bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023‒08‒13
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease.
  2. Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes.
  3. The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
  4. The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions.
  5. Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.
  6. Lipidomic analysis reveals differences in the extent of remyelination in the brain and spinal cord.
  7. The multifaceted roles of the brain glycogen.
  8. Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.
  9. Potential Clinical Applications of Pro-Resolving Lipids Mediators from Docosahexaenoic Acid.
  10. Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
  11. Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
  12. High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile, and cholesterol metabolism.
  13. Early decreased respiratory chain capacity in resuscitated experimental sepsis is a major contributor to lactate production.
  1. Neuron. 2023 Aug 01. pii: S0896-6273(23)00513-5. [Epub ahead of print]
    Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease.
    Sofia Essayan-Perez, Thomas C Südhof.
      Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
    Keywords:  Alzheimer’s disease; CRISPR-Cas9; RNA-seq; cholesterol; electrophysiology; gamma-secretase; neurons; presenilins; synapses; synaptic physiology
    DOI:  https://doi.org/10.1016/j.neuron.2023.07.005
  2. Int J Mol Sci. 2023 Aug 06. pii: 12488. [Epub ahead of print]24(15):
    Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes.
    Daniela Valenti, Rosa Anna Vacca.
      Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves regulated from a series of signaling proteins to achieve the best efficiency in producing energy, in establishing a network and in performing their own de novo synthesis or clearance. Dysfunctions in signaling processes that control mitochondrial biogenesis, dynamics and bioenergetics are increasingly associated with impairment in brain development and involved in a wide variety of neurodevelopmental disorders. Here, we review recent evidence proving the emerging role of mitochondria as master regulators of brain bioenergetics, highlighting their control skills in brain neurodevelopment and cognition. We analyze, from a mechanistic point of view, mitochondrial bioenergetic dysfunction as causally interrelated to the origins of typical genetic intellectual disability-related neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes. Finally, we discuss whether mitochondria can become therapeutic targets to improve brain development and function from a holistic perspective.
    Keywords:  Down syndrome; Fragile X syndrome; Rett syndrome; brain mitochondrial bioenergetics; genetic neurodevelopmental disorders; neurogenesis; neuroplasticity
    DOI:  https://doi.org/10.3390/ijms241512488
  3. Front Neurosci. 2023 ;17 1144896
    The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
    Kelley C Atkinson, Marvellous Osunde, Seema K Tiwari-Woodruff.
      Multiple sclerosis (MS) is a demyelinating, degenerating disorder of the central nervous system (CNS) that is accompanied by mitochondria energy production failure. A loss of myelin paired with a deficit in energy production can contribute to further neurodegeneration and disability in patients in MS. Mitochondria are essential organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation in all cells in the CNS, including neurons, oligodendrocytes, astrocytes, and immune cells. In the context of demyelinating diseases, mitochondria have been shown to alter their morphology and undergo an initial increase in metabolic demand. This is followed by mitochondrial respiratory chain deficiency and abnormalities in mitochondrial transport that contribute to progressive neurodegeneration and irreversible disability. The current methodologies to study mitochondria are limiting and are capable of providing only a partial snapshot of the true mitochondria activity at a particular timepoint during disease. Mitochondrial functional studies are mostly performed in cell culture or whole brain tissue, which prevents understanding of mitochondrial pathology in distinct cell types in vivo. A true understanding of cell-specific mitochondrial pathophysiology of MS in mouse models is required. Cell-specific mitochondria morphology, mitochondria motility, and ATP production studies in animal models of MS will help us understand the role of mitochondria in the normal and diseased CNS. In this review, we present currently used methods to investigate mitochondria function in MS mouse models and discuss the current advantages and caveats with using each technique. In addition, we present recently developed mitochondria transgenic mouse lines expressing Cre under the control of CNS specific promoters to relate mitochondria to disease in vivo.
    Keywords:  EAE; cuprizone; demyelination; inflammation; mitochondria; multiple sclerosis; myelin; remyelination
    DOI:  https://doi.org/10.3389/fnins.2023.1144896
  4. Neurobiol Dis. 2023 Aug 07. pii: S0969-9961(23)00270-X. [Epub ahead of print] 106255
    The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions.
    Zoeb Jiwaji, Giles E Hardingham.
      Brain metabolic pathways relating to bioenergetic and redox homeostasis are closely linked, and deficits in these pathways are thought to occur in many neurodegenerative diseases. Astrocytes play important roles in both processes, and growing evidence suggests that neuron-astrocyte inter-cellular signalling ensures brain bioenergetic and redox homeostasis in health. Moreover, alterations to this crosstalk have been observed in the context of neurodegenerative pathology. In this review, we summarise the current understanding of how neuron-astrocyte interactions influence brain metabolism and antioxidant functions in health as well as during neurodegeneration. It is apparent that deleterious and adaptive protective responses alter brain metabolism in disease, and that knowledge of both may illuminate targets for future therapeutic interventions.
    Keywords:  Alzheimer's disease; Antioxidants; Astrocyte; Cellular neuroscience; Glycolysis; Metabolism; Reactive oxygen species; Redox signalling
    DOI:  https://doi.org/10.1016/j.nbd.2023.106255
  5. Res Sq. 2023 Jul 25. pii: rs.3.rs-2276903. [Epub ahead of print]
    Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.
    Anne Miller, Elisa York, Sylwia Stopka, Juan Martínez-François, Md Amin Hossain, Gerard Baquer, Michael Regan, Nathalie Agar, Gary Yellen.
      Neuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices coupled with fast metabolite preservation, followed by mass spectrometry imaging (MALDI-MSI) to generate spatially resolved metabolomics and isotope tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs. Increased glucose metabolism in response to stimulation is accompanied by mobilization of endogenous inosine into pentose phosphates, via the action of purine nucleotide phosphorylase (PNP). The PNP reaction is an integral part of the neuronal response to stimulation, as inhibiting PNP leaves DGCs energetically impaired during recovery from strong activation. Performing MSI on brain slices bridges the gap between live cell physiology and the deep chemical analysis enabled by mass spectrometry.
    DOI:  https://doi.org/10.21203/rs.3.rs-2276903/v1
  6. bioRxiv. 2023 Jul 26. pii: 2023.07.24.550351. [Epub ahead of print]
    Lipidomic analysis reveals differences in the extent of remyelination in the brain and spinal cord.
    Nishama De Silv Mohotti, Hiroko Kobayashi, Jenna M Williams, Rashmi Binjawadagi, Michel P Evertsen, Ethan G Christ, Meredith D Hartley.
      During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1 -iCKO- Myrf mice. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.
    DOI:  https://doi.org/10.1101/2023.07.24.550351
  7. J Neurochem. 2023 Aug 09.
    The multifaceted roles of the brain glycogen.
    Kia H Markussen, Manuela Corti, Barry J Byrne, Craig W Vander Kooi, Ramon C Sun, Matthew S Gentry.
      Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.
    Keywords:  N-linked glycosylation; brain metabolism; congenital disorders of glycosylation; epilepsy; glycogen; glycogen storage disease
    DOI:  https://doi.org/10.1111/jnc.15926
  8. medRxiv. 2023 Jul 27. pii: 2023.07.25.23293055. [Epub ahead of print]
    Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.
    Alzheimer’s Disease Metabolomics Consortium (ADMC)
      Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). While metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed. We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies. Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B. Taken together, our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP.
    DOI:  https://doi.org/10.1101/2023.07.25.23293055
  9. Nutrients. 2023 Jul 26. pii: 3317. [Epub ahead of print]15(15):
    Potential Clinical Applications of Pro-Resolving Lipids Mediators from Docosahexaenoic Acid.
    María Paz Beyer, Luis A Videla, Camila Farías, Rodrigo Valenzuela.
      Docosahexaenoic acid (C22:6n-3, DHA) is the precursor of specialized pro-resolving lipid mediators (SPMs), such as resolvin, protectin, and maresin families which have been considered therapeutic bioactive compounds for human health. Growing evidence indicates that DHA and SPMs are beneficial strategies in the amelioration, regulation, and duration of inflammatory processes through different biological actions. The present review discusses the reported therapeutic benefits of SPMs on various diseases and their potential clinical applications.
    Keywords:  anti-inflammation; docosahexaenoic acid; maresins; protectins; resolvins series D; specialized pro-resolving mediators
    DOI:  https://doi.org/10.3390/nu15153317
  10. Int J Mol Sci. 2023 Aug 06. pii: 12486. [Epub ahead of print]24(15):
    Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
    Germán Plascencia-Villa, George Perry.
      The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer's and Parkinson's disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; mitochondrial dysfunction; neurodegeneration; neurons; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241512486
  11. Nat Commun. 2023 Aug 10. 14(1): 4726
    Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
    Ayelet M Rosenberg, Manish Saggar, Anna S Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard.
      The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.
    DOI:  https://doi.org/10.1038/s41467-023-39941-0
  12. J Lipid Res. 2023 Aug 07. pii: S0022-2275(23)00096-2. [Epub ahead of print] 100423
    High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile, and cholesterol metabolism.
    Nickolas Auclair, Alain T Sané, Léna Ahmarani, Nour-El-Houda Ould-Chikh, Nathalie Patey, Jean-François Beaulieu, Edgard Delvin, Schohraya Spahis, Emile Levy.
      BACKGROUND: Biallelic pathogenic variants of the Sar1b gene cause chylomicron retention disease (CRD) whose central phenotype is the inability to secrete chylomicrons (CM). Patients with CRD experience numerous clinical symptoms such as gastrointestinal, hepatic, neuromuscular, ophthalmic and cardiological abnormalities. Recently, the production of mice expressing either a targeted deletion or mutation of Sar1b recapitulated biochemical and gastrointestinal defects associated with CRD.OBJECTIVE: The present study was conducted to better understand little-known aspects of Sar1b mutations, including mouse embryonic development, lipid profile and lipoprotein composition in response to high-fat diet (HFD), gut and liver cholesterol metabolism, sex-specific effects, and genotype-phenotype differences.
    RESULTS: Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities. On HFD, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol and non-HDL cholesterol, and polyunsaturated fatty acids compared to those on the regular Chow diet. Divergences were also noted in lipoprotein lipid composition, lipid ratios (serving as indices of particle size) and lipoprotein-apolipoprotein distribution. Sar1b defects significantly reduce gut cholesterol accumulation while altering key players in cholesterol metabolism. Noteworthy, variations were observed between males and females, and between Sar1b deletion and mutation phenotypes.
    CONCLUSIONS: Overall, mutant animal findings reveal the importance of Sar1b in several biochemical, metabolic and developmental processes.
    Keywords:  Sar1b gene; and high-fat diet; chylomicron; embryonic lethality; intestinal fat malabsorption; lipoprotein composition
    DOI:  https://doi.org/10.1016/j.jlr.2023.100423
  13. Shock. 2023 Aug 07.
    Early decreased respiratory chain capacity in resuscitated experimental sepsis is a major contributor to lactate production.
    Magnus von Seth, Lars Hillered, Alexander Otterbeck, Katja Hanslin, Anders Larsson, Jan Sjölin, Miklós Lipcsey.
      BACKGROUND: Increased plasma lactate levels in patients with sepsis may be due to insufficient oxygen delivery, but mitochondrial dysfunction or accelerated glycolysis may also contribute. We studied the effect of the latter on muscle metabolism by using microdialysis in a sepsis model with sustained oxygen delivery and decreased energy consumption or mitochondrial blockade.METHODS: Pigs were subjected to continuous E. coli infusion (sepsis group, n = 12) or saline infusion (sham group, n = 4) for 3 hours (h). Protocolized interventions were applied to normalize the oxygen delivery and blood pressure. Microdialysis catheters were used to monitor muscle metabolism (naïve). The same catheters were used to block the electron transport chain with cyanide or the Na+/K+-ATPase inhibitor, ouabain locally.
    RESULTS: All pigs in the sepsis group had positive blood cultures and a Sequential Organ Failure Assessment (SOFA) score increase by at least 2, fulfilling the sepsis criteria. Plasma lactate was higher in the sepsis group than in the sham group (p < 0.001), whereas muscle glucose was lower in the sepsis group (p < 0.01). There were no changes in muscle lactate levels over time but lactate to pyruvate ratio (LPR) was elevated in the Sepsis vs. the Sham group (p < 0.05). Muscle lactate, LPR, and glutamate levels were higher in the sepsis group than in the sham group in the cyanide catheters (p < 0.001, all comparisons) and did not normalize in the former group.
    CONCLUSIONS: In this experimental study on resuscitated sepsis, we observed increased aerobic metabolism and preserved mitochondrial function. Sepsis and electron transport chain inhibition led to increased LPR, suggesting a decreased mitochondrial reserve capacity in early sepsis.
    DOI:  https://doi.org/10.1097/SHK.0000000000002190
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