bims-medebr 2025-09-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–09–21
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

APOE genotype-dependent differences in human astrocytic energy metabolism.
Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.
Cholesterol metabolism regulates Tauopathy in Alzheimer's disease.
Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease.
Neurons and astrocytes have distinct organelle signatures and responses to stress.
Temporal dynamics of CNS cholesterol esters correlate with demyelination and remyelination.
Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.
Ketogenic diet in neonates: effects, pitfalls, and a paradigm from a preterm newborn affected by pyruvate dehydrogenase deficiency.
Embracing Scientific Debate in Brain Metabolism.
Dysregulated Lipids in Alzheimer's Disease: Insights into Biological Pathways through LC-MS/MS Analysis of Human Brain Tissues.
Riboflavin in neurological diseases: therapeutic advances, metabolic insights, and emerging genetic strategies.
Glutamate decreases oxidative stress and lipid droplet formation in astrocytes.
Plasma Lipidomic Patterns Associated with Disease Activity in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (LIPID-CIDP).
Human apolipoprotein E ε4 allele modulates energy substrate availability, seizure burden, mortality and hippocampal injury, cell death and inflammation after neonatal hypoxic-ischemic brain injury.
Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.
CRISPR-edited iPSCs reveal BSN gene mutations induce neuronal hyperexcitability via astrocyte lipid accumulation.
Cholesterol Depletion with U18666A and Methyl-β Cyclodextrin Increased Small Molecule Permeability Across Brain Microvascular Endothelial Cells.
Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity.
L-carnitine: new perspectives on the management of preterm infants.

Front Cell Neurosci. 2025 ;19 1603657

APOE genotype-dependent differences in human astrocytic energy metabolism.

Vanessa Budny, Chantal Bodenmann, Kathrin J Zürcher, Maik Krüger, Sherida M de Leeuw, Rebecca Z Weber, Ruslan Rust, Luca Ravotto, Iván Ruminot, L Felipe Barros, Bruno Weber, Christian Tackenberg.

   Introduction: The main genetic risk factor for Alzheimer's disease (AD) is the presence of the apolipoprotein E4 (APOE4) allele. While APOE4 increases the risk of developing AD, the APOE2 allele is protective and APOE3 is risk-neutral. In the brain, APOE is primarily expressed by astrocytes and plays a key role in various processes including cholesterol and lipid transport, neuronal growth, synaptic plasticity, immune response and energy metabolism. Disruptions in brain energy metabolism are considered a major contributor to AD pathophysiology, raising a key question about how different APOE isoforms affect the energy metabolism of human astrocytes.
Methods: In this study, we generated astrocytes (iAstrocytes) from APOE-isogenic human induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE knockout (APOE-KO), and investigated APOE genotype-dependent changes in energy metabolism.
Results: ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in APOE4 iAstrocytes. In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in APOE4 iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that APOE does not affect lactate dynamics. In agreement with the increased glycolytic activity, APOE4 iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test. This was accompanied by elevated proton leak in APOE4 iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected. Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in APOE4 compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis. In general, APOE2 and APOE-KO iAstrocytes showed a very similar phenotype in all functional assays and differences between APOE2/APOE-KO and APOE4 were stronger than between APOE3 and APOE4.
Discussion: Our study provides evidence for APOE genotype-dependent effects on astrocyte energy metabolism and highlights alterations in the bioenergetic processes of the brain as important pathomechanisms in AD.

Keywords:  Alzheimer’s disease (AD); apolipoprotein E (APOE); energy metabolism; glycolysis; human astrocytes; induced pluripotent stem cells (iPSCs); mitochondrial function; mitochondrial uncoupling

DOI:  https://doi.org/10.3389/fncel.2025.1603657
bioRxiv. 2025 Sep 08. pii: 2025.09.04.674092. [Epub ahead of print]

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury.

Amir A Mehrabani-Tabari, Nivedita Hegdekar, Brian R Herb, Sazia Arefin Kachi, Chinmoy Sarkar, Sagarina Thapa, Dexter Ph Nguyen, Yulemni Morel, Mehari M Weldemariam, Ludovic Muller, W Temple Andrews, Marcia Cortes-Gutierrez, Xiaoxuan Fan, Natarajan Ayithan, Olivia Pettyjohn-Robin, Sabrina Bustos, Lacey K Greer, Jessica T Gore, Maureen A Kane, Seth A Ament, Jace W Jones, Marta M Lipinski.

CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.

DOI: https://doi.org/10.1101/2025.09.04.674092
Adv Protein Chem Struct Biol. 2025 ;pii: S1876-1623(24)00128-7. [Epub ahead of print]147 401-421

Cholesterol metabolism regulates Tauopathy in Alzheimer's disease.

Subashchandrabose Chinnathambi, Anusree Adityan, Madhura Chandrashekar.

  Cholesterol, produced by astrocytes, is vital for the formation and maintenance of synapse, highlighting the significance of lipid metabolism in neuronal health. Neural stem cells (NSCs) are versatile, self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes, playing a pivotal role in both embryonic development and adult neurogenesis. In the central nervous system (CNS), NSCs primarily reside in the subventricular zone (SVZ) and the sub-granular layer of the dentate gyrus, where they give rise to neural progenitors and subsequently to neurons and glial cells. Oligodendrocytes play a crucial role in the CNS function and myelin sheath formation, which is essential for rapid neuronal signal transmission. Astrocytes contribute to brain homeostasis by regulating lipid metabolism and providing metabolic support to neurons. Sphingolipids and phospholipids are integral to neural cell membrane structure and function, influencing processes such as neurogenesis, cell signaling, and synaptic plasticity. Furthermore, the ApoE4 allele impacts lipid metabolism, affecting the risk of neurodegenerative diseases. This paper explores the role of various cell types and lipids in the CNS, emphasizing the importance of lipid metabolism in maintaining neural function and the implications for neurodegenerative conditions.

Keywords:  Alzheimer’s disease; Amyloid-beta; Apolipoprotein; Astrocytes; Cholesterol metabolism; Glycerophospholipids; Myelination; Neural stem cells; Oligodendrocytes; Phospholipids; Sphingolipids

DOI:  https://doi.org/10.1016/bs.apcsb.2024.11.005
Front Neurosci. 2025 ;19 1636624

Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease.

Demos Kynigopoulos, Eleni Fella, Lucy Shahabian, Christiana C Christodoulou, Revekka Papacharalampous, Konstantinos Diskos, Lida Evmorfia Vagiaki, Kyriaki Sidiropoulou, Menelaos Pipis, Kleopas A Kleopa, Elena Panayiotou.

   Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, yet it remains unclear whether modulation of peripheral lipid and glucose metabolism can alter disease progression.
Methods: We investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months. Behavioral testing, hippocampal electrophysiology, ELISA, lipidomics, and adipokine profiling were performed to assess cognitive, synaptic, and molecular outcomes.
Results: Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression. Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments decreased amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in brain and serum. Lipidomic profiling of visceral adipose tissue revealed distinct lipid remodeling and highlighted candidate pathways linking systemic metabolism to central nervous system outcomes.
Discussion: These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence neurodegenerative and synaptic processes in AD. The results support metabolic interventions as a potential strategy to modify AD progression through peripheral-central metabolic crosstalk.

Keywords:  5xFAD mouse model; Alirocumab; Alzheimer’s disease; Gliclazide; glucose metabolism; lipid metabolism; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.3389/fnins.2025.1636624
Cell Rep. 2025 Sep 15. pii: S2211-1247(25)01051-4. [Epub ahead of print]44(9): 116280

Neurons and astrocytes have distinct organelle signatures and responses to stress.

Shannon N Rhoads, Weizhen Dong, Chih-Hsuan Hsu, Ngudiankama R Mfulama, Ridhi Yarlagadda, Joey V Ragusa, Michael Ye, Andy Henrie, Maria Clara Zanellati, Graham H Diering, Todd J Cohen, Sarah Cohen.

  Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live neural cells has not been performed. Here, we use multispectral imaging to simultaneously visualize six organelles-endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets-in live primary rodent neurons and astrocytes. We generate a dataset of 173 z stack and 98 time-lapse images, accompanied by quantitative "organelle signature" analysis. Comparative analysis reveals a clear cell-type specificity in organelle morphology and interactions. Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell-type-specific physiology and disease.

Keywords:  CP: Cell biology; CP: Neuroscience; Golgi; astrocytes; endoplasmic reticulum; lipid droplets; lysosomes; microscopy; mitochondria; neurons; organelles; peroxisomes

DOI:  https://doi.org/10.1016/j.celrep.2025.116280
bioRxiv. 2025 Sep 11. pii: 2025.09.06.674663. [Epub ahead of print]

Temporal dynamics of CNS cholesterol esters correlate with demyelination and remyelination.

Nishama De Silva Mohotti, Jenna M Williams, Rashmi Binjawadagji, Hiroko Kobayashi, Disni Dedunupitiya, Jack M Petersen, Alana Garcia, Meredith D Hartley.

Elevated cholesterol ester levels have been observed in the CNS of patients with neurological diseases, yet the source of cholesterol ester accumulation and whether it is directly linked to demyelination remains undefined. This study investigates the temporal dynamics of cholesterol esters using the Plp1-iCKO-Myrf mouse model, which features distinct phases of demyelination and remyelination. Our findings reveal that cholesterol ester levels increased with demyelination in both the brain and the spinal cord. In the brain, cholesterol esters declined to normal levels during remyelination, whereas cholesterol esters remained elevated in the spinal cord, which had limited remyelination. Expression of both acetyl-CoA-acyltransferase 1 (ACAT1) and lecithin-cholesterol acyltransferase (LCAT) were elevated during demyelination, suggesting the potential involvement of both proteins in the formation of cholesterol esters. Co-localization studies revealed that ACAT1 is predominantly expressed by microglia and LCAT is predominantly expressed by astrocytes during demyelination highlighting the active roles of glia cells in cholesterol ester metabolism. In addition, we showed that administering the remyelinating drug, Sob-AM2, effectively reduced the level of cholesterol ester accumulation in the brain during demyelination underscoring the potential that manipulating cholesterol ester regulatory pathways may offer for restoring cholesterol homeostasis and promoting remyelination in demyelinating diseases.

DOI: https://doi.org/10.1101/2025.09.06.674663
ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2868-2886

Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.

Smita Jain, Reetuparna Acharya, Lavkush Verma, Aparna Chauhan.

  Age-related cognitive decline, a hallmark of neurodegenerative disorders such as Alzheimer's disease, has been increasingly associated with metabolic dysregulation. Targeting metabolic pathways to enhance brain function and slow neurodegeneration presents a novel therapeutic approach. This review discusses key metabolic interventions that may reverse or delay cognitive decline. Mitochondrial dysfunction, oxidative stress, and impaired energy metabolism are central to neurodegenerative progression. Therapies aimed at boosting mitochondrial biogenesis, such as nicotinamide adenine dinucleotide (NAD+) precursors, adenosine monophosphate-activated protein kinase (AMPK) activators, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) modulators, have shown promise in improving neuronal energy balance and reducing oxidative damage. Metabolic interventions like caloric restriction, intermittent fasting, and ketogenic diets have demonstrated neuroprotective effects by enhancing insulin sensitivity, promoting autophagy, and shifting the brain's energy reliance toward ketone bodies, which improves cognitive function. These strategies also mitigate neuroinflammation, a key driver of neuronal damage, by modulating immune responses and reducing the accumulation of toxic protein aggregates. Lipid metabolism also plays a crucial role in maintaining neuronal integrity. Enhancing lipid turnover, optimizing fatty acid profiles, and regulating cholesterol homeostasis may improve synaptic plasticity and reduce neuroinflammation, offering additional therapeutic avenues. By integrating current insights into metabolic regulation, this review underscores the potential of metabolic therapies to reverse or mitigate the cognitive decline associated with aging. Advancing our understanding of the intricate relationship between metabolism and neurodegeneration may pave the way for novel treatments targeting age-related cognitive impairment.

Keywords:  caloric restriction; insulin signaling; lipid metabolism; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1021/acsptsci.5c00077
J Perinatol. 2025 Sep 17.

Ketogenic diet in neonates: effects, pitfalls, and a paradigm from a preterm newborn affected by pyruvate dehydrogenase deficiency.

Sokratis Katsoudas, Luis A Umana, Rebekah Clarke, Jennifer Thomas, Michelle Machie, Dimitrios Angelis.

The application of ketogenic diet (KD) in newborns is rare and mainly reserved for specific metabolic and seizure disorders. Furthermore, only case reports describe the effects of KD in premature infants. Here, we summarize the recent advances, indications, mechanisms of action and practical issues related to KD. We also provide a paradigm of a preterm male infant born at 34 weeks with pyruvate dehydrogenase deficiency, highlighting the therapeutic challenges and outcomes with the KD. This report underscores the complexities of managing metabolic disorders in neonates and the effects of KD.

DOI: https://doi.org/10.1038/s41372-025-02427-6
J Neurochem. 2025 Sep;169(9): e70230

Embracing Scientific Debate in Brain Metabolism.

Jens V Andersen, Blanca I Aldana, Lasse K Bak, Kevin L Behar, Karin Borges, Anthony Carruthers, Paul Cumming, Amin Derouiche, Carlos M Díaz-García, Kelly L Drew, João M N Duarte, Gustavo C Ferreira, Federico Giove, Albert Gjedde, Fahmeed Hyder, Maria S Ioannou, Oliver Kann, Tibor Kristian, James C K Lai, Graeme F Mason, Ewan C McNay, Maiken Nedergaard, Thaddeus S Nowak, Anant B Patel, Caroline D Rae, Timothy A Ryan, Patricia F Schuck, Ian A Simpson, Susan J Vannucci, Helle S Waagepetersen, Gary Yellen, Mary C McKenna.

  Brain metabolism is a fascinating and exciting research topic. Many new metabolic features of the brain continue to be unveiled and much remains to be discovered. To truly enable scientific progress, it is imperative that discoveries and theories are continually challenged through scholarly discussion. Here we address an earlier editorial by Bolaños et al. 2025 to underline the importance of embracing and respectfully engaging in scientific debate.

Keywords:  metabolic shuttles; metabolism; neuron–glia interactions

DOI:  https://doi.org/10.1111/jnc.70230
ACS Chem Neurosci. 2025 Sep 16.

Dysregulated Lipids in Alzheimer's Disease: Insights into Biological Pathways through LC-MS/MS Analysis of Human Brain Tissues.

Akeem Sanni, Andrew I Bennett, Moyinoluwa Adeniyi, Yehia Mechref.

  Alzheimer's Disease (AD), the leading cause of dementia, is characterized by complex pathological mechanisms that extend beyond amyloid-β plaques and tau tangles. This study investigates the dysregulation of lipids with a focus on phospholipids and sphingolipids, in human post-mortem AD brain tissue using lipidomics methodology. By employing a ZIC-HILIC LC-MS/MS platform, the lipidome of AD (N = 18) was compared to the control (N = 18). Out of 45 quantified lipid classes, 16 belonging to phospholipids and sphingolipids group are differentially expressed (p < 0.05; q < 0.05) in AD compared to control. Key findings include the upregulation of phosphatidylcholine (PC), phosphatidylglycerol (PG), ganglioside GD2 (GD2), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingomyelin (phSM), along with the downregulation of ganglioside GD1a in AD. The targeted analysis revealed that ganglioside GD1b exhibits a higher abundance than ganglioside GD1a across all sample groups. System biology analysis revealed that dysregulated lipids impact critical pathways, including glycerophospholipid biosynthesis and sphingolipid metabolism. Additionally, proteomics analysis on the samples showed that proteins such as Amyloid-β precursor protein, pleckstrin homology and SEC7 domain-containing protein 2 (PSD2), and RAC-gamma serine/threonine-protein kinase (AKT) play a role in phospholipid and sphingolipid dysregulation observed in AD. The dysregulated lipids are predicted to be involved in neuronal cell death, necrosis, and apoptosis, advancing our understanding of AD pathogenesis. The study highlights phospholipids and sphingolipids as promising biomarkers and potential therapeutic targets for AD, paving the way for possible diagnostic tools and personalized treatments.

Keywords:  AD; LC-MS/MS; ZIC-HILIC; amyloid-β; gangliosides; phospholipids

DOI:  https://doi.org/10.1021/acschemneuro.5c00230
Front Neurol. 2025 ;16 1663136

Riboflavin in neurological diseases: therapeutic advances, metabolic insights, and emerging genetic strategies.

Zhiming Tao, Jinglu Huo, Xiaosheng Hao, Jianmin Liang.

   Background: Riboflavin (vitamin B2), a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is essential for mitochondrial function, redox balance, and neuronal viability. Impairments in riboflavin transport and metabolism contribute to a growing spectrum of neurological diseases.
Objective: This review provides a comprehensive update on the therapeutic applications, metabolic mechanisms, and gene-based strategies involving riboflavin in neurological disorders.
Methods: We systematically analyzed clinical and experimental studies published between 2012 and 2025, focusing on riboflavin-responsive conditions and molecular mechanisms relevant to neurological pathology.
Results: Riboflavin supplementation-particularly in high doses-has demonstrated substantial efficacy in conditions such as riboflavin transporter deficiency (RTD), multiple acyl-CoA dehydrogenase deficiency (MADD), and migraine. Emerging data suggest potential benefit in Parkinson's disease, Alzheimer's disease, multiple sclerosis, and acute brain injury. Mechanistically, riboflavin supports mitochondrial bioenergetics, antioxidant systems, and epigenetic regulation. Recent advances in gene therapy and pharmacological chaperones targeting riboflavin-dependent pathways offer promising therapeutic directions.
Conclusion: Riboflavin is evolving from a conventional micronutrient into a multifaceted therapeutic agent in neurology. Integration of gene-based approaches, targeted delivery systems, and biomarker-guided interventions may establish riboflavin as a key component of precision medicine strategies for neurological disorders.

Keywords:  combination therapy; gene therapy; mitochondrial dysfunction; neurological diseases; riboflavin; vitamin B2

DOI:  https://doi.org/10.3389/fneur.2025.1663136
J Cell Sci. 2025 Sep 17. pii: jcs.263983. [Epub ahead of print]

Glutamate decreases oxidative stress and lipid droplet formation in astrocytes.

Luis Fernando Rubio-Atonal, Jinlan Chang, Julie Jacquemyn, Isha Ralhan, Iset Ilarraza, Maria S Ioannou.

  Astrocytes degrade fatty acids in response to glutamate while reducing the abundance of lipid droplets. But how glutamate regulates lipid droplets in astrocytes is unclear. Here we show that glutamate decreases the amount of reactive oxygen species which in turn, reduces autophagy and the amount of lipids in need of storage in lipid droplets. This decrease in lipid droplets and reactive oxygen species occurs independent of glutamate import through excitatory amino acid transporters (EAATs). However, activation of AMPK, downstream of EAATs, further promotes a decrease in lipid droplets. Glutamate also increases the pool of fused mitochondria capable of maintaining enhanced fatty acid metabolism. Our work reveals how astrocytic metabolism is regulated by glutamate that can serve to coordinate astrocyte physiology with neuronal activity.

Keywords:  Astrocytes; Autophagy; Fatty acid oxidation; Lipid droplet; Lipid peroxidation; Oxidative stress

DOI:  https://doi.org/10.1242/jcs.263983
J Lipid Res. 2025 Sep 17. pii: S0022-2275(25)00165-8. [Epub ahead of print] 100903

Plasma Lipidomic Patterns Associated with Disease Activity in Chronic Inflammatory Demyelinating Polyradiculoneuropathy (LIPID-CIDP).

Kristina Auf dem Brinke, Lisa-Marie Borsch, Christian Klose, Jana Zschüntzsch, Liza Vinhoven, Manuel Nietert, Seyed Siyawasch Justus Lattau, Dirk Fitzner.

  Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy that causes significant disability in patients. Although pathogenic mechanisms remain unclear, it is known that inflammation results in segmental demyelination. This study aims to investigate the plasma lipidomic profile of CIDP patients to identify lipid patterns associated with disease activity. Using high-throughput shotgun lipidomics, we analyzed and compared the plasma lipidome of 30 patients with CIDP (mean age ± SD: 60.7 ± 12.2 years) with that of 30 individuals diagnosed with non-demyelinating neurological disorders (OND; mean age ± SD: 52.8 ± 10.3 years). Lipids were quantified in absolute [pmol] and relative concentrations [mol%], and their levels were correlated with CIDP disease activity and clinical disability scores (R-ODS, INCAT and MRC). To control for confounders such as age and weight, strongly correlated lipids were excluded. The analysis identified 669 molecular lipid species across 15 lipid classes, revealing a significant elevation in the diacylglycerol (DAG) class in CIDP patients. Furthermore, specific lipid subspecies, including triacylglycerol (TAG), DAG, and ether-linked phosphatidylcholine (PC O-), were significantly correlated with disease activity. A set of distinct lipid subspecies, including phosphatidylcholine (PC), lyso-phosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), and cholesterol ester (CE) showed strong associations with clinical disability scores. These findings suggest that CIDP is characterized by distinct lipidomic profiles modulated by disease activity. This dataset could pave the way for future studies in larger cohorts evaluating the potential of plasma lipid profiles to serve as biomarkers for disease activity and severity, aiding to inform clinical management.

Keywords:  Chronic Inflammatory Demyelinating; Inflammation; Lipid Metabolism; Lipid droplets; Lipidomics; Lipotoxicity; Membrane Lipids; Phospholipids/ Metabolism; Polyradiculoneuropathy

DOI:  https://doi.org/10.1016/j.jlr.2025.100903
Dev Neurosci. 2025 Sep 16. 1-22

Human apolipoprotein E ε4 allele modulates energy substrate availability, seizure burden, mortality and hippocampal injury, cell death and inflammation after neonatal hypoxic-ischemic brain injury.

Michelle Nazareth, Sarah Ann Duck, Abigail Fassinger, Genesis Elmore, Charles Pinto, Michael Nugent, Mark St Pierre, Charles Lechner, Lauren L Jantzie, Frances J Northington, Susan J Vannucci, Lee J Martin, Raul Chavez-Valdez.

INTRODUCTION: Human apolipoprotein E allele ε4 (ApoE4) is the strongest genetic risk factor for some forms of adulthood neurodegeneration linked to energetic disturbances and inflammation. We hypothesized that ApoE4 also influences neonatal brain neurodegeneration after a hypoxic ischemic (HI) insult, resulting in energy substrates (i.e., glucose, ketone bodies) disturbances, hippocampal injury, cell death and inflammation.
METHODS: Right-sided brain HI was induced at P10 in wild type (wt, C57BL6) and humanized ApoE3 and ApoE4 mice with sham anesthesia-exposed littermates as controls. Seizure-like activity, survival, blood glucose (BG), and ketone bodies (KB) were determined immediately after the HI insult. The hippocampi were assessed 24h and 72h after the HI insult for residual volume, cell death (α-fodrin breakdown), inflammatory markers, and transcriptomics (RNAseq).
RESULTS: Wt, ApoE3 and ApoE4 mice were congenic (>99.8% transcriptome similarity). Female ApoE4 mice had worse seizures, lower survival and smaller residual hippocampal volumes than the ApoE3 mice. All three strains had lower BG after HI. ApoE4 mice also had lower KB. Low BG was associated with higher pro-inflammatory and cell death markers in the hippocampus in all HI genotype groups at 24h but more robustly in ApoE4 mice, and in combination with high KB, was strongly linked to cell death (greater α-fodrin breakdown).
CONCLUSION: Humanized ApoE4, compared to ApoE3, causes greater hippocampal injury, cell death and inflammation after a neonatal HI insult in association with low BG and underutilized KB. The mechanisms behind these associations need further investigation.

DOI: https://doi.org/10.1159/000548432
Metabol Open. 2025 Sep;27 100389

Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.

Faisal Alzenaidi, Osama Aldoweesh, Salman Alghofaili, Abdulaziz Fadel, Razan Ali Awad Lasloom, Dhay Alharbi, Faris Almalki, Atheer Ahmad Alkhairi, Maram Alharbi, Norah Ahmed Alhamdan, Ahmed Y Azzam.

   Introduction: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients.
Methods: Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes.
Results: Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52-1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68-2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02-0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50-1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection.
Conclusions: SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.

Keywords:  Alzheimer's disease; Dementia; Glucose metabolism; Metabolism; Selective serotonin reuptake inhibitors

DOI:  https://doi.org/10.1016/j.metop.2025.100389
Neurotherapeutics. 2025 Sep 16. pii: S1878-7479(25)00218-1. [Epub ahead of print] e00740

CRISPR-edited iPSCs reveal BSN gene mutations induce neuronal hyperexcitability via astrocyte lipid accumulation.

Haiying Chen, Shanshan Fan, Kanglian Chen, Feilong Wang, Meiting Lu, Yide Wu, Hailian Lu, Jinliang Li.

  Mutations in the BSN gene, encoding the presynaptic protein Bassoon, are implicated in epilepsy, but their impact on astrocytes remains unclear. Using CRISPR/Cas9, we introduced patient-derived BSN mutations (p.M1903V and c.5672insCG) into human induced pluripotent stem cells (iPSCs) and differentiated them into astrocytes. We found that mutant astrocytes exhibited significant lipid accumulation, evidenced by elevated free cholesterol, reduced arginase activity, and increased lipid droplets. Proteomic analysis revealed upregulation of lipid metabolism regulators, such as APOE and FASN. Electrophysiological recordings showed impaired Kir4.1 potassium channel function, depolarized resting membrane potential, and increased capacitance in mutant astrocytes following kainic acid stimulation. Co-culture experiments with neurons demonstrated that BSN-mutant astrocytes led to reduced neurite outgrowth, elevated neuronal apoptosis, increased pro-inflammatory cytokines (IL-1β, TNF-α), and neuronal hyperexcitability. These findings demonstrate that BSN mutations disrupt astrocyte lipid homeostasis and impair neurosupportive functions, thereby driving neuronal hyperexcitability. This study establishes astrocytes as critical mediators of epilepsy pathogenesis in BSN-related disorders and highlights lipid metabolism as a potential therapeutic target.

Keywords:  Astrocyte; CRISPR/Cas9; Genetic mutant; Lipid accumulation; Neuronal hyperexcitability

DOI:  https://doi.org/10.1016/j.neurot.2025.e00740
Ann Biomed Eng. 2025 Sep 17.

Cholesterol Depletion with U18666A and Methyl-β Cyclodextrin Increased Small Molecule Permeability Across Brain Microvascular Endothelial Cells.

Bilal Moiz, Viviana Alpizar Vargas, Ken D Brandon, Gurneet Sangha, Callie Weber, Andrew Li, Tristan Pepper, Matthew Walls, Anthony Qin, Sara Hart, Cristin Davidson, Kimberly Stroka, Forbes D Porter, Alisa Morss Clyne.

  Cholesterol is a vital component of the cell membrane and plays an essential role in mediating integral membrane protein function. Altered cholesterol regulation has been implicated in neurological diseases that are associated with blood-brain barrier breakdown. However, the role of brain barrier function in inherited disorders of cholesterol metabolism, such as Niemann-Pick disease C1 (NP-C1), remains unclear. In this study, we determined how cholesterol depletion with U18666A, a chemical inhibitor of NPC1 protein, as well as with the cholesterol-depleting agent methyl-β cyclodextrin (MβCD), impacted brain endothelial cell barrier function. We hypothesized that cholesterol depletion would decrease barrier integrity by disrupting tight junction protein continuity. To test this hypothesis, we differentiated human-induced pluripotent stem cells into brain microvascular endothelial cells (hiBMECs). We then assessed barrier integrity by quantifying trans-endothelial electrical resistance (TEER), small fluorescent molecule permeability, and tight junction continuity and protein levels. We now show that U18666A-treated hiBMECs demonstrated a 75% decrease in TEER and 9-fold increase in sodium fluorescein permeability. Similar trends were observed for hiBMECs treated with MβCD, which showed significantly lowered TEER (93% decrease) and increased sodium fluorescein permeability (20-fold higher). We also observed decreased continuity of the tight junction proteins occludin (13% lower) and claudin-5 (8% lower) as well as a 53% decrease in claudin-5 protein with U18666A treatment. Co-treating U18666A-treated hiBMECs with hydroxypropyl-β cyclodextrin (HPβCD), which releases lysosomal cholesterol, prevented these changes. Together, our results demonstrate that cholesterol is vital for hiBMEC barrier function and tight junction continuity. This study highlights the potential of therapeutics targeted to brain endothelium in NP-C1 and other cholesterol metabolism disorders.

Keywords:  Blood–brain barrier; Brain endothelial; Cholesterol; Niemann-Pick disease; Tight junction; iPSC-BMEC

DOI:  https://doi.org/10.1007/s10439-025-03841-9
Brain. 2025 Sep 16. pii: awaf328. [Epub ahead of print]

Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity.

Laetitia Marcadet, Mari Carmen Pelaez, Antoine Desmeules, Jeanne Serrano, Zhan Cheng, Sahara Khademullah, Elahe Parham, Jaimee Kennedy, Claire Troakes, Caroline Vance, Jorge Soliz, Heather D Durham, Liang Li, Paul A Dutchak, Chantelle F Sephton.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy, and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabeling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioral phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of CPT1, the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.

Keywords:  fatty acid oxidation (FAO); glycolysis; ketolysis; nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); withaferin A

DOI:  https://doi.org/10.1093/brain/awaf328
Front Nutr. 2025 ;12 1508441

L-carnitine: new perspectives on the management of preterm infants.

Mo Sisi, Lin Yong, Qiao Lixing, Guo Changsheng, Yao Jin, Zhou Hang, Cao Xing, Liu Heng.

  L-carnitine, a quaternary ammonium compound derived from amino acids, serves an essential role in fatty acid metabolism. The functions of L-carnitine include assisting long-chain fatty acyl-CoA across the mitochondrial membrane to promote mitochondrial β-oxidation, reducing oxidative stress damage, and maintaining cellular energy homeostasis. Therefore, postnatal L-carnitine deficiency may lead to impaired fatty acid oxidation, resulting in clinical manifestations of hypoglycemia, hypothermia, acidosis and infection. However, there is still no clear consensus on the need for prophylactic use of L-carnitine in the treatment of preterm infants. This review synthesizes the theoretical foundations and clinical evidence for L-carnitine in preterm infant management, revealing that L-carnitine exerts demonstrable effects on promoting neurodevelopment and preventing neonatal complications. Furthermore, it explores the potential value and current controversies surrounding its prophylactic application.

Keywords:  L-carnitine; hypoxic–ischemic encephalopathy; neurodevelopment; preterm infants; respiratory distress syndrome

DOI:  https://doi.org/10.3389/fnut.2025.1508441