bims-medebr 2024-12-08 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–12–08
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Dysregulation of energy metabolism in Alzheimer's disease.
Compound-Specific Isotope Analysis as a Potential Approach for Investigation of Cerebral Accumulation of Docosahexaenoic Acid: Previous Milestones and Recent Trends.
An acute microglial metabolic response controls metabolism and improves memory.
Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte-lineage cells established from patients with Sjögren-Larsson syndrome.
Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
Fatty acid binding protein 7 plays an important modulatory sex-dependent role on brain endocannabinoid levels and THC metabolism.
Diverting glial glycolytic flux towards neurons is a memory-relevant role of Drosophila CRH-like signalling.
Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.
The steady-state level of Plasma Membrane Ceramide is regulated by Neutral Sphingomyelinase 2.
Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.
Membrane mechanics dictate axonal pearls-on-a-string morphology and function.
Hyperactivation of Hedgehog signaling impedes myelin development and repair via cholesterol dysregulation in oligodendrocytes.
High glucose potentiates Zika virus induced-astroglial dysfunctions.

J Neurol. 2024 Dec 02. 272(1): 2

Dysregulation of energy metabolism in Alzheimer's disease.

Yue Yuan, Gang Zhao, Yang Zhao.

  Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Its etiology and associated mechanisms are still unclear, which largely hinders the development of AD treatment strategies. Many studies have shown that dysregulation of energy metabolism in the brain of AD is closely related to disease development. Dysregulation of brain energy metabolism in AD brain is associated with reduced glucose uptake and utilization, altered insulin signaling pathways, and mitochondrial dysfunction. In this study, we summarized the relevant pathways and mechanisms regarding the dysregulation of energy metabolism in AD. In addition, we highlight the possible role of mitochondrial dysfunction as a central role in the AD process. A deeper understanding of the relationship between energy metabolism dysregulation and AD may provide new insights for understanding learning memory impairment in AD patients and in improving AD prevention and treatment.

Keywords:  Alzheimer’s disease; Glucose metabolism; Glucose transporters; Mitochondrial autophagy; Mitochondrial dysfunction; Mitochondrial genetics; O-GlcNAc; Tau protein; β-Amyloid

DOI:  https://doi.org/10.1007/s00415-024-12800-8
Mol Neurobiol. 2024 Dec 05.

Compound-Specific Isotope Analysis as a Potential Approach for Investigation of Cerebral Accumulation of Docosahexaenoic Acid: Previous Milestones and Recent Trends.

Abdelmoneim H Ali, Mayssa Hachem, Mirja Kaizer Ahmmed.

  Docosahexaenoic acid (DHA, C22:6 n-3), a predominant omega-3 polyunsaturated fatty acid in brain, plays a vital role in cerebral development and exhibits functions with potential therapeutic effects (synaptic function, neurogenesis, brain inflammation regulation) in neurodegenerative diseases. The most common approaches of studying the cerebral accretion and metabolism of DHA involve the use of stable or radiolabeled tracers. Although these methods approved kinetic modeling of ratios and turnovers for fatty acids, they are associated with excessive costs, restrictive studies, and singular dosing effects. Compound-specific isotope analysis (CSIA) is recognized as a cost-effective alternative approach for investigating DHA metabolism in vitro and in vivo. This method involves determining variations in 13C content to identify the sources of specific compounds. This review comprehensively discusses a summary of different methods and recent advancements in CSIA application in studying DHA turnover in brain. Following, the ability and applications of CSIA by using gas-chromatography combined with isotope ratio mass-spectrometry to differentiate between natural endogenous DHA in brain and exogenous DHA are also highlighted. In general, the efficiency of CSIA has been demonstrated in utilizing natural 13C enrichment to distinguish between the incorporation of newly synthesized or pre-existing DHA into the brain and other body tissues, eliminating the need of tracers. This review provides comprehensive knowledge, which will have potential applications in both academia and industry for advancing the understanding in neurobiology and enhancing the development of nutritional strategies and pharmaceutical interventions targeting brain health.

Keywords:  Bioavailability, Neurological disorders; Brain; CSIA; Docosahexaenoic acid; GC-IRMS

DOI:  https://doi.org/10.1007/s12035-024-04643-1
Elife. 2024 Dec 03. pii: RP87120. [Epub ahead of print]12

An acute microglial metabolic response controls metabolism and improves memory.

Anne Drougard, Eric H Ma, Vanessa Wegert, Ryan Sheldon, Ilaria Panzeri, Naman Vatsa, Stefanos Apostle, Luca Fagnocchi, Judith Schaf, Klaus Gossens, Josephine Völker, Shengru Pang, Anna Bremser, Erez Dror, Francesca Giacona, Sagar Sagar, Michael X Henderson, Marco Prinz, Russell G Jones, John Andrew Pospisilik.

  Chronic high-fat feeding triggers metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial/learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing toward aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hr of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate toward anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuroprotective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

Keywords:  cell biology; diabetes; inflammation; memory; metabolism; microglia; mitochondria; mouse; neuroscience

DOI:  https://doi.org/10.7554/eLife.87120
Congenit Anom (Kyoto). 2025 Jan-Dec;65(1):65(1): e12587

Accumulation of ether phospholipids in induced pluripotent stem cells and oligodendrocyte-lineage cells established from patients with Sjögren-Larsson syndrome.

Yu Yamaguchi, Hironobu Okuno, Suzumi Tokuoka, Yoshihiro Kita, Tsukasa Sanosaka, Jun Kohyama, Kenji Kurosawa, Norio Sakai, Fuyuki Miya, Takao Takahashi, Kenjiro Kosaki, Hideyuki Okano.

  Sjögren-Larsson syndrome (SLS) is an autosomal recessive leukodystrophy characterized by ichthyosis, intellectual disability, and progressive spastic paralysis caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes the fatty aldehyde dehydrogenase, fatty aldehyde dehydrogenase (FALDH); FALDH catalyzes several metabolic reactions involved in fatty aldehyde oxidation. Only a few studies have been performed to determine the lipid profile of patients with SLS. In a previous postmortem study of the brain of a 65-year-old patient with SLS, lipidomic analysis revealed an accumulation of long-chain unsaturated ether lipid species in the white matter and gray matter. In the present study, we established a disease model using patient-derived neuronal and oligodendrocyte lineage cells to analyze the lipid metabolism and gene expression profiles in SLS. To achieve this, we generated induced pluripotent stem cells (iPSCs) from two patients with the SLS phenotype carrying previously known ALDH3A2 pathogenic variants: One was a compound heterozygote (c.1339A>G:p.(Lys447Glu) and c.57_132dup:p.(Ile45Serfs*34)) and the other was a homozygote (c.1339A>G: p.(Lys447Glu)). The FALDH activity was almost zero in the SLS-iPSC lines established from both patients. Phospholipid analysis of neurospheres, and oligospheres (spheres enriched with oligodendrocyte-lineage cells) derived from the iPSCs by liquid chromatography-mass spectrometry showed accumulation of ether phospholipids in the Sjögren-Larsson patient-derived neurospheres and oligospheres. The results are consistent with the previously reported accumulation of ether lipids in the postmortem brain tissue of an SLS patient. Therefore, iPSCs and iPSC-derived neurospheres and oligospheres established from SLS patients can be useful tools for future pathological analysis of the central nervous system pathophysiology in SLS.

Keywords:  FALDH; Sjögren‐Larsson syndrome; ether phospholipid; induced pluripotent stem cells; oligodendrocytes

DOI:  https://doi.org/10.1111/cga.12587
ASN Neuro. 2024 ;16(1): 2422268

Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.

Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried.

  Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.

Keywords:  Fermentation; glioblastoma; glutaminolysis; mitochondrial substrate level phosphorylation; succinate

DOI:  https://doi.org/10.1080/17590914.2024.2422268
PLoS One. 2024 ;19(12): e0313091

Fatty acid binding protein 7 plays an important modulatory sex-dependent role on brain endocannabinoid levels and THC metabolism.

Samantha L Penman, Alexandria S Senetra, Nicole M Roeder, Brittany J Richardson, Ojas Pareek, Yuji Owada, Yoshiteru Kagawa, Mark S Gold, Christopher R McCurdy, Abhisheak Sharma, Panayotis K Thanos.

Fatty acid binding protein 7 (FABP7) is present in the brain, but its interaction with the endocannabinoid system and phytocannabinoids is still not well understood. FABP7 has been proposed as a shuttle protein for trafficking endogenous cannabinoids, as well as an intracellular carrier of THC. In a mouse model of FABP7 global deletion, we used ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) to measure brain levels of Δ9 tetrahydrocannabinol (THC) as well as its primary metabolite, 11-hydroxy-THC (11-OH-THC), in male and female mice after acute inhalation of THC, compared to wild-type controls. We also measured brain levels of endogenous cannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) both at baseline and after acute THC inhalation. We found that in females, brain concentrations of 11-OH-THC were significantly reduced in FABP7-/- mice compared to FABP7+/+. Additionally, FABP7-/- females had significantly reduced AEA levels and significantly increased 2-AG levels in brain tissue compared to FABP7+/+. Vaporized THC administration had trending, but not significant, impacts on endocannabinoid concentrations in both males and females. Our findings suggest a sex-specific role of FABP7 in the metabolism of THC as well as the regulation of endocannabinoid levels in the brain.

DOI: https://doi.org/10.1371/journal.pone.0313091
Nat Commun. 2024 Dec 02. 15(1): 10467

Diverting glial glycolytic flux towards neurons is a memory-relevant role of Drosophila CRH-like signalling.

Raquel Francés, Yasmine Rabah, Thomas Preat, Pierre-Yves Plaçais.

An essential role of glial cells is to comply with the large and fluctuating energy needs of neurons. Metabolic adaptation is integral to the acute stress response, suggesting that glial cells could be major, yet overlooked, targets of stress hormones. Here we show that Dh44 neuropeptide, Drosophila homologue of mammalian corticotropin-releasing hormone (CRH), acts as an experience-dependent metabolic switch for glycolytic output in glia. Dh44 released by dopamine neurons limits glial fatty acid synthesis and build-up of lipid stores. Although basally active, this hormonal axis is acutely stimulated following learning of a danger-predictive cue. This results in transient suppression of glial anabolic use of pyruvate, sparing it for memory-relevant energy supply to neurons. Diverting pyruvate destination may dampen the need to upregulate glial glycolysis in response to increased neuronal demand. Although beneficial for the energy efficiency of memory formation, this mechanism reveals an ongoing competition between neuronal fuelling and glial anabolism.

DOI: https://doi.org/10.1038/s41467-024-54778-x
Neurosci Biobehav Rev. 2024 Dec 03. pii: S0149-7634(24)00440-8. [Epub ahead of print] 105971

Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.

Aurélien Riou, Aline Broeglin, Amandine Grimm.

  Mitochondrial transplantation is a new treatment strategy aimed at repairing cellular damage by introducing healthy mitochondria into injured cells. The approach shows promise in protecting brain function in various neurological disorders such as traumatic brain injury/ischemia, neurodegenerative diseases, cognitive disorders, and cancer. These conditions are often characterized by mitochondrial dysfunction, leading to impaired energy production and neuronal death. The review highlights promising preclinical studies where mitochondrial transplantation has been shown to restore mitochondrial function, reduce inflammation, and improve cognitive and motor functions in several animal models. It also addresses significant challenges that must be overcome before this therapy can be clinically applied. Current efforts to overcome these challenges, including advancements in isolation techniques, cryopreservation methods, finding an appropriate mitochondria source, and potential delivery routes, are discussed. Considering the rising incidence of neurological disorders and the limited effectiveness of current treatments, this review offers a comprehensive overview of the current state of mitochondrial transplantation research and critically assesses the remaining obstacles. It provides valuable insights that could steer future studies and potentially lead to more effective treatments for various brain disorders.

Keywords:  Cognitive disorders; ischemia; mitochondrial transplantation; neurodegenerative diseases; traumatic brain injury

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105971
J Lipid Res. 2024 Dec 02. pii: S0022-2275(24)00224-4. [Epub ahead of print] 100719

The steady-state level of Plasma Membrane Ceramide is regulated by Neutral Sphingomyelinase 2.

Anne G Ostermeyer-Fay, Abhay Kanodia, Ranjana Pathak, Maria Jose Hernandez-Corbacho, Aarnoud C van der Spoel, Yusuf A Hannun, Daniel Canals.

  During the last 30 years, an increasing number of cellular functions have been found to be regulated by the lipid ceramide. The diversity in the ceramide structure, leading to tens of ceramide species and the discrete distribution based on subcellular topology, could explain the wide variety of functions attributed to this bioactive lipid. One of these pools of ceramide resides in the plasma membrane, and several works have suggested that an increase in plasma membrane ceramide (PMCer) in response to stimulation leads to cell death and modulates cell adhesion and migration. However, there is a limitation in studying PMCer content in this location primarily due to the inability to quantify its mass. Our group recently developed a method to specifically quantitate PMCer. In this work, we interrogate what sphingolipid metabolizing enzymes are responsible for modulating the basal levels of plasma membrane ceramide. An in-silico prediction and experimental confirmation found an almost perfect correlation between the endogenous expression levels of neutral sphingomyelinase (nSMase2) and the amount of plasma membrane ceramide in unstimulated cells. Manipulating the expression levels of nSMase2, but not other candidate enzymes of ceramide metabolism, profoundly affected PMCer. Moreover, a physiologic induction of nSMase2 during cell confluence resulted in a nSMase2-dependent dramatic increase in PMCer. Together, these results identify nSMase2 as the primary enzyme to regulate plasma membrane ceramide.

Keywords:  GBA2; acid ceramidase; acid sphingomyelinase; cellular compartmentalization; ceramide; confluence; neutral ceramidase; neutral sphingomyelinase 2; plasma membrane ceramide; sphingolipids; sphingomyelin; sphingomyelin synthase 2; subcellular organelles

DOI:  https://doi.org/10.1016/j.jlr.2024.100719
Commun Biol. 2024 Nov 30. 7(1): 1597

Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity.

John J McInnis, Disha Sood, Lilu Guo, Michael R Dufault, Mariana Garcia, Rachel Passaro, Grace Gao, Bailin Zhang, James C Dodge.

Ceramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration. We show that human iPSC-derived neurons and glia differ in their rate of ceramide synthesis, ceramide isoform composition, and responses to altered ceramide levels. RNA-sequencing of cells treated to increase or decrease ceramides revealed connections to inflammation, ER stress, and apoptosis. Moreover, introducing labeled sphinganine showed that glia readily synthesize ceramide de novo and that neurons are relatively more sensitive to ceramide toxicity. Our findings provide a framework for understanding neurologic diseases with sphingolipid alternations and insights into designing therapeutics that target ceramide for treating them.

DOI: https://doi.org/10.1038/s42003-024-07231-0
Nat Neurosci. 2024 Dec 02.

Membrane mechanics dictate axonal pearls-on-a-string morphology and function.

Jacqueline M Griswold, Mayte Bonilla-Quintana, Renee Pepper, Christopher T Lee, Sumana Raychaudhuri, Siyi Ma, Quan Gan, Sarah Syed, Cuncheng Zhu, Miriam Bell, Mitsuo Suga, Yuuki Yamaguchi, Ronan Chéreau, U Valentin Nägerl, Graham Knott, Padmini Rangamani, Shigeki Watanabe.

Axons are ultrathin membrane cables that are specialized for the conduction of action potentials. Although their diameter is variable along their length, how their morphology is determined is unclear. Here, we demonstrate that unmyelinated axons of the mouse central nervous system have nonsynaptic, nanoscopic varicosities ~200 nm in diameter repeatedly along their length interspersed with a thin cable ~60 nm in diameter like pearls-on-a-string. In silico modeling suggests that this axon nanopearling can be explained by membrane mechanical properties. Treatments disrupting membrane properties, such as hyper- or hypotonic solutions, cholesterol removal and nonmuscle myosin II inhibition, alter axon nanopearling, confirming the role of membrane mechanics in determining axon morphology. Furthermore, neuronal activity modulates plasma membrane cholesterol concentration, leading to changes in axon nanopearls and causing slowing of action potential conduction velocity. These data reveal that biophysical forces dictate axon morphology and function, and modulation of membrane mechanics likely underlies unmyelinated axonal plasticity.

DOI: https://doi.org/10.1038/s41593-024-01813-1
iScience. 2024 Oct 18. 27(10): 111016

Hyperactivation of Hedgehog signaling impedes myelin development and repair via cholesterol dysregulation in oligodendrocytes.

Minxi Fang, Xuan Wang, Lixia Chen, Fang Li, Sitong Wang, Leyi Shen, Huanyi Yang, Lifen Sun, Xue Wang, Junlin Yang, Mengsheng Qiu, Xiaofeng Xu.

  The failure to remyelinate demyelinated axons poses a significant challenge in the treatment of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Here, we investigated the role of Hedgehog (Hh) signaling in myelin formation during development and under pathological conditions. Using conditional gain-of-function analyses, we found that hyperactivation of Hh signaling in oligodendrocyte precursor cells (OPCs) inhibits oligodendrocyte (OL) differentiation and myelination. Notably, sustained activation of Hh signaling in adult OPCs hinders myelin repair following LPC-induced focal demyelination. Through RNA sequencing, we discovered that genes associated with cholesterol synthesis were upregulated, and observed intracellular cholesterol accumulation in Hh-activated OPCs. Importantly, pharmacological stimulation of cholesterol transport was able to rescue the OL differentiation and myelination defects in mice. These findings establish a functional connection between Hh signaling, cholesterol homeostasis, and remyelination, providing insights for the strategic design of employing Hh signaling modulators in treating demyelinating neurodegenerative diseases.

Keywords:  Cell biology; Developmental biology; Pathophysiology

DOI:  https://doi.org/10.1016/j.isci.2024.111016
J Neurovirol. 2024 Dec 03.

High glucose potentiates Zika virus induced-astroglial dysfunctions.

Natalie Katherine Thomaz, Larissa Daniele Bobermin, Patrícia Sesterheim, Ana Paula Muterle Varela, Thais Fumaco, Marina Seady, Belisa Parmeggiani, Marina Concli Leite, Guilhian Leipnitz, Lucélia Santi, Walter O Beys-da-Silva, Jorge Almeida Guimarães, Paulo M Roehe, Carlos-Alberto Gonçalves, Diogo Onofre Souza, André Quincozes-Santos.

Zika virus (ZIKV) is a neurotropic flavivirus that induces congenital Zika syndrome and neurodevelopmental disorders. Given that ZIKV can infect and replicate in neural cells, neurological complications in adult brain are also observed. Glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration. These cells actively participate in metabolic, inflammatory and redox processes, and consequently, in the pathophysiology of neurodegenerative diseases, including diabetic encephalopathy. In this sense, changes in glucose metabolism can support the inflammatory activity of astroglial cells; however, the effects of increased glucose concentration during ZIKV infection have not yet been explored in astroglial cells. Here, we evaluated functional parameters of astroglial cells exposed to ZIKV upon normal and high glucose concentrations, focusing on inflammatory profile, oxidative stress, and expression of critical genes for astroglial functions. High glucose potentiated the pro-inflammatory and oxidative effects of ZIKV, as well as potentiated the downregulation of signaling pathways, such as Nrf-2 (nuclear factor erythroid derived 2 like 2), sirtuin 1 (SIRT1), peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and poly (ADP-ribose) polymerase (PARP). In summary, our results suggest that high glucose can favor the activation of inflammatory signaling while impairing cytoprotective pathways in astroglial cells exposed to ZIKV and reinforce the hypothesis that this virus is highly neurotrophic, with significant impact in glial cells.

DOI: https://doi.org/10.1007/s13365-024-01238-3