bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022–11–13
fifty papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Astrocyte strategies in the energy-efficient brain.
  2. GM3 synthase deficiency increases brain glucose metabolism in mice.
  3. Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain.
  4. ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis.
  5. Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases.
  6. Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease.
  7. A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.
  8. LRRK2 and Lipid Pathways: Implications for Parkinson's Disease.
  9. Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine.
  10. A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.
  11. Glycolysis regulates neuronal excitability via lactate receptor, HCA1R.
  12. Neurodegenerative Disorder Risk in Krabbe Disease Carriers.
  13. Glutamate Prevents Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic but Not Cortical Primary Rat Astrocytes.
  14. Menopause and development of Alzheimer's disease: Roles of neural glucose metabolism and Wnt signaling.
  15. Potential of Capric Acid in Neurological Disorders: An Overview.
  16. Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.
  17. Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.
  18. Mutation of the H12-helix of α-tubulin/MEC-12 disrupts the localization of neuronal mitochondria.
  19. Maternal Obesity and Gut Microbiota Are Associated with Fetal Brain Development.
  20. Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise.
  21. Role of SUMOylation in Neurodegenerative Diseases.
  22. ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction.
  23. Quantitative Analyses and Validation of Phospholipids and Sphingolipids in Ischemic Rat Brains.
  24. The FADS1 rs174550 Genotype Modifies the n-3 and n-6 PUFA and Lipid Mediator Responses to a High Alpha-Linolenic Acid and High Linoleic Acid Diets.
  25. Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.
  26. Mitochondrial Epilepsy, a Challenge for Neurologists.
  27. The significance of glycolysis index and its correlations with immune infiltrates in Alzheimer's disease.
  28. Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts.
  29. KIF2A deficiency causes early-onset neurodegeneration.
  30. Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics.
  31. Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.
  32. Inter-organ regulation by the brain in Drosophila development and physiology.
  33. Branched-Chain Amino Acids Are Linked with Alzheimer's Disease-Related Pathology and Cognitive Deficits.
  34. Mitochondrial glutamine transporter SLC1A5_var, a potential target to suppress astrocyte reactivity in Parkinson's Disease.
  35. The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
  36. Chronic Lead Exposure Disrupts Neurometabolic Activity in Mouse Brain: An ex vivo1H-[13C]-NMR Study.
  37. AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
  38. Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis.
  39. Neuroprotective Effects of Natural Antioxidants Against Branched-Chain Fatty Acid-Induced Oxidative Stress in Cerebral Cortex and Cerebellum Regions of the Rat Brain.
  40. Interrogating the Metabolomic Profile of Amyotrophic Lateral Sclerosis in the Post-Mortem Human Brain by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Mass Spectrometry Imaging (MSI).
  41. Protectins: Their biosynthesis, metabolism and structure-functions.
  42. Glyceryl triacetate feeding in mice increases plasma acetate levels but has no anticonvulsant effects in acute electrical seizure models.
  43. Effects of the ketogenic diet on cognition: a systematic review.
  44. Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries.
  45. Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.
  46. High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature.
  47. Dietary energy restriction in neurological diseases: what's new?
  48. Uncovering the biological basis of control energy: Structural and metabolic correlates of energy inefficiency in temporal lobe epilepsy.
  49. Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase-deficient mice.
  50. Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage.
  1. Essays Biochem. 2022 Nov 09. pii: EBC20220077. [Epub ahead of print]
    Astrocyte strategies in the energy-efficient brain.
    Irene Fernández-González, Elena Galea.
      Astrocytes generate ATP through glycolysis and mitochondrion respiration, using glucose, lactate, fatty acids, amino acids, and ketone bodies as metabolic fuels. Astrocytic mitochondria also participate in neuronal redox homeostasis and neurotransmitter recycling. In this essay, we aim to integrate the multifaceted evidence about astrocyte bioenergetics at the cellular and systems levels, with a focus on mitochondrial oxidation. At the cellular level, the use of fatty acid β-oxidation and the existence of molecular switches for the selection of metabolic mode and fuels are examined. At the systems level, we discuss energy audits of astrocytes and how astrocytic Ca2+ signaling might contribute to the higher performance and lower energy consumption of the brain as compared to engineered circuits. We finish by examining the neural-circuit dysregulation and behavior impairment associated with alterations of astrocytic mitochondria. We conclude that astrocytes may contribute to brain energy efficiency by coupling energy, redox, and computational homeostasis in neural circuits.
    Keywords:  Astrocytes; Mitochondria; bioenergetics
    DOI:  https://doi.org/10.1042/EBC20220077
  2. Mol Genet Metab. 2022 Oct 28. pii: S1096-7192(22)00421-8. [Epub ahead of print]137(4): 342-348
    GM3 synthase deficiency increases brain glucose metabolism in mice.
    Sivakama S Bharathi, Bob B Zhang, Eli Paul, Yuxun Zhang, Alexandra V Schmidt, Benjamin Fowler, Yijen Wu, Michael Tiemeyer, Kei-Ichiro Inamori, Jin-Ichi Inokuchi, Eric S Goetzman.
      GM3 synthase (GM3S) deficiency is a rare neurodevelopmental disorder caused by an inability to synthesize gangliosides, for which there is currently no treatment. Gangliosides are brain-enriched, plasma membrane glycosphingolipids with poorly understood biological functions related to cell adhesion, growth, and receptor-mediated signal transduction. Here, we investigated the effects of GM3S deficiency on metabolism and mitochondrial function in a mouse model. By indirect calorimetry, GM3S knockout mice exhibited increased whole-body respiration and an increased reliance upon carbohydrate as an energy source. 18F-FDG PET confirmed higher brain glucose uptake in knockout mice, and GM3S deficient N41 neuronal cells showed higher glucose utilization in vitro. Brain mitochondria from knockout mice respired at a higher rate on Complex I substrates including pyruvate. This appeared to be due to higher expression of pyruvate dehydrogenase (PDH) and lower phosphorylation of PDH, which would favor pyruvate entry into the mitochondrial TCA cycle. Finally, it was observed that blocking glucose metabolism with the glycolysis inhibitor 2-deoxyglucose reduced seizure intensity in GM3S knockout mice following administration of kainate. In conclusion, GM3S deficiency may be associated with a hypermetabolic phenotype that could promote seizure activity.
    Keywords:  GM3; Ganglioside; Glucose metabolism; Mitochondria; Seizure
    DOI:  https://doi.org/10.1016/j.ymgme.2022.10.006
  3. Int J Mol Sci. 2022 Oct 29. pii: 13186. [Epub ahead of print]23(21):
    Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain.
    Artem V Artiukhov, Vasily A Aleshin, Irina S Karlina, Alexey V Kazantsev, Daria A Sibiryakina, Alexander L Ksenofontov, Nikolay V Lukashev, Anastasia V Graf, Victoria I Bunik.
      Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (AcPMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine, and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. A comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease.
    Keywords:  2-oxoglutarate dehydrogenase; anxiety; branched chain 2-oxo acids; phosphonate and phosphinate analogs of pyruvate; protein acetylation; protein glutarylation; protein succinylation; pyruvate dehydrogenase; sirtuin 3; sirtuin 5
    DOI:  https://doi.org/10.3390/ijms232113186
  4. Antioxidants (Basel). 2022 Nov 01. pii: 2168. [Epub ahead of print]11(11):
    ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis.
    Erica Staurenghi, Valerio Leoni, Marco Lo Iacono, Barbara Sottero, Gabriella Testa, Serena Giannelli, Gabriella Leonarduzzi, Paola Gamba.
      The strongest genetic risk factor for sporadic Alzheimer's disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography-mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.
    Keywords:  ApoE4; alzheimer’s disease; apolipoprotein E; astrocytes; cholesterol metabolism; lipids; oxysterols
    DOI:  https://doi.org/10.3390/antiox11112168
  5. Nutrients. 2022 Oct 28. pii: 4550. [Epub ahead of print]14(21):
    Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases.
    Amanda Lo Van, Nathalie Bernoud-Hubac, Michel Lagarde.
      Docosahexaenoic acid-containing lysophosphatidylcholine (DHA-LysoPC) is presented as the main transporter of DHA from blood plasma to the brain. This is related to the major facilitator superfamily domain-containing protein 2A (Mfsd2a) symporter expression in the blood-brain barrier that recognizes the various lyso-phospholipids that have choline in their polar head. In order to stabilize the DHA moiety at the sn-2 position of LysoPC, the sn-1 position was esterified by the shortest acetyl chain, creating the structural phospholipid 1-acetyl,2-docosahexaenoyl-glycerophosphocholine (AceDoPC). This small structure modification allows the maintaining of the preferential brain uptake of DHA over non-esterified DHA. Additional properties were found for AceDoPC, such as antioxidant properties, especially due to the aspirin-like acetyl moiety, as well as the capacity to generate acetylcholine in response to the phospholipase D cleavage of the polar head. Esterification of DHA within DHA-LysoPC or AceDoPC could elicit more potent neuroprotective effects against neurological diseases.
    Keywords:  blood-brain-barrier; docosahexaenoic acid; lysophospholipids; neurological diseases; neuroprotection; phospholipids
    DOI:  https://doi.org/10.3390/nu14214550
  6. Biomedicines. 2022 Nov 01. pii: 2778. [Epub ahead of print]10(11):
    Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease.
    Aishat O Ameen, Kristine Freude, Blanca I Aldana.
      Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder.
    Keywords:  butyrate; decanoic acid; energy metabolism; hiPSC; neurodegeneration; octanoic acid
    DOI:  https://doi.org/10.3390/biomedicines10112778
  7. Metabolites. 2022 Oct 25. pii: 1019. [Epub ahead of print]12(11):
    A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.
    Erin R Saito, Cali E Warren, Cameron M Hanegan, John G Larsen, Johannes D du Randt, Mio Cannon, Jeremy Y Saito, Rachel J Campbell, Colin M Kemberling, Gavin S Miller, Jeffrey G Edwards, Benjamin T Bikman.
      Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer's disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O2 consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O2 ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease.
    Keywords:  hippocampus; ketogenic diet; metabolism; mitochondrial efficiency; recognition memory
    DOI:  https://doi.org/10.3390/metabo12111019
  8. Biomolecules. 2022 Oct 30. pii: 1597. [Epub ahead of print]12(11):
    LRRK2 and Lipid Pathways: Implications for Parkinson's Disease.
    Jasmin Galper, Woojin S Kim, Nicolas Dzamko.
      Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson's disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.
    Keywords:  BMP; LRRK2; Parkinson’s disease; ceramide; cholesterol; glucocerebrosidase; glucose; lipid; lysosome; metabolism
    DOI:  https://doi.org/10.3390/biom12111597
  9. Transl Neurodegener. 2022 Nov 07. 11(1): 48
    Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine.
    Ira Agrawal, Yong Shan Lim, Shi-Yan Ng, Shuo-Chien Ling.
      Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging  as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids.
    Keywords:  Amyotrophic lateral sclerosis; Arachidonic acid; Ceramides; Cholesterol esters; Eicosanoids; Fatty acids; Lysophosphatidylcholine; Phospholipids; Sphingolipids; Triglycerides
    DOI:  https://doi.org/10.1186/s40035-022-00322-0
  10. Cureus. 2022 Oct;14(10): e29903
    A Rare Case of Type B Neonatal Pyruvate Carboxylase Enzyme Deficiency Presenting With Refractory Lactic Acidosis in the Early Neonatal Period.
    Saima Sharif, Pradeep Kumar Velumula, Praveen Kumar Boddu, Deniz Altinok, Nithi Fernandes.
      Pyruvate carboxylase (PC) enzyme deficiency is a rare genetic disorder inherited in an autosomal recessive (AR) manner. PC, a mitochondrial enzyme, converts pyruvate to oxaloacetate (OAA), which enters the tricarboxylic acid (TCA) cycle. Based on the tissue type, intermediate metabolites of the TCA cycle play a vital role in gluconeogenesis, lipogenesis, synthesis of nicotinamide adenine dinucleotide phosphate (NADPH), and neurotransmitter glutamate in the astrocytes. The severity of clinical presentation depends on the type of PC deficiency and on the residual enzyme activity. We present a term female infant admitted with refractory lactic acidosis that developed soon after birth. On biochemical evaluation, serum ammonia was 125 µmol/L; plasma amino acid analysis showed elevated citrulline, lysine, proline, decreased glutamine, and aspartic acid; urine organic acid analysis showed markedly increased lactic acid, and moderately elevated 3-hydroxy-butyric and acetoacetic acid. MRI brain demonstrated abnormal diffuse white matter edema, loculated and septate large cysts along the caudothalamic notch as well as lateral aspect of the frontal horn bilaterally. Magnetic resonance (MR) spectroscopy showed large amounts of lactate peak. Molecular genetic analysis showed two pathogenic variants in the PC gene confirming the diagnosis of PC enzyme deficiency. The infant was discharged home on palliative and hospice care, and she died on the 22nd day after birth.
    Keywords:  acidosis lactic; lactate peak; magnetic resonance spectroscopy (mrs); pyruvate carboxylase; pyruvate carboxylase enzyme deficiency; term neonate
    DOI:  https://doi.org/10.7759/cureus.29903
  11. Brain. 2022 Nov 08. pii: awac419. [Epub ahead of print]
    Glycolysis regulates neuronal excitability via lactate receptor, HCA1R.
    Daria Skwarzynska, Huayu Sun, John Williamson, Izabela Kasprzak, Jaideep Kapur.
      Repetitively firing neurons during seizures accelerate glycolysis to meet energy demand, which leads to the accumulation of extracellular glycolytic by-product lactate. Here, we demonstrate that lactate rapidly modulates neuronal excitability in times of metabolic stress via the hydroxycarboxylic acid receptor type 1 (HCA1R) to modify seizure activity. The extracellular lactate concentration, measured by a biosensor, rose quickly during brief and prolonged seizures. In two epilepsy models, mice lacking HCA1R (lactate receptor) were more susceptible to developing seizures. Moreover, HCA1R deficient (knock out, KO) mice developed longer and more severe seizures than wild-type littermates (WT). Lactate perfusion decreased neuronal tonic and phasic activity of CA1 pyramidal neurons in GCAMP7 imaging experiments. HCA1R agonist, 3Cl-HBA, reduced the activity of CA1 neurons in HCA1R WT but not in KO mice. In patch-clamp recordings, both lactate and 3CL-HBA hyperpolarized CA1 pyramidal neurons. HCA1R activation reduced the spontaneous EPSC frequency and altered the paired-pulse ratio of evoked EPSCs in HCA1R WT but not in KO mice, suggesting it diminished presynaptic release of excitatory neurotransmitters. Overall, our studies demonstrate that excessive neuronal activity accelerates glycolysis to generate lactate, which translocates to the extracellular space to slow neuronal firing and inhibit excitatory transmission via HCA1R. These studies may identify novel anticonvulsant target and seizure termination mechanisms.
    Keywords:  HCA1R; epileptic seizures; lactate; lactate receptor; neuronal excitability
    DOI:  https://doi.org/10.1093/brain/awac419
  12. Int J Mol Sci. 2022 Nov 04. pii: 13537. [Epub ahead of print]23(21):
    Neurodegenerative Disorder Risk in Krabbe Disease Carriers.
    Lorenza Vantaggiato, Enxhi Shaba, Alfonso Carleo, Daiana Bezzini, Giovanna Pannuzzo, Alice Luddi, Paola Piomboni, Luca Bini, Laura Bianchi.
      Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc -/-), heterozygous (galc +/-), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions.
    Keywords:  Alzheimer disease; Lewy body; Parkinson disease; demyelination; globoid cell leukodystrophy; multiple sclerosis; neurodegeneration; neuroinflammation; ubiquitin dependent degradation
    DOI:  https://doi.org/10.3390/ijms232113537
  13. Cells. 2022 Oct 29. pii: 3422. [Epub ahead of print]11(21):
    Glutamate Prevents Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic but Not Cortical Primary Rat Astrocytes.
    Paul G Weightman Potter, Kate L J Ellacott, Andrew D Randall, Craig Beall.
      Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglycaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and hypothalamic (HTAS) primary rat astrocytes were measured in acute and recurrent low glucose using extracellular flux analyses. RLG caused mitochondrial adaptations in both HTAS and CRTAS, many of which were attenuated by glutamate exposure during low glucose (LG) treatments. We observed an increase in capacity of HTAS to metabolise glutamine after RLG exposure. Demonstrating astrocytic heterogeneity in the response to LG, CRTAS increased cellular acidification, a marker of glycolysis in LG, whereas this decreased in HTAS. The directional change in intracellular Ca2+ levels of each cell type, correlated with the change in extracellular acidification rate (ECAR) during LG. Further examination of glutamate-induced Ca2+ responses in low glucose treated CRTAS and HTAS identified sub-populations of glucose-excited- and glucose-inhibited-like cells with differing responses to glutamate. Lastly, release of the gliotransmitter ATP by HTAS was elevated by RLG, both with and without concurrent glutamate exposure. Therefore, hypothalamic astrocytes adapt to RLG by increasing glutamate uptake and oxidation in a manner that prevents RLG-induced mitochondrial adaptations.
    Keywords:  astrocytes; diabetes mellitus; glutamic acid; glycemic control; hypoglycemia; hypothalamus; mitochondria; type 1
    DOI:  https://doi.org/10.3390/cells11213422
  14. Front Endocrinol (Lausanne). 2022 ;13 1021796
    Menopause and development of Alzheimer's disease: Roles of neural glucose metabolism and Wnt signaling.
    Paulina Villaseca, Pedro Cisternas, Nibaldo C Inestrosa.
      Late onset Alzheimer´s disease (AD) is a neurodegenerative disease with gender differences in its onset and progression, being the prevalence predominant in women and at an earlier age than in men. The pathophysiology of the menopausal condition has been associated to this dementia, playing major roles regarding both endocrine and glucose metabolism changes, amongst other mechanisms. In the current review we address the role of estrogen deficiency in the processes involved in the development of AD, including amyloid precursor protein (APP) processing to form senile plaques, Tau phosphorylation forming neurofibrillary tangles, Wnt signaling and AD neuropathology, the role of glucose brain metabolism, Wnt signaling and glucose transport in the brain, and our research contribution to these topics.
    Keywords:  APP - amyloid precursor protein; alzheimer´s disease; estrogen; glucose brain metabolism; menopause; tau phosphorylation; wnt signaling
    DOI:  https://doi.org/10.3389/fendo.2022.1021796
  15. Neurochem Res. 2022 Nov 07.
    Potential of Capric Acid in Neurological Disorders: An Overview.
    Nikhila Shekhar, Sakshi Tyagi, Sweta Rani, Ajit Kumar Thakur.
      To solve the restrictions of a classical ketogenic diet, a modified medium-chain triglyceride diet was introduced which required only around 60% of dietary energy. Capric acid (CA), a small molecule, is one of the main components because its metabolic profile offers itself as an alternate source of energy to the brain in the form of ketone bodies. This is possible with the combined capability of CA to cross the blood-brain barrier and achieve a concentration of 50% concentration in the brain more than any other fatty acid in plasma. Natural sources of CA include vegetable oils such as palm oil and coconut oil, mammalian milk and some seeds. Several studies have shown that CA has varied action on targets that include AMPA receptors, PPAR-γ, inflammatory/oxidative stress pathways and gut dysbiosis. Based on these lines of evidence, CA has proved to be effective in the amelioration of neurological diseases such as epilepsy, affective disorders and Alzheimer's disease. But these studies still warrant more pre-clinical and clinical studies that would further prove its efficacy. Hence, to understand the potential of CA in brain disease and associated comorbid conditions, an advance and rigorous molecular mechanistic study, apart from the reported in-vitro/in-vivo studies, is urgently required for the development of this compound through clinical setups.
    Keywords:  Capric acid; Ketogenic diet; Metabolism; Neurological disorders; Neurotransmitter
    DOI:  https://doi.org/10.1007/s11064-022-03809-4
  16. Elife. 2022 11 08. pii: e77791. [Epub ahead of print]11
    Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.
    Ioannis Zalachoras, Eva Ramos-Fernández, Fiona Hollis, Laura Trovo, João Rodrigues, Alina Strasser, Olivia Zanoletti, Pascal Steiner, Nicolas Preitner, Lijing Xin, Simone Astori, Carmen Sandi.
      Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in <i>in vivo</i> experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual's capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.
    Keywords:  effort; glutathione; human; motivation; neuroscience; nucleus accumbens; rat
    DOI:  https://doi.org/10.7554/eLife.77791
  17. Biomolecules. 2022 Oct 29. pii: 1595. [Epub ahead of print]12(11):
    Metabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective.
    Jara Tabitha Hees, Angelika Bettina Harbauer.
      Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell such as a neuron adapts to local differences in mitochondrial demand. In this review, we discuss regulatory mechanisms controlling mitochondrial biogenesis thereby making a case for differential regulation at the transcriptional and translational level. In neurons, additional regulation can occur due to the axonal localization of mRNAs encoding mitochondrial proteins. Hitchhiking of mRNAs on organelles including mitochondria as well as contact site formation between mitochondria and endolysosomes are required for local mitochondrial biogenesis in axons linking defects in any of these organelles to the mitochondrial dysfunction seen in various neurological disorders.
    Keywords:  AMPK; PGC-1α; insulin; mTORC1; mitochondrial biogenesis; neurons; transcription; translation
    DOI:  https://doi.org/10.3390/biom12111595
  18. MicroPubl Biol. 2022 ;2022
    Mutation of the H12-helix of α-tubulin/MEC-12 disrupts the localization of neuronal mitochondria.
    Jean-Sébastien Teoh, Samiksha Dhananjay, Brent Neumann.
      Microtubules are essential components of the cytoskeleton that allow bi-lateral neuronal transport. Correct regulation of these complex intracellular transport processes is central to neuronal function. However, despite major advancements in our knowledge, we still lack a complete understanding on how neuronal transport is regulated. Here, we provide further evidence for the importance of the highly conserved N-terminal H12-helix of α-tubulin. We show that a mutation in this region results in the mistargeting of axonal mitochondria in Caenorhabditis elegans , thereby establishing the importance of the H12-helix in regulating mitochondrial transport in neurons.
    DOI:  https://doi.org/10.17912/micropub.biology.000659
  19. Nutrients. 2022 Oct 27. pii: 4515. [Epub ahead of print]14(21):
    Maternal Obesity and Gut Microbiota Are Associated with Fetal Brain Development.
    Sanjay Basak, Ranjit K Das, Antara Banerjee, Sujay Paul, Surajit Pathak, Asim K Duttaroy.
      Obesity in pregnancy induces metabolic syndrome, low-grade inflammation, altered endocrine factors, placental function, and the maternal gut microbiome. All these factors impact fetal growth and development, including brain development. The lipid metabolic transporters of the maternal-fetal-placental unit are dysregulated in obesity. Consequently, the transport of essential long-chain PUFAs for fetal brain development is disturbed. The mother's gut microbiota is vital in maintaining postnatal energy homeostasis and maternal-fetal immune competence. Obesity during pregnancy changes the gut microbiota, affecting fetal brain development. Obesity in pregnancy can induce placental and intrauterine inflammation and thus influence the neurodevelopmental outcomes of the offspring. Several epidemiological studies observed an association between maternal obesity and adverse neurodevelopment. This review discusses the effects of maternal obesity and gut microbiota on fetal neurodevelopment outcomes. In addition, the possible mechanisms of the impacts of obesity and gut microbiota on fetal brain development are discussed.
    Keywords:  brain development; fetal development; maternal obesity; microbiota; obesity; placenta; pregnancy
    DOI:  https://doi.org/10.3390/nu14214515
  20. Antioxidants (Basel). 2022 Oct 27. pii: 2116. [Epub ahead of print]11(11):
    Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise.
    Giorgia Scarfò, Rebecca Piccarducci, Simona Daniele, Ferdinando Franzoni, Claudia Martini.
      The human brain is primarily composed of lipids, and their homeostasis is crucial to carry on normal neuronal functions. In order to provide an adequate amount of lipid transport in and out of the central nervous system, organisms need a set of proteins able to bind them. Therefore, alterations in the structure or function of lipid-binding proteins negatively affect brain homeostasis, as well as increase inflammation and oxidative stress with the consequent risk of neurodegeneration. In this regard, lifestyle changes seem to be protective against neurodegenerative processes. Nutraceutical supplementation with antioxidant molecules has proven to be useful in proving cognitive functions. Additionally, regular physical activity seems to protect neuronal vitality and increases antioxidant defenses. The aim of the present review was to investigate mechanisms that link lipid-binding protein dysfunction and oxidative stress to cognitive decline, also underlining the neuroprotective effects of diet and exercise.
    Keywords:  apolipoproteins; lipid-binding proteins; neurodegenerative disease; nutraceutical supplement; physical activity
    DOI:  https://doi.org/10.3390/antiox11112116
  21. Cells. 2022 Oct 27. pii: 3395. [Epub ahead of print]11(21):
    Role of SUMOylation in Neurodegenerative Diseases.
    Nicolas Mandel, Nitin Agarwal.
      Neurodegenerative diseases (NDDs) are irreversible, progressive diseases with no effective treatment. The hallmark of NDDs is the aggregation of misfolded, modified proteins, which impair neuronal vulnerability and cause brain damage. The loss of synaptic connection and the progressive loss of neurons result in cognitive defects. Several dysregulated proteins and overlapping molecular mechanisms contribute to the pathophysiology of NDDs. Post-translational modifications (PTMs) are essential regulators of protein function, trafficking, and maintaining neuronal hemostasis. The conjugation of a small ubiquitin-like modifier (SUMO) is a reversible, dynamic PTM required for synaptic and cognitive function. The onset and progression of neurodegenerative diseases are associated with aberrant SUMOylation. In this review, we have summarized the role of SUMOylation in regulating critical proteins involved in the onset and progression of several NDDs.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; SUMOylation; diabetic peripheral neuropathy; neuronal diseases; post-translational modifications
    DOI:  https://doi.org/10.3390/cells11213395
  22. Mol Genet Metab Rep. 2022 Dec;33 100932
    ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction.
    Rachel Wolfe, Paige Heiman, Olivia D'Annibale, Anuradha Karunanidhi, Alyssa Powers, Marianne Mcguire, Bianca Seminotti, Steven F Dobrowolski, Miguel Reyes-Múgica, Kathryn S Torok, Al-Walid Mohsen, Jerry Vockley, Lina Ghaloul-Gonzalez.
      Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the ITCH gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoimmune hepatitis, thyroiditis, and enteropathy, among other organ manifestations. It was originally described in 10 consanguineous Old Order Amish patients, and more recently in two patients of White British and Black German ethnicities. While the role of ITCH protein in apoptosis and inflammation has previously been characterized, a defect in cellular bioenergetics has not yet been reported in ITCH deficiency. Here we present a Caucasian female originally evaluated for possible mitochondrial respiratory chain deficiency, who ultimately was found to have two novel variants in ITCH with absence of ITCH protein in patient derived fibroblasts. Clinical studies of patient muscle showed mitochondrial DNA copy number of 57% compared to controls. Functional studies in skin fibroblasts revealed decreased activity of mitochondrial fatty acid oxidation and oxidative phosphorylation, and decreased overall ATP production. Our findings confirm mitochondrial energy dysfunction in a patient with ITCH deficiency offering the opportunity to assess alternative therapeutic options.
    Keywords:  Apoptosis; Autoimmune disease; DMEM, Dulbecco's Modified Eagle Medium; E3 ligase; ETC, Mitochondrial electron transport chain; FAO, Fatty acid oxidation; FOXP3, Forkhead box P3 protein; HECT, Homologous to the E6-Associated Protein C-Terminus; IBD, Inflammatory Bowel Disease; IF, Immunofluorescence analysis; ITCH; MAVS, Mitochondrial antiviral signaling protein; Mitochondrial dysfunction; NOTCH1, Notch receptor 1 protein; OCR, Oxygen consumption rate; OXPHOS, Oxidative Phosphorylation; TAX1BP1, TAX1-binding protein 1; TFP, Trifunctional protein; TXNIP, Thioredoxin Interacting Protein; Tregs, T regulatory cells; UPS, Ubiquitin proteasome system; Ubiquitination; VLCAD, Very long-chain acyl-CoA dehydrogenase protein
    DOI:  https://doi.org/10.1016/j.ymgmr.2022.100932
  23. Metabolites. 2022 Nov 06. pii: 1075. [Epub ahead of print]12(11):
    Quantitative Analyses and Validation of Phospholipids and Sphingolipids in Ischemic Rat Brains.
    Chiung-Yin Huang, Ping-Ju Tsai, Hsuan-Wen Wu, I-Ting Chen, Hay-Yan J Wang.
      Prior MALDI mass spectrometry imaging (MALDI-MSI) studies reported significant changes in phosphatidylcholines (PCs), lysophosphatidylcholines (LPCs), and sphingomyelins (SMs) in ischemic rat brains yet overlooked the information on other classes of PLs and SLs and provided very little or no validation on the detected lipid markers. Relative quantitation of four classes of PLs and two classes of SLs in the ischemic and normal temporal cortex (TCX), parietal cortex (PCX), and striatum (ST) of rats was performed with hydrophilic interaction chromatography (HILIC)-tandem mass spectrometry (MS/MS) analyses, and the marker lipid species was identified by multivariate data analysis and validated with additional tissue cohorts. The acquired lipid information was sufficient in differentiating individual anatomical regions under different pathological states, identifying region-specific ischemic brain lipid markers and revealing additional PL and SL markers not reported previously. Validation of orthogonal partial least square discriminating analysis (OPLS-DA) identified ischemic brain lipid markers yielded much higher classification accuracy, precision, specificity, sensitivity, and lower false positive and false negative rates than those from the volcano plot analyses using conventional statistical significance and a fold change of two as the cutoff and provided a wider prospective to ischemia-associated brain lipid changes.
    Keywords:  hydrophilic interaction chromatography–tandem mass spectrometry; ischemic stroke; lipidomics; multivariate data analyses; phospholipids; sphingolipids; tissue lipid biomarkers
    DOI:  https://doi.org/10.3390/metabo12111075
  24. Mol Nutr Food Res. 2022 Nov 11. e2200351
    The FADS1 rs174550 Genotype Modifies the n-3 and n-6 PUFA and Lipid Mediator Responses to a High Alpha-Linolenic Acid and High Linoleic Acid Diets.
    Topi Meuronen, Maria A Lankinen, Johan Kolmert, Vanessa de Mello Laaksonen, Taisa Sallinen, Jyrki Ågren, Kirsi A Virtanen, Markku Laakso, Craig E Wheelock, Jussi Pihlajamäki, Ursula Schwab.
       SCOPE: The fatty acid composition of plasma lipids, which is associated with biomarkers and risk of non-communicable diseases, is regulated by dietary polyunsaturated fatty acids (PUFAs) and variants of fatty acid desaturase (FADS). We investigated the interactions between dietary PUFAs and FADS1 rs174550 variant.
    METHODS AND RESULTS: Participants (n = 118), homozygous for FADS1 rs174550 variant (TT and CC) followed a high alpha-linolenic acid (ALA, 5 percent of energy (E-%)) or a high linoleic acid (LA, 10 E-%) diet during an 8-week randomized controlled intervention. Fatty acid composition of plasma lipids and PUFA-derived lipid mediators were quantified by gas and liquid chromatography mass spectrometry, respectively. The high-LA diet increased the concentration of plasma LA, but not its lipid mediators. The concentration of plasma arachidonic acid decreased in carriers of CC and remained unchanged in the TT genotype. The high-ALA diet increased the concentration of plasma ALA and its cytochrome P450-derived epoxides and dihydroxys, and cyclooxygenase-derived monohydroxys. Concentrations of plasma eicosapentaenoic acid and its mono- and dihydroxys increased only in TT genotype carriers.
    CONCLUSIONS: These findings suggest the potential for genotype-based recommendations for PUFA consumption, resulting in modulation of bioactive lipid mediators which can exert beneficial effects in maintaining health.
    Keywords:  FADS; alpha-linolenic acid; eicosanoid; eicosapentaenoic acid; linoleic acid; octadecanoid
    DOI:  https://doi.org/10.1002/mnfr.202200351
  25. Front Endocrinol (Lausanne). 2022 ;13 972890
    Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders.
    Valentina Spigoni, Gloria Cinquegrani, Nicolas Thomas Iannozzi, Giulia Frigeri, Giulia Maggiolo, Marta Maggi, Vanessa Parello, Alessandra Dei Cas.
      Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as "nutritional ketosis". The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate <i>via</i> GPR43 and of β-OHB <i>via</i> GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies <i>per se</i>, independently of weight loss, only studies comparing ketogenic <i>vs</i> isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.
    Keywords:  GPCR (G protein coupled receptors); ketogenic diet; ketone bodies; metabolic disorder; very low carbohydrate ketogenic diet
    DOI:  https://doi.org/10.3389/fendo.2022.972890
  26. Int J Mol Sci. 2022 Oct 30. pii: 13216. [Epub ahead of print]23(21):
    Mitochondrial Epilepsy, a Challenge for Neurologists.
    Piervito Lopriore, Fábio Gomes, Vincenzo Montano, Gabriele Siciliano, Michelangelo Mancuso.
      Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects &gt;1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.
    Keywords:  Leigh syndrome; MELAS; MERRF; POLG-related disorders; epilepsy; mitochondrial epilepsy; primary mitochondrial disease; stroke-like episode
    DOI:  https://doi.org/10.3390/ijms232113216
  27. Front Immunol. 2022 ;13 960906
    The significance of glycolysis index and its correlations with immune infiltrates in Alzheimer's disease.
    Zhiqiang Qiu, Xuanyang Bai, Xiangwen Ji, Xiang Wang, Xinye Han, Duo Wang, Fenjun Jiang, Yihua An.
      Alzheimer's disease (AD) is a common neurodegenerative disorder without an effective treatment, and results in an increasingly serious health problem. However, its pathogenesis is complex and poorly understood. Nonetheless, the exact role of dysfunctional glucose metabolism in AD pathogenesis remains unclear. We screened 28 core glycolysis-related genes and introduced a novel metric, the glycolysis index, to estimate the activation of glycolysis. The glycolysis index was significantly lower in the AD group in four different brain regions (frontal cortex, FC; temporal cortex, TC; hippocampus, HP; and entorhinal cortex, EC) than that in the control group. Combined with differential expression and over-representation analyses, we determined the clinical and pathological relevance of glycolysis in AD. Subsequently, we investigated the role of glycolysis in the AD brain microenvironment. We developed a glycolysis-brain cell marker connection network, which revealed a close relationship between glycolysis and seven brain cell types, most of which presented abundant variants in AD. Using immunohistochemistry, we detected greater infiltrated microglia and higher expression of glycolysis-related microglia markers in the APP/PS1 AD model than that in the control group, consistent with our bioinformatic analysis results. Furthermore, the excellent predictive value of the glycolysis index has been verified in different populations. Overall, our present findings revealed the clinical and biological significance of glycolysis and the brain microenvironment in AD.
    Keywords:  Alzheimer’s disease; brain cell markers; glycolysis index; microglia; prognostic indicator
    DOI:  https://doi.org/10.3389/fimmu.2022.960906
  28. Front Neurosci. 2022 ;16 1009125
    Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts.
    Ioannis Angelopoulos, Georgios Gakis, Kyriakos Birmpas, Christina Kyrousi, Evagelia Eva Habeos, Konstantina Kaplani, Zoi Lygerou, Ioannis Habeos, Stavros Taraviras.
      The neural stem cell niche is a key regulator participating in the maintenance, regeneration, and repair of the brain. Within the niche neural stem cells (NSC) generate new neurons throughout life, which is important for tissue homeostasis and brain function. NSCs are regulated by intrinsic and extrinsic factors with cellular metabolism being lately recognized as one of the most important ones, with evidence suggesting that it may serve as a common signal integrator to ensure mammalian brain homeostasis. The aim of this review is to summarize recent insights into how metabolism affects NSC fate decisions in adult neural stem cell niches, with occasional referencing of embryonic neural stem cells when it is deemed necessary. Specifically, we will highlight the implication of mitochondria as crucial regulators of NSC fate decisions and the relationship between metabolism and ependymal cells. The link between primary cilia dysfunction in the region of hypothalamus and metabolic diseases will be examined as well. Lastly, the involvement of metabolic pathways in ependymal cell ciliogenesis and physiology regulation will be discussed.
    Keywords:  cell mechanics; ciliopathies; ependymal; metabolism; neural stem cell niche; neural stem cells; subventricular zone (SVZ)
    DOI:  https://doi.org/10.3389/fnins.2022.1009125
  29. Proc Natl Acad Sci U S A. 2022 11 16. 119(46): e2209714119
    KIF2A deficiency causes early-onset neurodegeneration.
    Nuria Ruiz-Reig, Georges Chehade, Janne Hakanen, Mohamed Aittaleb, Keimpe Wierda, Joris De Wit, Laurent Nguyen, Philippe Gailly, Fadel Tissir.
      KIF2A is an atypical kinesin that has the capacity to depolymerize microtubules. Patients carrying mutations in KIF2A suffer from progressive microcephaly and mental disabilities. While the role of this protein is well documented in neuronal migration, the relationship between its dysfunction and the pathobiology of brain disorders is unclear. Here, we report that KIF2A is dispensable for embryogenic neurogenesis but critical in postnatal stages for maturation, connectivity, and maintenance of neurons. We used a conditional approach to inactivate KIF2A in cortical progenitors, nascent postmitotic neurons, and mature neurons in mice. We show that the lack of KIF2A alters microtubule dynamics and disrupts several microtubule-dependent processes, including neuronal polarity, neuritogenesis, synaptogenesis, and axonal transport. KIF2A-deficient neurons exhibit aberrant electrophysiological characteristics, neuronal connectivity, and function, leading to their loss. The role of KIF2A is not limited to development, as fully mature neurons require KIF2A for survival. Our results emphasize an additional function of KIF2A and help explain how its mutations lead to brain disorders.
    Keywords:  brain wiring; neurodegeneration; neurodevelopment; neuronal polarity
    DOI:  https://doi.org/10.1073/pnas.2209714119
  30. Cells. 2022 Oct 25. pii: 3372. [Epub ahead of print]11(21):
    Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics.
    Konstantinos I Avgerinos, Roger J Mullins, Michael Vreones, Maja Mustapic, Qinghua Chen, Denise Melvin, Dimitrios Kapogiannis, Josephine M Egan.
      Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated β-hydroxybutyrate over 34-h periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer's disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity.
    Keywords:  empagliflozin; glutamate; glutamine; insulin signaling; magnetic resonance spectroscopy; neuronal-origin extracellular vesicles; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/cells11213372
  31. Prostaglandins Leukot Essent Fatty Acids. 2022 Nov;pii: S0952-3278(22)00122-3. [Epub ahead of print]186 102510
    Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.
    Juno Van Valkenburgh, Marlon Vincent V Duro, Erica Burnham, Quan Chen, Shaowei Wang, Jenny Tran, Bilal E Kerman, Sung Hee Hwang, Xiaodan Liu, Naomi S Sta Maria, Francesca Zanderigo, Etienne Croteau, Stanley I Rapoport, Stephen C Cunnane, Russell E Jacobs, Hussein N Yassine, Kai Chen.
      Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [18F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.
    Keywords:  ApoE4; Arachidonic acid; Brain imaging; Fatty acid; PET-MR
    DOI:  https://doi.org/10.1016/j.plefa.2022.102510
  32. J Neurogenet. 2022 Nov 12. 1-13
    Inter-organ regulation by the brain in Drosophila development and physiology.
    Sunggyu Yoon, Mingyu Shin, Jiwon Shim.
      The brain plays an essential role in regulating physiological homeostasis by communicating with other organs. Neuronal cells either directly innervate target tissues and transmit signals or secrete systemic factors into the hemolymph to regulate bodily functions, including physiology, development, metabolism, and immunity. In this review, we discuss the systemic functions of inter-organ communication mediated by the brain in four distinct categories: (1) nutrient sensing and feeding, (2) gastrointestinal activity and metabolism, (3) development and metamorphosis, and (4) immunity and hematopoiesis. First, we describe how chemosensory signals are sensed and transmitted to the brain in Drosophila and how the brain stimulates or modifies feeding behavior. Second, we summarize the brain-organ axis that regulates appetite activities and neuroendocrine pathways that maintain metabolic homeostasis. Third, we discuss how overall development in Drosophila is achieved by insulin and how it affects ecdysone signaling to initiate pupariation. Finally, we discuss how the central or peripheral nervous system controls hematopoiesis and innate immunity in Drosophila larvae. Given the functional parallels between Drosophila and humans, homologous pathways are likely to be conserved in human development and disease models, and the fly model system will continue to provide mechanistic insights into understanding complex interactions.
    Keywords:  Drosophila; gut-brain; innate immunity; inter-organ interaction
    DOI:  https://doi.org/10.1080/01677063.2022.2137162
  33. Cells. 2022 Nov 07. pii: 3523. [Epub ahead of print]11(21):
    Branched-Chain Amino Acids Are Linked with Alzheimer's Disease-Related Pathology and Cognitive Deficits.
    Md Abu Bakkar Siddik, Caitlyn A Mullins, Alyssa Kramer, Harsh Shah, Ritchel B Gannaban, Masoud Zabet-Moghaddam, Ryan M Huebinger, Vijay K Hegde, Sheba M J MohanKumar, Puliyur S MohanKumar, Andrew C Shin.
      Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with a complex pathophysiology. Type 2 diabetes (T2D) is a strong risk factor for AD that shares similar abnormal features including metabolic dysregulation and brain pathology such as amyloid and/or Tau deposits. Emerging evidence suggests that circulating branched-chain amino acids (BCAAs) are associated with T2D. While excess BCAAs are shown to be harmful to neurons, its connection to AD is poorly understood. Here we show that individuals with AD have elevated circulating BCAAs and their metabolites compared to healthy individuals, and that a BCAA metabolite is correlated with the severity of dementia. APPSwe mouse model of AD also displayed higher plasma BCAAs compared to controls. In pursuit of understanding a potential causality, BCAA supplementation to HT-22 neurons was found to reduce genes critical for neuronal health while increasing phosphorylated Tau. Moreover, restricting BCAAs from diet delayed cognitive decline and lowered AD-related pathology in the cortex and hippocampus in APP/PS1 mice. BCAA restriction for two months was sufficient to correct glycemic control and increased/restored dopamine that were severely reduced in APP/PS1 controls. Treating 5xFAD mice that show early brain pathology with a BCAA-lowering compound recapitulated the beneficial effects of BCAA restriction on brain pathology and neurotransmitters including norepinephrine and serotonin. Collectively, this study reveals a positive association between circulating BCAAs and AD. Our findings suggest that BCAAs impair neuronal functions whereas BCAA-lowering alleviates AD-related pathology and cognitive decline, thus establishing a potential causal link between BCAAs and AD progression.
    Keywords:  5xFAD; APP/PS1; Aβ-42; BCAA; Tau; diet restriction; glucose metabolism; neurotransmitters
    DOI:  https://doi.org/10.3390/cells11213523
  34. Cell Death Dis. 2022 Nov 09. 13(11): 946
    Mitochondrial glutamine transporter SLC1A5_var, a potential target to suppress astrocyte reactivity in Parkinson's Disease.
    Yang Liu, Lei Cao, Yuting Song, Zhengwei Kang, Ting Liu, Jianhua Ding, Gang Hu, Ming Lu.
      SLC1A5 variant (SLC1A5_var) is identified as a mitochondrial glutamine transporter in cancer cells recently. However, the role of SLC1A5_var in Parkinson's disease (PD) is completely unknown. Here, we found the significant downregulation of SLC1A5_var in astrocytes and midbrain of mice treated with MPTP/MPP+ and LPS. Importantly, overexpression of SLC1A5_var ameliorated but knockdown of SLC1A5_var exacerbated MPTP/MPP+- and LPS-induced mitochondrial dysfunction. Consequently, SLC1A5_var provided beneficial effects on PD pathology including improvement of PD-like motor symptoms and rescue of dopaminergic (DA) neuron degeneration through maintaining mitochondrial energy metabolism. Moreover, SLC1A5_var reduced astrocyte reactivity via inhibition of A1 astrocyte conversion. Further investigation demonstrated that SLC1A5_var restrained the secretion of astrocytic pro-inflammatory cytokines by blunting TLR4-mediated downstream pathways. This is the first study to prove that astrocytic SLC1A5_var inhibits neuroinflammation, and rescues the loss of DA neurons and motor symptoms involved in PD progression, which provides a novel target for PD treatment.
    DOI:  https://doi.org/10.1038/s41419-022-05399-z
  35. Immunometabolism (Cobham). 2022 Oct;4(4): e00011
    The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
    Juan F Codocedo, Gary E Landreth.
      Hexokinases (HKs) catalyze the first and irreversible step of glucose metabolism. Its product, glucose-6-phosphate (G-6P) serves as a precursor for catabolic processes like glycolysis for adenosine 5'-triphosphate (ATP) production and anabolic pathways including the pentose phosphate pathway (PPP) for the generation of intermediaries like nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-P. Thus, the cellular fate of glucose is important not only for growth and maintenance, but also to determine different cellular activities. Studies in immune cells have demonstrated an intimate linkage between metabolic pathways and inflammation, however the precise molecular mechanisms that determine the cellular fate of glucose during inflammation or aging are not completely understood. Here we discuss a study by De Jesus et al that describes the role of HK1 cytosolic localization as a critical regulator of glucose flux by shunting glucose into the PPP at the expense of glycolysis, exacerbating the inflammatory response of macrophages. The authors convincingly demonstrate a novel mechanism that is independent of its mitochondrial functions, but involve the association to a protein complex that inhibits glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase. We expand the discussion by comparing previous studies related to the HK2 isoform and how cells have evolved to regulate the mitochondrial association of these two isoforms by non-redundant mechanism.
    Keywords:  glucose; hexokinase
    DOI:  https://doi.org/10.1097/IN9.0000000000000011
  36. Neurotoxicology. 2022 Nov 08. pii: S0161-813X(22)00178-4. [Epub ahead of print]
    Chronic Lead Exposure Disrupts Neurometabolic Activity in Mouse Brain: An ex vivo1H-[13C]-NMR Study.
    K S Varadarajan, Puneet Bagga, Akila Ramesh, Anup N Chugani, Anant B Patel.
      Lead poisoning has been identified as a problem in adults as well as in children. Chronic exposure to lead has been implicated in neurological disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In the present study, we evaluated the impact of chronic lead exposure on cerebral glutamatergic and GABAergic metabolic activity in mice. C57BL6 mice were provided lead acetate in drinking water for two months. The regional cerebral metabolic activity was measured using 1H-[13C]-NMR spectroscopy in conjunction with infusion of [1,6-13C2]glucose. The blood Pb2+ increased significantly in lead acetate treated mice. Concomitantly, there was a significant reduction in the forelimb strength. The level of m-inositol was elevated in the cerebral cortex of mice chronically exposed to lead. The glutamatergic neurometabolic activity was found to be reduced following chronic lead exposure in the cerebral cortex, hippocampus, and striatum. In contrast, the GABAergic fluxes were impaired in the hippocampus and thalamus only. The metabolic fluxes in the cerebellum were unperturbed to Pb toxicity. In conclusion, we report that chronic lead exposure in mice leads to an impairment in forelimb strength, and perturbation neurometabolism in brain regions involved in cognition and movement.
    Keywords:  GABA; Glutamate; Neurometabolism; Neurotransmitter cycle; TCA Cycle
    DOI:  https://doi.org/10.1016/j.neuro.2022.11.005
  37. Sci Adv. 2022 Nov 11. 8(45): eabo7956
    AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
    Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.
      Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abo7956
  38. Int J Mol Sci. 2022 Nov 04. pii: 13560. [Epub ahead of print]23(21):
    Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis.
    Alessia Mauri, Alessandra Duse, Giacomo Palm, Roberto Previtali, Stefania Maria Bova, Sara Olivotto, Sara Benedetti, Francesca Coscia, Pierangelo Veggiotti, Cristina Cereda.
      GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients, clinically suspect of GLUT1DS from both sporadic and familial cases, have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift, and splice site variants. Their structural mapping on the X-ray structure of GLUT1 strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters.
    Keywords:  GLUT1 deficiency syndrome; GLUT1 structure analysis; novel SLC2A1 variants
    DOI:  https://doi.org/10.3390/ijms232113560
  39. ACS Omega. 2022 Nov 01. 7(43): 38269-38276
    Neuroprotective Effects of Natural Antioxidants Against Branched-Chain Fatty Acid-Induced Oxidative Stress in Cerebral Cortex and Cerebellum Regions of the Rat Brain.
    Shaista Chaudhary, Pinky, Suhel Parvez.
      Valproic acid (VPA) is short branched-chain fatty acid (BCFA) derived from valeric acids which are naturally produced by Valeriana officinalis (flowering plant). Neurotoxicity caused by BCFA-like VPA may be mediated by oxidative stress, according to research involving the cerebral cortex and cerebellum. In the present study, we explored the possible protective effect of different antioxidants such as melatonin, quercetin, and piperine on VPA exposure by using a supernatant preparation of the cerebral cortex and cerebellum regions of the rat brain. The present study revealed that melatonin, quercetin, and piperine significantly prevented VPA-induced oxidative stress in the cerebral cortex and cerebellum regions. VPA was also observed to lower the level of reduced glutathione, and this effect was significantly mitigated by these antioxidants. Melatonin, quercetin, and piperine also ameliorated and altered the activities of AChE, Na+, K+ATPase, and MAO in the cerebral cortex and cerebellum. Results of this study also suggest that prior treatment of antioxidants like melatonin, quercetin, and piperine helps in combating the oxidative stress induced by VPA in the cerebral cortex and cerebellum region of the rat brain. Thus, sufficient dietary intake of these antioxidants by individuals at high risk of VPA exposure could prove beneficial in combating the adverse effect of VPA.
    DOI:  https://doi.org/10.1021/acsomega.2c00163
  40. Metabolites. 2022 Nov 10. pii: 1096. [Epub ahead of print]12(11):
    Interrogating the Metabolomic Profile of Amyotrophic Lateral Sclerosis in the Post-Mortem Human Brain by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Mass Spectrometry Imaging (MSI).
    Alexandria L Sohn, Lingyan Ping, Jonathan D Glass, Nicholas T Seyfried, Emily C Hector, David C Muddiman.
      Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease characterized by progressive loss of motor function with an average survival time of 2-5 years after diagnosis. Due to the lack of signature biomarkers and heterogenous disease phenotypes, a definitive diagnosis of ALS can be challenging. Comprehensive investigation of this disease is imperative to discovering unique features to expedite the diagnostic process and improve diagnostic accuracy. Here, we present untargeted metabolomics by mass spectrometry imaging (MSI) for comparing sporadic ALS (sALS) and C9orf72 positive (C9Pos) post-mortem frontal cortex human brain tissues against a control cohort. The spatial distribution and relative abundance of metabolites were measured by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI for association to biological pathways. Proteomic studies on the same patients were completed via LC-MS/MS in a previous study, and results were integrated with imaging metabolomics results to enhance the breadth of molecular coverage. Utilizing METASPACE annotation platform and MSiPeakfinder, nearly 300 metabolites were identified across the sixteen samples, where 25 were identified as dysregulated between disease cohorts. The dysregulated metabolites were further examined for their relevance to alanine, aspartate, and glutamate metabolism, glutathione metabolism, and arginine and proline metabolism. The dysregulated pathways discussed are consistent with reports from other ALS studies. To our knowledge, this work is the first of its kind, reporting on the investigation of ALS post-mortem human brain tissue analyzed by multiomic MSI.
    Keywords:  Amyotrophic lateral sclerosis (ALS); IR-MALDESI MSI; mass spectrometry imaging; multiomic; neurodegenerative disease
    DOI:  https://doi.org/10.3390/metabo12111096
  41. Biochem Pharmacol. 2022 Oct 28. pii: S0006-2952(22)00424-5. [Epub ahead of print]206 115330
    Protectins: Their biosynthesis, metabolism and structure-functions.
    Trond Vidar Hansen, Charles N Serhan.
      Several lipoxygenase enzymes and cyclooxygenase-2 stereoselectively convert the polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and n-3 docosapentaenoic acid into numerous oxygenated products. Biosynthetic pathway studies have shown, during the resolution phase of acute inflammation, that distinct families of endogenous products are formed. These products were named specialized pro-resolving mediators, given their specialized functions in the inflammation-resolution circuit, enhancing the return of inflamed and injured tissue to homeostasis. The lipoxins, resolvins, protectins and maresins, together with the sulfido-conjugates of the resolvins, protectins and maresins, constitute the four individual families of these local mediators. When administrated in vivo in a wide range of human disease models, the specialized pro-resolving mediators display potent bioactions. The detailed and individual biosynthetic steps constituting the biochemical pathways, the metabolism, recent reports on structure-function studies and pharmacodynamic data of the protectins, are presented herein. Emphasis is on the structure-function results on the recent members of the sulfido conjugated protectins and further metabolism of protectin D1. Moreover, the members of the individual families of specialized pro-resolving mediators and their biosynthetic precursor are presented. Today 43 specialized pro-resolving mediators possessing pro-resolution and anti-inflammatory bioactions are reported and confirmed, constituting a basis for resolution pharmacology. This emerging biomedical field provides a new approach for drug discovery, that is also discussed.
    Keywords:  Biosynthesis; Cyclooxygenase-2; Lipoxygenases; Protectins; Resolution pharmacology; Specialized pro-resolving mediators
    DOI:  https://doi.org/10.1016/j.bcp.2022.115330
  42. Epilepsy Behav. 2022 Nov 04. pii: S1525-5050(22)00413-9. [Epub ahead of print]137(Pt A): 108964
    Glyceryl triacetate feeding in mice increases plasma acetate levels but has no anticonvulsant effects in acute electrical seizure models.
    Weizhi Xu, Elliott S Neal, Manuel Plan, Karin Borges.
       INTRODUCTION: Acetate has been shown to have neuroprotective and anti-inflammatory effects. It is oxidized by astrocytes and can thus provide auxiliary energy to the brain in addition to glucose. Therefore, we hypothesized that it may protect against seizures, which is investigated here by feeding glyceryl triacetate (GTA), to provide high amounts of acetate without raising sodium or acid levels.
    METHOD: CD1 male mice were fed controlled diets with or without GTA for up to three weeks. Body weights, blood glucose levels, plasma short-chain fatty acid levels, and other hematological parameters were monitored. Seizure thresholds were determined in 6 Hz and maximal electroshock seizure threshold (MEST) tests. Antioxidant capacities were evaluated in the cerebral cortex and plasma using a ferric reducing antioxidant power (FRAP) assay and Trolox equivalent antioxidant capacity assay.
    RESULTS: Body weight gain was similar with both diets with and without GTA in two experiments. Glyceryl triacetate-fed groups showed 2-3- and 1.6-fold increased acetate and propionate levels in plasma, respectively. Glucose levels were unaltered in blood collected from the tail tip but increased in trunk blood. No differences were found in the activity of cerebral cortex acetyl-CoA synthetase. In the 6 Hz threshold test, seizure thresholds were lower by 3 mA and 2.4 mA after 8 and 14 days, respectively, in the GTA compared to the control diet-fed group, but showed no difference on day 16, showing that GTA has small, but inconsistent proconvulsant effects in this model. In MEST tests, a slightly increased seizure threshold (1 mA) was found on day 19 in the GTA-fed group, but not in another experiment on day 21. There were no differences in antioxidant capacity in plasma or cortex between the two groups.
    CONCLUSION: Glyceryl triacetate feeding showed no antioxidant effects nor beneficial changes in acute electrical seizure threshold mouse models, despite its ability to increase plasma acetate levels.
    Keywords:  6 Hz model; Acetate; Auxiliary fuel; Epilepsy; Maximal electroshock seizure threshold; Short-chain fatty acid
    DOI:  https://doi.org/10.1016/j.yebeh.2022.108964
  43. Nutr Neurosci. 2022 Nov 10. 1-21
    Effects of the ketogenic diet on cognition: a systematic review.
    Arun Chinna-Meyyappan, Fabiano Alves Gomes, Elena Koning, Jennifer Fabe, Vitor Breda, Elisa Brietzke.
       INTRODUCTION: Ketogenic diet (KD) therapy has been used as a dietary intervention in drug-resistant epilepsy for several years. Research currently suggests that KD therapy may carry neuroprotective and cognition enhancing effects for individuals with non-epileptic conditions as well as for healthy individuals. Therefore, KD may have potential as a non-invasive, nutritional treatment approach for difficult to manage conditions such as neurodegenerative illnesses or mood disorders. The aim of this review is to summarize the available evidence on ketogenic interventions and the resulting cognitive outcomes.
    MATERIALS AND METHODS: The paper was based on PRISMA 2020 guidelines. The search was conducted in June 2021 on the following databases: CENTRAL, PubMed, EMBASE, PsycInfo, Web of Science. The search yielded 2014 studies, of which 49 were included.
    RESULTS: There were 22 animal studies assessing murine models and 27 studies on humans. The primary indications in these studies were epileptic conditions, neurodegenerative disorders, cognitive impairment, and healthy populations.
    DISCUSSION: Administration of KD seems to confer cognitive-enhancing effects in areas such as working memory, reference memory and attention. Studies found that KD treatment in animals has the potential to alleviate age-related cognitive decline. Over 80% of the 27 human studies reported a favourable effect of intervention, and none reported a detrimental effect of KD. While these findings suggest that KD may improve the functioning of certain cognitive domains, definitive conclusions were limited by studies with small sample sizes, the absence of controls and randomization, and the lack of objective measures of cognition.
    Keywords:  Ketosis; attention; cognition; executive function; ketogenic diet; low-carbohydrate; nutrition; working memory
    DOI:  https://doi.org/10.1080/1028415X.2022.2143609
  44. J Neural Transm (Vienna). 2022 Nov 06.
    Targeting the brain 5-HT7 receptor to prevent hypomyelination in a rodent model of perinatal white matter injuries.
    Cindy Bokobza, Alice Jacquens, David Guenoun, Blandine Bianco, Anne Galland, Maxime Pispisa, Alexandra Cruz, Manuela Zinni, Valérie Faivre, Anne Roumier, Sophie Lebon, Tania Vitalis, Zsolt Csaba, Tifenn Le Charpentier, Leslie Schwendimann, Pierrette Young-Ten, Vincent Degos, Patricia Monteiro, Pascal Dournaud, Pierre Gressens, Juliette Van Steenwinckel.
      Approximately 15 million babies are born prematurely every year and many will face lifetime motor and/or cognitive deficits. Children born prematurely are at higher risk of developing perinatal brain lesions, especially white matter injuries (WMI). Evidence in humans and rodents demonstrates that systemic inflammation-induced neuroinflammation, including microglial and astrocyte reactivity, is the prominent processes of WMI associated with preterm birth. Thus, a new challenge in the field of perinatal brain injuries is to develop new neuroprotective strategies to target neuroinflammation to prevent WMI. Serotonin (5-HT) and its receptors play an important role in inflammation, and emerging evidence indicates that 5-HT may regulate brain inflammation by the modulation of microglial reactivity and astrocyte functions. The present study is based on a mouse model of WMI induced by intraperitoneal (i.p.) injections of IL-1β during the first 5 days of life. In this model, certain key lesions of preterm brain injuries can be summarized by (i) systemic inflammation, (ii) pro-inflammatory microglial and astrocyte activation, and (iii) inhibition of oligodendrocyte maturation, leading to hypomyelination. We demonstrate that Htr7 mRNA (coding for the HTR7/5-HT7 receptor) is significantly overexpressed in the anterior cortex of IL-1β-exposed animals, suggesting it as a potential therapeutic target. LP-211 is a specific high-affinity HTR7 agonist that crosses the blood-brain barrier (BBB). When co-injected with IL-1β, LP-211 treatment prevented glial reactivity, the down-regulation of myelin-associated proteins, and the apparition of anxiety-like phenotypes. Thus, HTR7 may represent an innovative therapeutic target to protect the developing brain from preterm brain injuries.
    Keywords:  Astrocyte; HTR7; Microglia; Myelination; Neurodevelopmental disorders; Preterm birth; Serotonin
    DOI:  https://doi.org/10.1007/s00702-022-02556-8
  45. Am J Physiol Endocrinol Metab. 2022 Nov 01. 323(5): E448-E466
    Female and male C57BL/6J offspring exposed to maternal obesogenic diet develop altered hypothalamic energy metabolism in adulthood.
    Debra Kulhanek, Juan E Abrahante Llorens, Lauren Buckley, Ivan Tkac, Raghavendra Rao, Megan E Paulsen.
      Maternal obesity is exceedingly common and strongly linked to offspring obesity and metabolic disease. Hypothalamic function is critical to obesity development. Hypothalamic mechanisms causing obesity following exposure to maternal obesity have not been elucidated. Therefore, we studied a cohort of C57BL/6J dams, treated with a control or high-fat-high-sugar diet, and their adult offspring to explore potential hypothalamic mechanisms to explain the link between maternal and offspring obesity. Dams treated with obesogenic diet were heavier with mild insulin resistance, which is reflective of the most common metabolic disease in pregnancy. Adult offspring exposed to maternal obesogenic diet had no change in body weight but significant increase in fat mass, decreased glucose tolerance, decreased insulin sensitivity, elevated plasma leptin, and elevated plasma thyroid-stimulating hormone. In addition, offspring exposed to maternal obesity had decreased energy intake and activity without change in basal metabolic rate. Hypothalamic neurochemical profile and transcriptome demonstrated decreased neuronal activity and inhibition of oxidative phosphorylation. Collectively, these results indicate that maternal obesity without diabetes is associated with adiposity and decreased hypothalamic energy production in offspring. We hypothesize that altered hypothalamic function significantly contributes to obesity development. Future studies focused on neuroprotective strategies aimed to improve hypothalamic function may decrease obesity development.NEW & NOTEWORTHY Offspring exposed to maternal diet-induced obesity demonstrate a phenotype consistent with energy excess. Contrary to previous studies, the observed energy phenotype was not associated with hyperphagia or decreased basal metabolic rate but rather decreased hypothalamic neuronal activity and energy production. This was supported by neurochemical changes in the hypothalamus as well as inhibition of hypothalamic oxidative phosphorylation pathway. These results highlight the potential for neuroprotective interventions in the prevention of obesity with fetal origins.
    Keywords:  energy metabolism; fetal development; hypothalamus; obesity; sex differences
    DOI:  https://doi.org/10.1152/ajpendo.00100.2022
  46. Int J Mol Sci. 2022 Oct 27. pii: 13044. [Epub ahead of print]23(21):
    High Glycemia and Soluble Epoxide Hydrolase in Females: Differential Multiomics in Murine Brain Microvasculature.
    Saivageethi Nuthikattu, Dragan Milenkovic, Jennifer E Norman, John Rutledge, Amparo Villablanca.
      The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.
    Keywords:  EETs; dementia; female sex; high glycemic diet; hippocampus; microvascular; multi-omics; soluble epoxide hydrolase inhibitor
    DOI:  https://doi.org/10.3390/ijms232113044
  47. Eur J Nutr. 2022 Nov 11.
    Dietary energy restriction in neurological diseases: what's new?
    Boxin Zhang, Roujie Huang, Shaokang Xu, Yuzhen He, Jiaxin Li, Lily Wan, Bo Xiao, Zhaohui Luo.
      Energy-restricted diet is a specific dietary regimen, including the continuous energy-restricted diet and the intermittent energy-restricted diet. It has been proven effective not only to reduce weight and extend the lifespan in animal models, but also to regulate the development and progression of various neurological diseases such as epilepsy, cerebrovascular diseases (stroke), neurodegenerative disorders (Alzheimer's disease and Parkinson's disease) and autoimmune diseases (multiple sclerosis). However, the mechanism in this field is still not clear and a systematic neurological summary is still missing. In this review, we first give a brief summary of the definition and mainstream strategies of energy restrictions. We then review evidence about the effects of energy-restricted diet from both animal models and human trials, and update the current understanding of mechanisms underlying the biological role of energy-restricted diet in the fight against neurological diseases. Our review thus contributes to the modification of dietary regimen and the search for special diet mimics.
    Keywords:  Dietary restriction; Epilepsy; Intermittent fasting; Ischemic stroke; Neurodegenerative disease; Special diet mimetic
    DOI:  https://doi.org/10.1007/s00394-022-03036-1
  48. Sci Adv. 2022 Nov 11. 8(45): eabn2293
    Uncovering the biological basis of control energy: Structural and metabolic correlates of energy inefficiency in temporal lobe epilepsy.
    Xiaosong He, Lorenzo Caciagli, Linden Parkes, Jennifer Stiso, Teresa M Karrer, Jason Z Kim, Zhixin Lu, Tommaso Menara, Fabio Pasqualetti, Michael R Sperling, Joseph I Tracy, Dani S Bassett.
      Network control theory is increasingly used to profile the brain's energy landscape via simulations of neural dynamics. This approach estimates the control energy required to simulate the activation of brain circuits based on structural connectome measured using diffusion magnetic resonance imaging, thereby quantifying those circuits' energetic efficiency. The biological basis of control energy, however, remains unknown, hampering its further application. To fill this gap, investigating temporal lobe epilepsy as a lesion model, we show that patients require higher control energy to activate the limbic network than healthy volunteers, especially ipsilateral to the seizure focus. The energetic imbalance between ipsilateral and contralateral temporolimbic regions is tracked by asymmetric patterns of glucose metabolism measured using positron emission tomography, which, in turn, may be selectively explained by asymmetric gray matter loss as evidenced in the hippocampus. Our investigation provides the first theoretical framework unifying gray matter integrity, metabolism, and energetic generation of neural dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abn2293
  49. J Neuroinflammation. 2022 Nov 09. 19(1): 271
    Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase-deficient mice.
    Ke Zhong, Yu Huang, Prince Last Mudenda Zilundu, Yaqiong Wang, Yingying Zhou, Guangyin Yu, Rao Fu, Sookja Kim Chung, Yamei Tang, Xiao Cheng, Lihua Zhou.
      Brachial plexus root avulsion (BPRA) is frequently caused by high-energy trauma including traffic accident and birth trauma, which will induces massive motoneurons (MNs) death as well as loss of motor and sensory function in the upper limb. The death of MNs is attributed to energy deficiency, neuroinflammation and oxidative stress at the injured ventral horn of spinal cord triggered by BPRA injury. It has been reported which aldose reductase (AR), an endogenous enzyme that catalyzes fructose synthesis, positively correlates with the poor prognosis following cerebral ischemic injury, diabetic retinopathy and diabetic peripheral neuropathy. However, the role of AR in BPRA remains unknown. Herein, we used a mouse model and found that in the spinal cord of BPRA mice, the upregulation of AR correlated significantly with (1) an inactivated SIRT1-AMPK-mTOR pathway and disrupted autophagy; (2) increased byproducts accumulation of lipid peroxidation metabolism and neuroinflammation; and (3) increased MNs death. Furthermore, our results demonstrated the role of AR in BPRA injury whereby the absence of AR (AR knockout mice, AR-/-) prevented the hyper-neuroinflammation and disrupted autophagy as well as motor neuron death caused by BPRA injury. Finally, we further demonstrate that AR inhibitor epalrestat is neuroprotective against BPRA injury by increasing autophagy level, alleviating neuroinflammation and rescuing MNs death in mice. Collectively, our data demonstrate that the AR upregulation in the spinal cord is an important factor contributing to autophagy disruption, neuroinflammation and MNs death following brachial plexus roots avulsion in mice. Our study also provides a promising therapy drug to assist re-implantation surgery for the treatment of BPRA.
    Keywords:  Aldose reductase; Autophagy; Brachial plexus root avulsion; Motoneurons death; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-022-02632-6
  50. Mol Neurobiol. 2022 Nov 11.
    Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage.
    Lu Lin, Zhou Chen, Cuihua Huang, Yubin Wu, Lishan Huang, Lijing Wang, Sujie Ke, Libin Liu.
      Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.
    Keywords:  Blood-brain barrier; Cognitive dysfunction; Hypoglycemia; Mito-TEMPO; Oxidative stress; Pericyte
    DOI:  https://doi.org/10.1007/s12035-022-03101-0
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