bims-medebr 2025-08-31 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–08–31
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer's disease.
Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.
APOE4 reprograms microglial lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications.
Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes.
Neurobiology of mitochondrial dynamics in sleep.
Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.
Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer's disease progression.
RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.
Pro-Inflammatory Microglia Exacerbate High-Altitude-Induced Cognitive Impairment by Driving Lipid Droplet Accumulation in Astrocytes.
Widespread but moderate genetic overlap between circulating polyunsaturated fatty acids and brain disorders.
Maternal blood glucose level is correlated to offspring brain fatty acid composition in a mouse model for gestational diabetes mellitus.
Mitochondrial Microproteins: Emerging Regulators in Neurodevelopment and Neurodegeneration.
Review of methods for the determination of cellular cholesterol content: principles, advantages, limitations, applications, and perspectives.
Astrocytes: Orchestrators of brain gas exchange and oxygen homeostasis.
Targeted lipidomics dataset of central nervous system and plasma from mice with experimental autoimmune encephalomyelitis.
Lipid-Laden Microglia: Characterization and Roles in Diseases.
From imaging to intervention: emerging potential of PET biomarkers to shape therapeutic strategies for TBI-induced neurodegeneration.
iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder.
Cerebral glucose delivery, transport and metabolism: Theory and modeling using four, three, and two tissue compartments.

Transl Psychiatry. 2025 Aug 25. 15(1): 316

Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer's disease.

Vanessa Budny, Iván Ruminot, Maha Wybitul, Valerie Treyer, L Felipe Barros, Christian Tackenberg.

The human brain has high energy demands and tightly regulated mechanisms ensure its activity-dependent energy supply. Glucose hypometabolism is associated with brain aging and has also been linked to neurodegenerative diseases such as Alzheimer's disease (AD). The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for AD while APOE2 reduces the risk and APOE3 has been referred to as risk neutral allele. APOE is a major lipid carrier in the brain and is not only involved in the build-up of the two AD hallmark pathologies, β-amyloid (Aβ) plaques and neurofibrillary tangles, but also in several other (patho-)physiological processes including immune response, neuronal growth, synaptic plasticity and energy metabolism. Although there has been recent progress in understanding APOE biology, the exact mechanisms of how APOE (especially APOE4) affects brain energy metabolism are still largely unclear. This review highlights the recent evidence of how APOE isoforms differentially affect the bioenergetic homeostasis of the brain, thereby affecting AD etiology and pathophysiology, and identifies critical questions and emerging topics that require further investigation.

DOI: https://doi.org/10.1038/s41398-025-03550-w
Biochim Biophys Acta Mol Basis Dis. 2025 Aug 19. pii: S0925-4439(25)00369-2. [Epub ahead of print]1871(8): 168021

Mission cholesterol: Uncovering its hidden role in ALS neurodegeneration.

Anna Fernàndez-Bernal, Natàlia Mota, Reinald Pamplona, Estela Area-Gómez, Manuel Portero-Otin.

  Cholesterol is a central determinant of membrane architecture, signaling, and cellular homeostasis in the central nervous system (CNS). While historically viewed as a structural component, emerging evidence highlights its dynamic regulatory role in neuronal function, particularly through its compartmentalized synthesis, trafficking, and turnover. This review examines the complex landscape of cholesterol metabolism in the CNS, emphasizing the cooperative roles of astrocytes and neurons, the partitioning of biosynthetic pathways, and the barriers that distinguish brain cholesterol pools from peripheral sources. We focus on mitochondria-associated endoplasmic reticulum membranes (MAMs) as key regulatory platforms for cholesterol sensing, esterification, and signaling, underscoring their emerging role in neurodegenerative diseases. Disruptions in MAM integrity, lipid raft composition, and transcriptional regulation of cholesterol-handling genes have been linked to pathologies such as amyotrophic lateral sclerosis (ALS), particularly through the actions of TDP-43. By consolidating recent findings from lipidomics, cell biology, and disease models, we propose that cholesterol dyshomeostasis constitutes a shared mechanistic axis across diverse neurodegenerative conditions. Understanding this axis offers novel insights into the metabolic vulnerability of neurons and highlights cholesterol metabolism as a promising target for therapeutic intervention.

Keywords:  Amyotrophic Lateral Sclerosis; Astrocyte; Blood-brain-barrier; Endoplasmic reticulum; Neuron

DOI:  https://doi.org/10.1016/j.bbadis.2025.168021
Biosci Trends. 2025 Aug 21.

APOE4 reprograms microglial lipid metabolism in Alzheimer's disease: Mechanisms and therapeutic implications.

Jiajie Chen, Shuoyan Zhao, Yingying Zhou, Luyao Wang, Qin Chen, Kai Zheng.

  The apolipoprotein E ε4 (APOE ε4) allele, the strongest genetic risk factor for late-onset Alzheimer's disease (AD), induces cell-type-specific disturbances in brain lipid metabolism. Although impacting astrocytes and neurons, its most pronounced effects occur in microglia, where it causes energy metabolism deficits and promotes the formation of lipid droplet-accumulating microglia, triggering a cascade of neurodegenerative responses. This review comprehensively examines how microglial APOE4-driven lipid metabolic dysregulation exacerbates neuroinflammation and compromises phagocytic capacity, particularly in the clearance of amyloid-β, phosphorylated-tau, and pathological synapses. Mechanistically, microglial APOE4 activates neuroinflammation via LilrB3-mediated type I interferon signaling and induces lipid metabolic imbalance through PU.1/NF-κB-driven transcriptional reprogramming and ER stress-SREBP2 activation. These disturbances exacerbate neuroinflammation, promote lipid droplet accumulation and cholesterol overload, impair lysosomal function, and ultimately compromise microglial phagocytosis. The resulting disruption of neuron-microglia interactions further amplifies neurotoxicity in AD. Furthermore, this review summarizes emerging therapeutic strategies targeting APOE4-related pathway in microglia. By synthesizing these insights, this review highlights the multifaceted role of microglial APOE4 in AD pathology, with particular emphasis on the central role of lipid metabolism dysregulation, and provides new intervention ideas for reducing its damage to brain function.

Keywords:  Alzheimer's disease; apolipoprotein E4; lipid metabolism; microglia; neuroinflammation; phagocytosis

DOI:  https://doi.org/10.5582/bst.2025.01148
Neurochem Res. 2025 Aug 23. 50(5): 275

Coapplication of Adenine with Inosine or Guanosine Supports Rapid ATP Restoration by ATP-deprived Cultured Primary Astrocytes.

Gabriele Karger, Ralf Dringen.

  Astrocytes contain a high concentration of adenosine triphosphate (ATP) that enables these cells to perform their physiological functions in brain. To investigate the mechanisms involved in astrocytic ATP restoration, the ATP content of cultured primary rat astrocytes was first depleted by a preincubation with the mitochondrial uncoupler BAM15 before extracellular substrates and their combinations were applied to foster ATP restoration. To test for the contribution of the purine salvage pathway to synthesize new adenosine monophosphate (AMP) for ATP restoration, several purine nucleosides and purine bases as well as their combinations were applied. In the absence of glucose, partial ATP restoration was found for incubations with inosine and guanosine that was lowered by forodesine, an inhibitor of purine nucleoside phosphorylase. In glucose-fed cells, the coapplication of micromolar concentrations of adenine with inosine or guanosine, but not with ribose, accelerated ATP restoration in a concentration-dependent manner. By such treatments, 80% of the initial ATP content were restored within 40 min. The supporting effects of inosine and guanosine on ATP restoration were prevented by the presence of forodesine, demonstrating the contribution of purine nucleoside phosphorylase in the ATP restoration observed. These data demonstrate that ATP-deprived astrocytes need for rapid ATP restoration - in addition to glucose as energy substrate - an adenine source and inosine or guanosine as precursor for the ribose phosphate moiety of ATP.

Keywords:  ATP restoration; Astrocytes; Guanosine; Inosine; Purine nucleosides; Purine salvage pathway; Ribose

DOI:  https://doi.org/10.1007/s11064-025-04511-x
J Physiol. 2025 Aug 22.

Neurobiology of mitochondrial dynamics in sleep.

Raffaele Sarnataro.

  The cycling of sleep and wakefulness reshapes neuronal activity, gene expression, and cellular metabolism of the brain. Such reshuffling of brain metabolism implicates key mediation by mitochondria. Mitochondrial dynamics enable organelles to adapt their morphofunction to changing metabolic demands, and experimental evidence increasingly links these processes to sleep-wake regulation. Across species, sleep loss perturbs mitochondrial gene expression, increases oxidative stress, and disrupts organelle structure, particularly in energy-demanding brain regions. In Drosophila, sleep-control neurons projecting to the dorsal fan-shaped body (dFBNs) exhibit a homeostatic feedback mechanism coupling mitochondrial activity to behavioural state. As sleep pressure elevates, dopaminergic inhibition reduces dFBN excitability and ATP consumption, triggering mitochondrial fission and accumulation of reactive oxygen species (ROS) that biochemically prime the neurons for subsequent sleep induction. Upon relief of inhibition during recovery sleep, dFBNs elevate their activity, consume ATP, and undergo mitochondrial fusion to restore energy balance. Artificial modulation of mitochondrial morphology and ATP production in these neurons bidirectionally alters sleep. dFBNs' elevated OxPhos expression and mitochondrial turnover render them sensitive to metabolic shifts and capable of encoding internal states. While dFBNs remain the only known neurons where mitochondrial dynamics are coupled to sleep behaviour, other populations, like mammalian cortical neurons or fly Kenyon cells, also display mitochondrial changes after sleep loss. Sleep, like other state-dependent behaviours including hunger and memory, imposes shifting energetic demands on specific neuronal populations. Mitochondrial dynamics may thus provide a conserved, cell-autonomous mechanism for tuning neural excitability and sleep pressure, enabling brain-wide coordination of metabolic and behavioural homeostasis.

Keywords:  ATP; energy; homeostasis; metabolism; mitochondria; neurobiology; neuron; sleep

DOI:  https://doi.org/10.1113/JP288054
Metabolites. 2025 Jul 31. pii: 508. [Epub ahead of print]15(8):

Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential.

Marta Pawłowska, Joanna Kruszka, Marta Porzych, Jakub Garbarek, Jarosław Nuszkiewicz.

  Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; beta-hydroxybutyrate; cognitive decline; ketogenic diet; ketone bodies; mitochondrial dysfunction; neuroinflammation

DOI:  https://doi.org/10.3390/metabo15080508
J Adv Res. 2025 Aug 25. pii: S2090-1232(25)00659-9. [Epub ahead of print]

Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer's disease progression.

Hongli Li, Zhihao Zhao, Lemei Zhu, Yejun Tan, Zheyu Zhang, Zhen Zhang, Jin Kang, Hongmei Lu, Weijun Peng, Qian Wu.

   INTRODUCTION: Tracking spatial lipidomic changes during Alzheimer's disease (AD) progression is crucial for elucidating the underlying mechanisms of the disease.
OBJECTIVES: This study aims to investigate the spatial-temporal lipidomic alterations and their associated metabolic enzyme changes during AD progression.
METHODS: The spatial lipidomic changes and corresponding alterations in metabolic enzymes during AD progression in amyloid precursor protein/presenilin-1 (APP/PS1) mice were thoroughly analyzed using an advanced ambient mass spectrometry imaging (MSI) technique, complemented by immunofluorescence (IF) imaging.
RESULTS: Distinct lipidomic differences were observed between AD and wild-type (WT) mice in both the hippocampus (HP) and thalamus (TH), with the TH region exhibiting more significant lipid changes than the HP. A total of 88 lipid species with age- and region-specific alterations were identified, primarily within the sphingolipid, glycerolipid, and glycerophospholipid metabolic pathways. These metabolic changes were corroborated by IF imaging, which demonstrated spatial variations in the corresponding enzymes within the lipid metabolic pathways. Notably, a significant downregulation of hexosylceramides (HexCers) in the white matter of aged APP/PS1 mice suggests potential white matter abnormalities linked to AD. Correlation analysis further revealed that reduced HexCers were associated with the inhibited sulfatide-HexCer pathway, potentially driven by diminished ARSA levels, a factor known to be involved in microglial activation and inflammation. Additionally, upregulation of diacylglycerol (DG), observed even during the pre-symptomatic phase of AD, suggests DG as an early diagnostic biomarker. A strong correlation between the spatial changes in the DG-to-phosphatidylcholine (PC) ratio and phospholipase C (PLC) expression indicates that DG upregulation may result from PLC activation, a process known to be induced by amyloid β.
CONCLUSIONS: This study provides an expanded spatial, temporal, and chemical perspective on AD mechanisms, offering potential avenues for enhancing early diagnosis and therapeutic strategies.

Keywords:  Alzheimer’s disease; Ambient mass spectrometry imaging; Glycerolipid & glycerophospholipid metabolism; Spatial lipidomics; Sphingolipid metabolism

DOI:  https://doi.org/10.1016/j.jare.2025.08.044
EMBO J. 2025 Aug 26.

RTN4IP1 is required for the final stages of mitochondrial complex I assembly and CoQ biosynthesis.

Monika Oláhová, Rachel M Guerra, Jack J Collier, Juliana Heidler, Kyle Thompson, Chelsea R White, Paulina Castañeda-Tamez, Alfredo Cabrera-Orefice, Robert N Lightowlers, Zofia M A Chrzanowska-Lightowlers, Alexander Galkin, Ilka Wittig, David J Pagliarini, Robert W Taylor.

  A biochemical deficiency of mitochondrial complex I (CI) underlies approximately 30% of cases of primary mitochondrial disease, yet the inventory of molecular machinery required for CI assembly remains incomplete. We previously characterised patients with isolated CI deficiency caused by segregating variants in RTN4IP1, a gene that encodes a mitochondrial NAD(P)H oxidoreductase. Here, we demonstrate that RTN4IP1 deficiency causes a CI assembly defect in both patient fibroblasts and knockout cells, and report that RTN4IP1 is a bona fide CI assembly factor. Complexome profiling revealed accumulation of unincorporated ND5-module and impaired N-module production. RTN4IP1 patient fibroblasts also exhibited defective coenzyme Q biosynthesis, substantiating a second function of RTN4IP1. Thus, our data reveal RTN4IP1 plays necessary and independent roles in both the terminal stages of CI assembly and in coenzyme Q metabolism, and that pathogenic RTN4IP1 variants impair both functions in patients with mitochondrial disease.

Keywords:  Coenzyme Q; Complex I Assembly; Complexome Profiling; Mitochondria; RTN4IP1

DOI:  https://doi.org/10.1038/s44318-025-00533-x
Antioxidants (Basel). 2025 Jul 26. pii: 918. [Epub ahead of print]14(8):

Pro-Inflammatory Microglia Exacerbate High-Altitude-Induced Cognitive Impairment by Driving Lipid Droplet Accumulation in Astrocytes.

Xiaoyang Fan, Sitong Cao, Yujie Fang, Li Zhu, Xueting Wang.

  High-altitude cognitive impairment (HACI) results from acute or chronic exposure to hypoxic conditions. Brain lipid homeostasis is crucial for cognitive function, and lipid droplet (LD) accumulation in glia cells is linked to cognitive decline in aging and stroke. However, whether high-altitude exposure affects brain lipid homeostasis is unclear. Microglia, key regulators of brain homeostasis and inflammation, play a significant role in pathological cognitive impairment and are implicated in LD formation. This study investigates whether lipid dysregulation contributes to HACI and explores microglia-driven mechanisms and potential interventions. Mice were exposed to a simulated 7000 m altitude for 48 h, followed by a week of recovery. Cognitive function and LD accumulation in brain cells were assessed. Microglia were depleted using PLX5622, and mice were exposed to hypoxia or lipopolysaccharide (LPS) to validate microglia's role in driving astrocytic LD accumulation and cognitive decline. Minocycline was used to inhibit inflammation. In vitro, co-culture systems of microglia and astrocytes were employed to confirm microglia-derived pro-inflammatory factors' role in astrocytic LD accumulation. Hypobaric hypoxia exposure induced persistent cognitive impairment and LD accumulation in hippocampal astrocytes and microglia. Microglia depletion alleviated cognitive deficits and reduced astrocytic LD accumulation. Hypoxia or LPS did not directly cause LD accumulation in astrocytes but activated microglia to release IL-1β, inducing astrocytic LD accumulation. Microglia depletion also mitigated LPS-induced cognitive impairment and astrocytic LD accumulation. Minocycline reduced hypoxia-induced LD accumulation in co-cultured astrocytes and improved cognitive function. Hypoxia triggers pro-inflammatory microglial activation, leading to LD accumulation and the release of IL-1β, which drives astrocytic LD accumulation and neuroinflammation, exacerbating HACI. Minocycline effectively restores brain lipid homeostasis and mitigates cognitive impairment. This study provides novel insights into HACI mechanisms and suggests potential therapeutic strategies.

Keywords:  IL-1β; astrocyte; high-altitude cognitive impairment; inflammation; lipid droplets; microglia; minocycline

DOI:  https://doi.org/10.3390/antiox14080918
J Lipid Res. 2025 Aug 25. pii: S0022-2275(25)00152-X. [Epub ahead of print] 100890

Widespread but moderate genetic overlap between circulating polyunsaturated fatty acids and brain disorders.

Huifang Xu, Yitang Sun, Michael Francis, Claire F Cheng, Nitya T R Modulla, J Thomas Brenna, Charleston W K Chiang, Kaixiong Ye.

   BACKGROUND: Polyunsaturated fatty acids (PUFAs) are indispensable for proper neuronal function. PUFA deficiency and imbalance have been linked to various brain disorders, including major depressive disorder (MDD) and anxiety. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown.
METHODS: We utilized genome-wide association summary statistics from six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917). We performed genome-wide analysis for each of the 120 trait pairs. We evaluated the correlation of genetic effects with genetic correlation, estimated the number of shared genetic variants with polygenic overlap, and prioritized potential causal relationships with two-sample Mendelian randomization (MR). We pinpointed specific shared variants with colocalization and statistical fine-mapping.
RESULTS: Genetic correlation and polygenic overlap analyses revealed a widespread but moderate shared genetic basis for 77 PUFA-brain disorder trait pairs. MR suggested potential causal relationships for 16 pairs. Colocalization identified 40 shared loci (13 unique) and 22 candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2), and rs4818766 (ADARB1). These genes were mapped to lipid metabolism pathways. Integrating evidence from multiple approaches, we prioritized four PUFA-brain disorder pairs with potential causal links, including PUFA% with MDD, and omega-6% with alcohol consumption.
CONCLUSIONS: These findings reveal a widespread but moderate shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for potential effects of PUFAs on certain brain disorders, especially MDD and alcohol consumption. Future studies are needed to elucidate potential causal effects.

Keywords:  Brain disorders; Causal relationship; Genetic correlations; Polyunsaturated fatty acids; Shared genetic basis

DOI:  https://doi.org/10.1016/j.jlr.2025.100890
Prostaglandins Leukot Essent Fatty Acids. 2025 Aug 15. pii: S0952-3278(25)00037-7. [Epub ahead of print]206 102700

Maternal blood glucose level is correlated to offspring brain fatty acid composition in a mouse model for gestational diabetes mellitus.

Lidewij Schipper, Noela Schaap, Yixian Liu, Hongyu Li, Weiping Han, Louise Harvey.

  Gestational diabetes mellitus (GDM) may increase the risk of suboptimal neurocognitive development in infants. Maternal supply of omega-3 and -6 long chain polyunsaturated fatty acids (LCPUFAs), including eicosapentaeonic acid, docosahexaenoic acid and arachidonic acid, are critical for offspring brain development. To study the effects of GDM on offspring brain fatty acid composition, C57BL/6J mice were exposed to short-term high-fat diet feeding and low-dose streptozotocin treatments before pregnancy. Maternal blood glucose levels positively correlated to offspring brain omega 6:omega 3 ratio at postnatal day 2 and day 21, which appeared to be driven specifically by higher omega-6 LCPUFA levels. GDM may be associated with impaired brain fatty acid profile in offspring, and this may underpin altered neurodevelopmental outcomes after GDM pregnancies. These findings support further investigation into the therapeutic potential of postnatal dietary interventions targeting fatty acid status in infants born after GDM.

Keywords:  Gestational diabetes mellitus; Long chain polyunsaturated fatty acids; Neurodevelopment; Offspring

DOI:  https://doi.org/10.1016/j.plefa.2025.102700
Bioessays. 2025 Aug 22. e70058

Mitochondrial Microproteins: Emerging Regulators in Neurodevelopment and Neurodegeneration.

Nada Borghol, Sozerko Yandiev, Julien Courchet.

  Recent advances in genomics uncovered a large number of microproteins, which are peptides of less than 100 amino-acids encoded by small open reading frames. In contrast to their identification, the validation of the functions of microproteins remains challenging. Especially, what are their biological functions in the cell and how this relates to disease conditions are still largely unknown. Although microproteins ensure a plethora of cellular functions, recent evidence demonstrate that they may disproportionately affect cellular metabolism. In this review, we will address the roles of mitochondrial-targeted microproteins, and especially how this class of protein regulates neuronal metabolism in neurodevelopment and neurodegeneration, and may contribute to axonal and dendritic metabolic disorders.

Keywords:  metabolism; microproteins; mitochondria; neurodegeneration; neurodevelopment; neuron

DOI:  https://doi.org/10.1002/bies.70058
Anal Sci. 2025 Aug 27.

Review of methods for the determination of cellular cholesterol content: principles, advantages, limitations, applications, and perspectives.

Zihang Zhou, Jiangyu Zong, Ning Xu.

  Imbalances in cellular cholesterol homeostasis are associated with various diseases, and accurate determination of cholesterol levels and distribution is essential for a thorough understanding of cellular physiopathology. In this review, we comprehensively analyzed various techniques for cellular cholesterol determination. They include indirect methods based on SREBP2 activity monitoring, gas chromatography-liquid chromatography coupling, enzyme analysis, improved Abell-Kendall method, cholesterol-specific probes such as filipin III and cholesterol-dependent cytolysin, and cholesterol analogs such as dehydroergosterol, BODIPY-cholesterol, label-free as well as labeling Raman assays and mass spectrometry imaging techniques such as matrix-assisted laser desorption/ionization mass spectrometry imaging, desorption electrospray ionization mass spectrometry imaging, and nanoscale secondary ion mass spectrometry technology. Principles, advantages, and limitations of each technique are discussed in detail, their characteristics in terms of sensitivity, spatial resolution, and temporal resolution are compared in detail. Finally, suggestions for selecting the technique for different experimental objectives are also given. These findings will help researchers choose the most suitable method according to their own needs, provide strong support for cellular cholesterol research, and promote the development of related fields to better elucidate the significance of cellular cholesterol in normal biologic activities and also its intrinsic relationship with diseases.

Keywords:  Biological assay; Cholesterol; Cholesterol analogues; Mass spectrometry imaging; Probe technology

DOI:  https://doi.org/10.1007/s44211-025-00842-5
J Physiol. 2025 Aug 25.

Astrocytes: Orchestrators of brain gas exchange and oxygen homeostasis.

Isabel N Christie.

  If we consider neurons like muscles during exercise, the demand for oxygen (O2) and carbon dioxide (CO2) elimination is constantly changing. This review summarises the evidence that astrocytes are essential for homeostasis of the respiratory gases in the brain, with a particular focus on oxygen homeostasis. Astrocytes surround cerebral blood vessels and sense changes in oxygen availability in the milieu. They contribute to pH homeostasis and are increasingly recognized for their contribution to central chemosensitivity, particularly in detecting changes in CO2 and proton (H+) concentrations. They are one of the cell types that govern changes in cerebral perfusion rate. Cerebral perfusion dynamically matches tissue metabolism, to balance O2 delivery and CO2 removal. By examining the role of astrocytes as both sensors and effectors in this homeostatic balancing act, this review argues that astrocytes influence the metabolic environment of neural networks with profound implications for cognitive function.

Keywords:  astrocyte; brain; gas exchange; homeostasis; hypoxia; oxygen transport; perfusion

DOI:  https://doi.org/10.1113/JP288934
Data Brief. 2025 Oct;62 111948

Targeted lipidomics dataset of central nervous system and plasma from mice with experimental autoimmune encephalomyelitis.

Jörn Lötsch, Irmgard Tegder, Natasja de Bruin, Dominique Thomas, Gerd Geisslinger.

  This dataset was generated from a preclinical study that used the relapsing-remitting experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice to examine lipid signalling in neuroinflammation. The study examined how the reference compounds FTY720 (fingolimod, 0.5 mg/kg/day) affected the autotaxin/lysophosphatidic acid (ATX/LPA) axis and related lipid mediators. The mice were divided into three groups: control (no EAE), EAE, and EAE plus fingolimod. Tissue samples were collected from the plasma, cerebellum, hippocampus, and prefrontal cortex, resulting in 26 biological samples. Targeted lipidomics was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify 62 lipid species, including lysophosphatidic acids, ceramides, sphingoid bases, and endocannabinoids. The dataset is provided in both raw and imputed formats, along with comprehensive sample-level metadata. The data are organized into three comma-separated values (CSV) files: (1) the original quantitative lipidomics data matrix with missing values, (2) a log₁₀-transformed imputed dataset with missing values addressed using random forest imputation, and (3) a metadata file detailing the characteristics of the samples, group assignments, and tissue type. Standardized variable naming and detailed metadata facilitate cross-referencing and integration with other datasets. This resource enables comparative analyses of lipid profiles across tissues and treatment groups. It supports statistical and machine learning applications and enables the evaluation of data augmentation strategies, including statistical and generative AI approaches. This dataset can be reused in studies of neuroinflammation, lipid signalling, and biomarker discovery, as well as in the development of methods for computational biology and omics data analysis.

Keywords:  Data science; Lipidomics; Machine learning; Mouse model; Multiple sclerosis; Preclinical pharmacology

DOI:  https://doi.org/10.1016/j.dib.2025.111948
Cells. 2025 Aug 19. pii: 1281. [Epub ahead of print]14(16):

Lipid-Laden Microglia: Characterization and Roles in Diseases.

Jiani Xing, Takese McKenzie, Jian Hu.

  Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). LLMs have been implicated in various neuroinflammatory and neurodegenerative diseases, functioning as both regulators/indicators of inflammation and potential therapeutic targets. This review summarizes the current research on LLMs, focusing on disease-specific regulators and functions, protective roles, interactions with neighboring cells, and advances in diagnostic and analytical tools. We also discuss the blurred distinction between LLMs and macrophages, inconsistent terminology, and major knowledge gaps across different disease contexts. Deciphering the composition, formation, and dynamics of lipid droplets in microglia is critical for uncovering how microglial states shift under diverse pathological stimuli. A clearer view of these mechanisms may reveal novel roles of LLMs and open new avenues for therapeutic intervention.

Keywords:  lipid droplet analytical tools; lipid droplets; lipid metabolism; microglia; neurodegeneration

DOI:  https://doi.org/10.3390/cells14161281
Front Neurol. 2025 ;16 1637243

From imaging to intervention: emerging potential of PET biomarkers to shape therapeutic strategies for TBI-induced neurodegeneration.

Anna O Giarratana.

  This review examines the role of positron emission tomography (PET) imaging tracers in advancing our understanding of traumatic brain injury (TBI) induced neurodegeneration and the therapeutic targets they help to identify. It focuses on tracers used to evaluate post-TBI alterations in metabolism, amyloid, tau, neuroinflammation, and neurotransmitter systems. These molecular imaging tools provide critical insights into pathophysiological processes such as disrupted glucose metabolism, amyloid deposition, tau accumulation, chronic neuroinflammatory responses, and neurotransmitter dysregulation. The review also explores how these tracers, as imaging biomarkers, may guide future therapeutic strategies. Finally, it discusses the challenges and opportunities associated with integrating PET imaging into TBI diagnosis, longitudinal monitoring, and treatment planning.

Keywords:  PET/CT; PET/MRI; brain injury; concussion; neurodegeneration; neurotheranostics; precision medicine; traumatic brain injury (TBI)

DOI:  https://doi.org/10.3389/fneur.2025.1637243
Transl Psychiatry. 2025 Aug 25. 15(1): 315

iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder.

Dana El Soufi El Sabbagh, Alencar Kolinski Machado, Lauren Pappis, Erika Leigh Beroncal, Delphine Ji, George Nader, Prathyusha Ravi Chander, Jaehyoung Choi, Angela Duong, Hyunjin Jeong, Bruna Panizzutti, Chiara Cristina Bortolasci, Andrea Szatmari, Peter Carlen, Margaret Hahn, Liliana Attisano, Michael Berk, Ken Walder, Ana Cristina Andreazza.

Bipolar disorder (BD) is increasingly recognized as a disease with both mitochondrial dysfunction and heightened inflammatory reactivity, yet contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a more physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. The effect of a Bioactive Flavonoid Extract (BFE), a potential therapeutic, was also explored and yielded a partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.

DOI: https://doi.org/10.1038/s41398-025-03529-7
J Cereb Blood Flow Metab. 2025 Aug 25. 271678X251366074

Cerebral glucose delivery, transport and metabolism: Theory and modeling using four, three, and two tissue compartments.

Anina Seidemo, Linda Knutsson, Nirbhay N Yadav, Pia C Sundgren, Ronnie Wirestam, Peter Cm van Zijl.

  Flux equations describing brain D-glucose uptake are presented for up to four tissue compartments: blood, endothelial intracellular space in the blood-brain barrier (BBB), extravascular-extracellular space (EES), and intracellular space. Transport rates are described by Michaelis-Menten kinetics, including half-saturation constants (KT) and maximum rates for transport (Tmax) over the BBB and the cell membrane (CMB). These transport parameters and the maximum rate for hexokinase-catalyzed metabolism (VmaxHK) were determined by numerical fitting of the models to both steady-state and dynamic D-glucose uptake data in human gray matter from MRS. Two-, three-, and four-compartment results are compared, including effects of incorporating an endothelial compartment with unequal ratios (RA/L) of GLUT1 receptors on abluminal and luminal membranes. Four-compartment fitting with RA/L=2.0 resulted in TmaxBBB=0.804±0.131 µmol/g/min, KTBBB=6.20±1.53 mM, TmaxCMB=1.04±0.25 µmol/g/min, KTCMB=3.10±0.70 mM and VmaxHK=0.260±0.039 µmol/g/min, comparing well with the simpler models. A model with at least three tissue compartments (blood, EES, cell) is essential for quantification and interpretation of dynamic glucose-enhanced (DGE) MRI data in brain tumors, where signal intensities depend on compartmental pH in addition to concentration, and where the signal contribution from the EES is dominant. It should also be relevant to PET and MR(S) studies of pathologies where the BBB is compromised.

Keywords:  4-Tissue-compartment model; Cerebral glucose metabolism; Glucose transport; Kinetic modeling; Michaelis-Menten kinetics

DOI:  https://doi.org/10.1177/0271678X251366074