulation of PI (18:0/19:2). Additionally, in CIH conditions, lipid droplets (LDs) typically accumulate as a result of metabolism disorders. Disorders of lipid metabolism and the abnormal accumulation of LDs in neurons cause neuronal damage and behavioral disorders. The altered levels of LPI, PC, PE, and PI in OSA patients might provide new insights into understanding lipid metabolism disorders in the nervous system.

Keywords:  Chronic intermittent hypoxia; Lipid Droplets; Lipid metabolism disorders; Obstructive sleep apnea; Quantitative lipidomic

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111319
Int J Mol Sci. 2025 Mar 18. pii: 2719. [Epub ahead of print]26(6):

Metabolic Pattern of Brain Death-NMR-Based Metabolomics of Cerebrospinal Fluid.

Beata Toczylowska, Piotr Kalinowski, Agata Kacka-Piotrowska, Paulina Duda, Michał Grąt, Elzbieta Zieminska.

  The aim of this study was to gain insight into the biochemical status of cerebrospinal fluid in the presence of brain death in life-supported patients. The biochemical status was determined via in vitro NMR spectroscopy of cerebrospinal fluid (CSF) obtained by lumbar puncture from 22 patients with confirmed brain death and compared with that of 34 control patients (without neurological diseases). Forty-one NMR signals from raw CSF samples and 20 signals from lipid extracts were analyzed using univariate and multivariate statistical methods. ANOVA revealed significant differences in all analyzed signals. No single biochemical marker was found to predict brain death. The CSF metabolic profiles of patients who died differed significantly from those of patients in the control group. There were many statistically significantly different compounds, including amino acids, ketone bodies, lactate, pyruvate, citrate, guanidinoacetate, choline, and glycerophosphocholine. Analysis of lipids revealed significant differences in cholesterol, estriol, and phosphoethanolamine. Discriminant analysis allows the analysis of metabolic profiles instead of single biomarkers of cerebrospinal fluid compounds. The results of our analysis allowed us to split the groups-the control group, which consisted of patients with a normal biochemical CSF composition, and the brain death group-with confirmed brain death.

Keywords:  NMR spectroscopy; biomarkers; brain death; cerebrospinal fluid; discriminant analysis; lipidomics; metabolomics

DOI:  https://doi.org/10.3390/ijms26062719
Neurobiol Aging. 2025 Mar 18. pii: S0197-4580(25)00053-3. [Epub ahead of print]150 146-156

Age-related differences in resting glutamate levels and glutamate uptake in the hippocampus and frontal cortex of C57BL/6 mice.

Francois Pomerleau, Brittany A Sulkowski, Cocanut Suhail, Jorge E Quintero, O Meagan Littrell, M Paul Murphy, Peter Huettl, Greg A Gerhardt.

  In normal aging, little is known in human and animal models about functional changes to glutamate neuronal systems that may contribute to age-related cognitive differences. The present studies investigated glutamate neuronal signaling in the hippocampus (dentate gyrus) and frontal cortex (infralimbic) of young adult (3-8 months), middle-aged (10-13 months), and aged (15-27 months) male and female C57BL/6 mice using microelectrode electrode array (MEA) recording technology to measure second-by-second resting levels of glutamate in anesthetized mice. Glutamate regulation was investigated in vivo by inhibiting the uptake of glutamate by local application of the competitive non-transportable blocker of excitatory amino acid transporters DL-threo-beta-benzyloxyaspartate (TBOA). Resting levels of glutamate and TBOA-induced changes in extracellular glutamate concentration were reliably measured in the hippocampus and frontal cortex of young adult, middle-aged, and aged mice and were seen to significantly increase in aging in the hippocampus. In the frontal cortex we observed an increase only in the middle-aged animals. TBOA produced robust changes in extracellular glutamate in the hippocampus and frontal cortex which showed significant changes in the kinetics of the signals in the middle-aged mice. Interestingly, the variance of the resting glutamate levels in the hippocampus of aged female mice was greater than in aged male mice, supporting a possible age-related gender difference in glutamate function. Taken together, these data support that glutamate signaling in the hippocampus and frontal cortex of aged mice is affected in normal aging with changes in glial regulation of glutamate uptake observed from the TBOA effects in the middle-aged mice.

Keywords:  Aging; Amino acid transporters; Glia; Glutamate receptors; Neurons; Neurotransmission

DOI:  https://doi.org/10.1016/j.neurobiolaging.2025.03.008