bims-medebr 2022-08-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒08‒28
24 papers selected by
Regina F. Fernández
Johns Hopkins University

Metabolism of Exogenous [2,4-13C]β-Hydroxybutyrate following Traumatic Brain Injury in 21-22-Day-Old Rats: An Ex Vivo NMR Study.
Fatty acid sensing in the brain: The role of glia-neuronal metabolic crosstalk and horizontal lipid flux.
β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices.
Analysis of Brain Lipids in the Early-Onset Tay-Sachs Disease Mouse Model With the Combined Deficiency of β-Hexosaminidase A and Neuraminidase 3.
Brief exposure of neuronal cells to levels of SCFAs observed in human systemic circulation impair lipid metabolism resulting in apoptosis.
Mitochondrial Dysregulation and the Influence in Neurodegenerative Diseases.
Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults.
Mitochondrial behavior when things go wrong in the axon.
Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice.
Who knew? PPARs may act in the brain too.
Glycerol-3-phosphate shuttle is a backup system securing metabolic flexibility in neurons.
Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer's Disease.
HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer's Disease Pathogenesis.
Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.
Formation of N-acyl-phosphatidylethanolamines by cytosolic phospholipase A2ε in an ex vivo murine model of brain ischemia.
Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.
Fatty acid translocase: a culprit of lipid metabolism dysfunction in disease.
Stretch stress propels glutamine dependency and glycolysis in optic nerve head astrocytes.
Serine ether glycerophospholipids: Decrements in the frontal cortex associated with mild cognitive impairment and Alzheimer's disease.
ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex.
Phosphatidylserine, inflammation, and central nervous system diseases.
Glucose Metabolism Disorders: Challenges and Opportunities for Diagnosis and Treatment.
Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild-Moderate Neonatal Hypoxia-Ischemia Brain Injury Model.
Relevance of ω-6 GLA Added to ω-3 PUFAs Supplements for ADHD: A Narrative Review.

Metabolites. 2022 Jul 29. pii: 710. [Epub ahead of print]12(8):

Metabolism of Exogenous [2,4-13C]β-Hydroxybutyrate following Traumatic Brain Injury in 21-22-Day-Old Rats: An Ex Vivo NMR Study.

Susanna Scafidi, Jennifer Jernberg, Gary Fiskum, Mary C McKenna.

  Traumatic brain injury (TBI) is leading cause of morbidity in young children. Acute dysregulation of oxidative glucose metabolism within the first hours after injury is a hallmark of TBI. The developing brain relies on ketones as well as glucose for energy. Thus, the aim of this study was to determine the metabolism of ketones early after TBI injury in the developing brain. Following the controlled cortical impact injury model of TBI, 21-22-day-old rats were infused with [2,4-13C]β-hydroxybutyrate during the acute (4 h) period after injury. Using ex vivo 13C-NMR spectroscopy, we determined that 13C-β-hydroxybutyrate (13C-BHB) metabolism was increased in both the ipsilateral and contralateral sides of the brain after TBI. Incorporation of the label was significantly higher in glutamate than glutamine, indicating that 13C-BHB metabolism was higher in neurons than astrocytes in both sham and injured brains. Our results show that (i) ketone metabolism was significantly higher in both the ipsilateral and contralateral sides of the injured brain after TBI; (ii) ketones were extensively metabolized by both astrocytes and neurons, albeit higher in neurons; (iii) the pyruvate recycling pathway determined by incorporation of the label from the metabolism of 13C-BHB into lactate was upregulated in the immature brain after TBI.

Keywords:  developing brain; ketone bodies; metabolism; traumatic brain injury; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/metabo12080710
Biochimie. 2022 Aug 20. pii: S0300-9084(22)00216-4. [Epub ahead of print]

Fatty acid sensing in the brain: The role of glia-neuronal metabolic crosstalk and horizontal lipid flux.

Nicholas Cleland, Kimberley D Bruce.

  The central control of energy homeostasis is a regulatory axis that involves the sensing of nutrients, signaling molecules, adipokines, and neuropeptides by neurons in the metabolic centers of the hypothalamus. However, non-neuronal glial cells are also abundant in the hypothalamus and recent findings have underscored the importance of the metabolic crosstalk and horizontal lipid flux between glia and neurons to the downstream regulation of systemic metabolism. New transgenic models and high-resolution analyses of glial phenotype and function has revealed that glia sit at the nexus between lipid metabolism and neural function, and therefore may markedly impact the brain's response to dietary lipids or the supply of brain-derived lipids. Glia comprise the main cellular compartment involved in lipid synthesis, lipoprotein production, and lipid processing in the brain. In brief, tanycytes provide an interface between peripheral lipids and neurons, astrocytes produce lipoproteins that transport lipids to neurons and other glia, oligodendrocytes use brain-derived and dietary lipids to myelinate axons and influence neuronal function, while microglia can remove unwanted lipids in the brain and contribute to lipid re-utilization through cholesterol efflux. Here, we review recent findings regarding glial-lipid transport and highlight the specific molecular factors necessary for lipid processing in the brain and, and how dysregulation of glial-neuronal metabolic crosstalk contributes to imbalanced energy homeostasis. Furthering our understanding of glial lipid metabolism will guide the design of future studies that target horizontal lipid processing in the brain to ameliorate the risk of developing obesity and metabolic disease.

Keywords:  Astrocytes; Fatty acids; Glia; Lipid; Metabolism; Microglia; Neurons; Tanycytes

DOI:  https://doi.org/10.1016/j.biochi.2022.08.012
Neurochem Res. 2022 Aug 23.

β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex Slices.

Jens V Andersen, Emil W Westi, Elliott S Neal, Blanca I Aldana, Karin Borges.

  Ketogenic diets and medium-chain triglycerides are gaining attention as treatment of neurological disorders. Their major metabolites, β-hydroxybutyrate (βHB) and the medium-chain fatty acids (MCFAs) octanoic acid (C8) and decanoic acid (C10), are auxiliary brain fuels. To which extent these fuels compete for metabolism in different brain cell types is unknown. Here, we used acutely isolated mouse cerebral cortical slices to (1) compare metabolism of 200 µM [U-13C]C8, [U-13C]C10 and [U-13C]βHB and (2) assess potential competition between metabolism of βHB and MCFAs by quantifying metabolite 13C enrichment using gas chromatography-mass spectrometry (GC-MS) analysis. The 13C enrichment in most metabolites was similar with [U-13C]C8 and [U-13C]C10 as substrates, but several fold lower with [U-13C]βHB. The 13C enrichment in glutamate was in a similar range for all three substrates, whereas the 13C enrichments in citrate and glutamine were markedly higher with both [U-13C]C8 and [U-13C]C10 compared with [U-13C]βHB. As citrate and glutamine are indicators of astrocytic metabolism, the results indicate active MCFA metabolism in astrocytes, while βHB is metabolized in a different cellular compartment. In competition experiments, 12C-βHB altered 13C incorporation from [U-13C]C8 and [U-13C]C10 in only a few instances, while 12C-C8 and 12C-C10 only further decreased the low [U-13C]βHB-derived 13C incorporation into citrate and glutamine, signifying little competition for oxidative metabolism between βHB and the MCFAs. Overall, the data demonstrate that βHB and MCFAs are supplementary fuels in different cellular compartments in the brain without notable competition. Thus, the use of medium-chain triglycerides in ketogenic diets is likely to be beneficial in conditions with carbon and energy shortages in both astrocytes and neurons, such as GLUT1 deficiency.

Keywords:  Astrocytes; Decanoic acid; Epilepsy; Ketone bodies; MCFA; Octanoic acid

DOI:  https://doi.org/10.1007/s11064-022-03726-6
Front Mol Biosci. 2022 ;9 892248

Analysis of Brain Lipids in the Early-Onset Tay-Sachs Disease Mouse Model With the Combined Deficiency of β-Hexosaminidase A and Neuraminidase 3.

Melike Can, Tugce Sengül, Secil Akyildiz Demir, Orhan K İnci, Hande Basırlı, Volkan Seyrantepe.

  Introduction: Tay-Sachs disease is an autosomal recessively inherited lysosomal storage disease that results from loss-of-function mutations in the HEXA gene coding β-hexosaminidase A. HEXA gene deficiency affects the central nervous system owing to GM2 ganglioside accumulation in lysosomes resulting in progressive neurodegeneration in patients. We recently generated a novel mice model with a combined deficiency of β-hexosaminidase A and neuraminidase 3 (Hexa-/-Neu3-/-) that mimics both the neuropathological and clinical abnormalities of early-onset Tay-Sachs disease. Here, we aimed to explore the secondary accumulation of lipids in the brain of Hexa-/-Neu3-/- mice. Materials and Methods: In the cortex and hippocampus of five-month-old WT, Hexa-/-, Neu3-/-, and Hexa-/-Neu3-/- mice, lipid levels belonging to glycerolipids, glycerophospholipids, and sterol lipids were evaluated using a shotgun lipidomics approach. The levels of myelin were also assessed by luxol fast blue staining and immunohistochemistry using antibodies against myelin basic protein. We further examined glycoconjugate and cholesterol levels by periodic acid-Schiff and filipin staining, respectively. Toluidine blue staining was also performed to display axonal degeneration. Results: Among glycerophospholipids, we demonstrated elevated levels of phosphatidylcholine-ether and lysophosphatidylcholine while decreased levels of phosphatidylcholine and phosphatidylserine in both cortex and hippocampus of Hexa-/-Neu3-/- mice. In the glycerolipid class, we showed an alleviated level of sphingomyelin in both cortex and hippocampus, but the higher levels of diacylglycerol and triacylglycerol were detected in only the hippocampus of Hexa-/-Neu3-/- mice. The lower level of sterol was also detected in the cortex of Hexa-/-Neu3-/- mice but not in the hippocampus. Histochemical studies showed a decrease in the myelin level and axonal degeneration indicating neuronal pathology in the brain of Hexa-/-Neu3-/- mice. Although glycoconjugate accumulation was evident both in the cortex and hippocampus, we did not detect any changes in the level of cholesterol. Conclusion: Our results indicate that alterations in lipid metabolism and neuropathology, such as demyelination and axonal degeneration, might be related to the dysfunctionality of lipid-related cellular pathways like autophagy. Understanding of brain-specific lipid alterations contributes to evaluating the effectiveness of treatments in Hexa-/-Neu3-/- mice in future studies.

Keywords:  Tay–Sachs disease; brain; gangliosides; lipidomics; mouse model

DOI:  https://doi.org/10.3389/fmolb.2022.892248
Sci Rep. 2022 Aug 23. 12(1): 14355

Brief exposure of neuronal cells to levels of SCFAs observed in human systemic circulation impair lipid metabolism resulting in apoptosis.

Tiffany A Fillier, Shrushti Shah, Karen M Doody, Thu H Pham, Isabelle Aubry, Michel L Tremblay, Sukhinder K Cheema, Jacqueline Blundell, Raymond H Thomas.

Communication between gut microbiota and the brain is an enigma. Alterations in the gut microbial community affects enteric metabolite levels, such as short chain fatty acids (SCFAs). SCFAs have been proposed as a possible mechanism through which the gut microbiome modulate brain health and function. This study analyzed for the first time the effects of SCFAs at levels reported in human systemic circulation on SH-SY5Y human neuronal cell energy metabolism, viability, survival, and the brain lipidome. Cell and rat brain lipidomics was done using high resolution mass spectrometry (HRMS). Neuronal cells viability, survival and energy metabolism were analyzed via flow cytometer, immunofluorescence, and SeahorseXF platform. Lipidomics analysis demonstrated that SCFAs significantly remodeled the brain lipidome in vivo and in vitro. The most notable remodulation was observed in the metabolism of phosphatidylethanolamine plasmalogens, and mitochondrial lipids carnitine and cardiolipin. Increased mitochondrial mass, fragmentation, and hyperfusion occurred concomitant with the altered mitochondrial lipid metabolism resulting in decreased neuronal cell respiration, adenosine triphosphate (ATP) production, and increased cell death. This suggests SCFAs at levels observed in human systemic circulation can adversely alter the brain lipidome and neuronal cell function potentially negatively impacting brain health outcomes.

DOI: https://doi.org/10.1038/s41598-022-18363-w
Adv Exp Med Biol. 2022 ;1382 109-118

Mitochondrial Dysregulation and the Influence in Neurodegenerative Diseases.

Giuliana S Zuccoli, Victor Corasolla Carregari.

  Mitochondrial function is essential to ensure vital cellular processes. Given the energy requirement of the brain, neuronal function, viability, and survival are closely related to proper mitochondrial function. Dysregulation of mitochondrial processes can lead to several detrimental effects in the cells and stablish the condition of mitochondrial dysfunction. This dysfunction is proposed to be greatly implicated in several neurodegenerative diseases, with evidence of compromised mitochondrial function and dynamics in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Keywords:  Brain metabolism; Mitochondrial dysfunction; Neurogenerative diseases; Proteomics

DOI:  https://doi.org/10.1007/978-3-031-05460-0_8
Neuropsychopharmacology. 2022 Aug 22.

Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults.

Antoine Hone-Blanchet, Botond Antal, Liam McMahon, Andrew Lithen, Nathan A Smith, Steven Stufflebeam, Yi-Fen Yen, Alexander Lin, Bruce G Jenkins, Lilianne R Mujica-Parodi, Eva-Maria Ratai.

Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (D-βHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of D-βHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of D-βHB compared to active control glucose (N = 26). Effect of age and blood levels of D-βHB and glucose were used to further explore the effect of D-βHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of D-βHB. Importantly, the effect was specific to D-βHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of D-βHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.

DOI: https://doi.org/10.1038/s41386-022-01364-8
Front Cell Neurosci. 2022 ;16 959598

Mitochondrial behavior when things go wrong in the axon.

Victorio M Pozo Devoto, Isaac G Onyango, Gorazd B Stokin.

  Axonal homeostasis is maintained by processes that include cytoskeletal regulation, cargo transport, synaptic activity, ionic balance, and energy supply. Several of these processes involve mitochondria to varying degrees. As a transportable powerplant, the mitochondria deliver ATP and Ca2+-buffering capabilities and require fusion/fission to maintain proper functioning. Taking into consideration the long distances that need to be covered by mitochondria in the axons, their transport, distribution, fusion/fission, and health are of cardinal importance. However, axonal homeostasis is disrupted in several disorders of the nervous system, or by traumatic brain injury (TBI), where the external insult is translated into physical forces that damage nervous tissue including axons. The degree of damage varies and can disconnect the axon into two segments and/or generate axonal swellings in addition to cytoskeletal changes, membrane leakage, and changes in ionic composition. Cytoskeletal changes and increased intra-axonal Ca2+ levels are the main factors that challenge mitochondrial homeostasis. On the other hand, a proper function and distribution of mitochondria can determine the recovery or regeneration of the axonal physiological state. Here, we discuss the current knowledge regarding mitochondrial transport, fusion/fission, and Ca2+ regulation under axonal physiological or pathological conditions.

Keywords:  axonal degeneration; calcium homeostasis; mitochondria; mitochondrial dynamics; mitochondrial transport; traumatic brain injury

DOI:  https://doi.org/10.3389/fncel.2022.959598
Neural Regen Res. 2023 Mar;18(3): 568-576

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice.

Lu-Yao Li, Qi Wang, Lu Deng, Zhen Lin, Jing-Jing Lin, Xin-Ye Wang, Tian-Yang Shen, Yi-Hui Zheng, Wei Lin, Pei-Jun Li, Xiao-Qin Fu, Zhen-Lang Lin.

  Recent studies have shown that chlorogenic acid (CGA), which is present in coffee, has protective effects on the nervous system. However, its role in neonatal hypoxic-ischemic brain injury remains unclear. In this study, we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA. We found that CGA intervention effectively reduced the volume of cerebral infarct, alleviated cerebral edema, restored brain tissue structure after injury, and promoted axon growth in injured brain tissue. Moreover, CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival. In addition, changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA. Furthermore, CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2. In summary, our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis, providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Keywords:  chlorogenic acid; ferroptosis; glutathione peroxidase 4; lipid peroxidation; neonatal hypoxic-ischemic brain injury; neurons; neuroprotection; oxidative stress; oxygen-glucose deprivation; system Xc–

DOI:  https://doi.org/10.4103/1673-5374.350203
Nat Metab. 2022 Aug;4(8): 965-966

Who knew? PPARs may act in the brain too.

Randy J Seeley, Christopher J Rhodes.

DOI: https://doi.org/10.1038/s42255-022-00625-6
J Neurosci. 2022 Aug 19. pii: JN-RM-0193-22. [Epub ahead of print]

Glycerol-3-phosphate shuttle is a backup system securing metabolic flexibility in neurons.

Ankit Dhoundiyal, Vanessa Goeschl, Stefan Boehm, Helmut Kubista, Matej Hotka.

Electrical activity in neurons is highly energy demanding and accompanied by rises in cytosolic Ca2+ Cytosolic Ca2+, in turn, secures energy supply by pushing mitochondrial metabolism either through augmented NADH transfer into mitochondria via the malate aspartate shuttle (MAS) or via direct activation of dehydrogenases of the TCA cycle after passing into the matrix through the mitochondrial Ca2+ uniporter (MCU). Another Ca2+-sensitive booster of mitochondrial ATP synthesis is the glycerol-3-phosphate shuttle (G3PS) whose role in neuronal energy supply has remained elusive. Essential components of G3PS are expressed in hippocampal neurons. Single neuron metabolic measurements in primary hippocampal cultures derived from rat pups of either sex reveal only moderate, if any, constitutive activity of G3PS. However, during electrical activity neurons fully rely on G3PS when MAS and MCU are unavailable. Under these conditions, G3PS is required for appropriate action potential firing. Accordingly, G3PS safeguards metabolic flexibility of neurons to cope with energy demands of electrical signaling.SIGNIFICANCE STATEMENT:Ca2+ ions are known to provide a link between the energy-demanding electrical activity and an adequate ATP supply in neurons. To do so, Ca2+ acts both, from outside and inside of the mitochondrial inner membrane. Neuronal function critically depend on this regulation and its defects are often found in various neurological disorders. Although interest in neuronal metabolism increases, many aspects thereof have remained unresolved. In particular, a Ca2+-sensitive NADH shuttling system, the glycerol-3-phosphate shuttle, has been largely ignored with respect to its function in neurons. Our results demonstrate that this shuttle is functional in hippocampal neurons and safeguards ATP supply and appropriate action potential firing when malate aspartate shuttle and mitochondrial Ca2+ uniporter are unavailable, thereby ensuring neuronal metabolic flexibility.

DOI: https://doi.org/10.1523/JNEUROSCI.0193-22.2022
Biomedicines. 2022 Aug 12. pii: 1956. [Epub ahead of print]10(8):

Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer's Disease.

Md Riad Chowdhury, Hee Kyung Jin, Jae-Sung Bae.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, failure of neurotransmission, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed many therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as distinctive mediators to be associated with the pathology of AD. Reportedly, alteration in the metabolism of sphingolipids and their metabolites result in the dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates AD progression. Considering the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Herein, we describe the ceramide synthesis pathway and its involvement in the dysregulation of homeostasis, which eventually leads to AD. Furthermore, this review references different therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent the disease progression.

Keywords:  Alzheimer’s disease; amyloid beta; autophagy; ceramide; mitochondrial dysfunction; senescence

DOI:  https://doi.org/10.3390/biomedicines10081956
Int J Mol Sci. 2022 Aug 19. pii: 9356. [Epub ahead of print]23(16):

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer's Disease Pathogenesis.

Carla Borràs, Aina Mercer, Sònia Sirisi, Daniel Alcolea, Joan Carles Escolà-Gil, Francisco Blanco-Vaca, Mireia Tondo.

  The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer's disease (AD). Alzheimer's disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

Keywords:  Alzheimer’s disease; HDL; apolipoprotein E; central nervous system; cholesterol efflux; cholesterol trafficking; dementia

DOI:  https://doi.org/10.3390/ijms23169356
Brain Commun. 2022 ;4(4): fcac202

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.

Jeremy J Laukka, Kevin M Kain, Anirudha S Rathnam, Jasloveleen Sohi, Dalal Khatib, John Kamholz, Jeffrey A Stanley.

  Pelizaeus-Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus-Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus-Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus-Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus-Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus-Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus-Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus-Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus-Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus-Merzbacher disease.

Keywords:  Pelizaeus–Merzbacher disease; biochemistry; high-energy phosphate; membrane phospholipids; phosphorus magnetic resonance spectroscopy

DOI:  https://doi.org/10.1093/braincomms/fcac202
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Aug 18. pii: S1388-1981(22)00112-3. [Epub ahead of print] 159222

Formation of N-acyl-phosphatidylethanolamines by cytosolic phospholipase A2ε in an ex vivo murine model of brain ischemia.

S M Khaledur Rahman, Zahir Hussain, Katsuya Morito, Naoko Takahashi, Mohammad Mamun Sikder, Tamotsu Tanaka, Ken-Ichi Ohta, Masaki Ueno, Hiroo Takahashi, Tohru Yamamoto, Makoto Murakami, Toru Uyama, Natsuo Ueda.

  N-Acyl-phosphatidylethanolamines (NAPEs), a minor class of membrane glycerophospholipids, accumulate along with their bioactive metabolites, N-acylethanolamines (NAEs) during ischemia. NAPEs can be formed through N-acylation of phosphatidylethanolamine by cytosolic phospholipase A2ε (cPLA2ε, also known as PLA2G4E) or members of the phospholipase A and acyltransferase (PLAAT) family. However, the enzyme responsible for the NAPE production in brain ischemia has not yet been clarified. Here, we investigated a possible role of cPLA2ε using cPLA2ε-deficient (Pla2g4e-/-) mice. As analyzed with brain homogenates of wild-type mice, the age dependency of Ca2+-dependent NAPE-forming activity showed a bell-shape pattern being the highest at the first week of postnatal life, and the activity was completely abolished in Pla2g4e-/- mice. However, liquid chromatography-tandem mass spectrometry revealed that the NAPE levels of normal brain were similar between wild-type and Pla2g4e-/- mice. In contrast, post-mortal accumulations of NAPEs and most species of NAEs were only observed in decapitated brains of wild-type mice. These results suggested that cPLA2ε is responsible for Ca2+-dependent formation of NAPEs in the brain as well as the accumulation of NAPEs and NAEs during ischemia, while other enzyme(s) appeared to be involved in the maintenance of basal NAPE levels.

Keywords:  Brain ischemia; Endocannabinoid; N-acyl-phosphatidylethanolamine; N-acylethanolamine; N-acyltransferase; Phospholipase A(2)

DOI:  https://doi.org/10.1016/j.bbalip.2022.159222
Biomedicines. 2022 Aug 11. pii: 1943. [Epub ahead of print]10(8):

Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.

Yongjun Kou, Feng Geng, Deliang Guo.

  Glioblastoma (GBM) is the most lethal primary brain tumor. With limited therapeutic options, novel therapies are desperately needed. Recent studies have shown that GBM acquires large amounts of lipids for rapid growth through activation of sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that regulates fatty acid and cholesterol synthesis, and cholesterol uptake. Interestingly, GBM cells divert substantial quantities of lipids into lipid droplets (LDs), a specific storage organelle for neutral lipids, to prevent lipotoxicity by increasing the expression of diacylglycerol acyltransferase 1 (DGAT1) and sterol-O-acyltransferase 1 (SOAT1), which convert excess fatty acids and cholesterol to triacylglycerol and cholesteryl esters, respectively. In this review, we will summarize recent progress on our understanding of lipid metabolism regulation in GBM to promote tumor growth and discuss novel strategies to specifically induce lipotoxicity to tumor cells through disrupting lipid storage, a promising new avenue for treating GBM.

Keywords:  DGAT1; SOAT1; SREBP-1; cholesterol; fatty acids; glioblastoma; lipid droplets; lipotoxicity

DOI:  https://doi.org/10.3390/biomedicines10081943
Immunometabolism (Cobham). 2022 Jul;4(3): e00001

Fatty acid translocase: a culprit of lipid metabolism dysfunction in disease.

Joseph E Rupert, Mikhail G Kolonin.

  Dysregulation of lipid deposition into and mobilization from white adipose tissue (WAT) underlies various diseases. Long-chain fatty acids (LCFA) and cholesterol trafficking in and out of adipocytes is a process relying on transporters shuttling lipids from the plasma membrane (PM) to lipid droplets (LD). CD36 is the fatty acid translocase (FAT) that transports LCFA and cholesterol across the PM. Interactions of CD36 with proteins PHB1, ANX2, and CAV1 mediate intercellular lipid transport between adipocytes, hematopoietic, epithelial, and endothelial cells. Intracellularly, the FAT complex has been found to regulate LCFA trafficking between the PM and LD. This process is regulated by CD36 glycosylation and S-acylation, as well as by post-translational modifications of PHB1 and ANX2, which determine both protein-protein interactions and the cellular localization of the complex. Changes in extracellular and intracellular LCFA levels have been found to induce the post-translational modifications and the function of the FAT complex in lipid uptake and mobilization. The role of the CD36/PHB1/ANX2 complex may span beyond lipid trafficking. The requirement of PHB1 for mitochondrial oxidative metabolism in brown adipocytes has been revealed. Cancer cells which take advantage of lipids mobilized by adipocytes and oxidized in leukocytes are indirectly affected by the function of FAT complex in other tissues. The direct importance of CD36 interaction with PHB1/and ANX2 in cancer cells remains to be established. This review highlights the multifaceted roles of the FAT complex in systemic lipid trafficking and discuss it as a potential target in metabolic disease and cancer.

Keywords:  fatty acid translocase; lipid metabolism

DOI:  https://doi.org/10.1097/IN9.0000000000000001
Front Neurosci. 2022 ;16 957034

Stretch stress propels glutamine dependency and glycolysis in optic nerve head astrocytes.

Nathaniel Pappenhagen, Eric Yin, Autumn B Morgan, Charles C Kiehlbauch, Denise M Inman.

  Glaucoma is an optic neuropathy that leads to irreversible blindness, the most common subtype of which is typified by a chronic increase in intraocular pressure that promotes a stretch injury to the optic nerve head. In rodents, the predominant glial cell in this region is the optic nerve head astrocyte that provides axons with metabolic support, likely by releasing lactate produced through astrocytic glycolysis. Our primary hypothesis is that stretching of the optic nerve head astrocytes alters their metabolic activity, thereby advancing glaucoma-associated degeneration by compromising the metabolic support that the astrocytes provide to the axons in the optic nerve head. Metabolic changes in optic nerve head astrocytes were investigated by subjecting them to 24 h of 12% biaxial stretch at 1 Hz then measuring the cells' bioenergetics using a Seahorse XFe24 Analyzer. We observed significant glycolytic and respiratory activity differences between control and stretched cells, including greater extracellular acidification and lower ATP-linked respiration, yet higher maximal respiration and spare capacity in stretched optic nerve head astrocytes. We also determined that both control and stretched optic nerve head astrocytes displayed a dependency for glutamine over pyruvate or long-chain fatty acids for fuel. The increased use of glycolysis as indicated by the extracellular acidification rate, concomitant with a dependency on glutamine, suggests the need to replenish NAD + for continued glycolysis and provision of carbon for TCA cycle intermediates. Stretch alters optic nerve astrocyte bioenergetics to support an increased demand for internal and external energy.

Keywords:  astrocyte; glaucoma; glycolysis; metabolism; optic nerve head

DOI:  https://doi.org/10.3389/fnins.2022.957034
Front Aging Neurosci. 2022 ;14 981868

Serine ether glycerophospholipids: Decrements in the frontal cortex associated with mild cognitive impairment and Alzheimer's disease.

Paul L Wood, Randall L Woltjer.

  Ether glycerophospholipids (GPL) are involved in membrane fluidity and fusion. Vinyl-ether GPL are also conjectured to provide antioxidant capacity in the brain. The roles of these lipids in the processes involved in the development of dementia are not understood but choline and ethanolamine vinyl-ether GPL (i.e., plasmalogens) are decreased in the brains of subjects with dementia. In contrast, serine ether and vinyl-ether GPL have not been investigated in human brain. We therefore undertook an evaluation of these lipids, utilizing high-resolution mass spectrometry (HR-MS), in tissues from control and dementia subjects that we had previously characterized in-depth. We can report for the first time that a number of serine ether GPL and a more limited number of serine plasmalogens are present in human frontal cortex. In addition, we found that some of these frontal cortex lipids are decreased in Mild Cognitive Impairment (MCI), early-onset Alzheimer's disease (EOAD), and late-onset AD (LOAD). In contrast no alterations in serine ether GPL were monitored in the frontal cortex of donors with schizophrenia, demonstrating disease specificity. These data suggest that further studies of the roles of ether GPL, including serine ether GPL, in brain function are worthy of undertaking.

Keywords:  Alzheimer’s; MCI; dementia; frontal cortex; serine ether glycerophospholipid

DOI:  https://doi.org/10.3389/fnagi.2022.981868
J Biol Chem. 2022 Aug 22. pii: S0021-9258(22)00854-7. [Epub ahead of print] 102411

ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex.

Jahangir Iqbal, Manuel D Suarez, Pradeep K Yadav, Meghan T Walsh, Yimeng Li, Yiyang Wu, Zhengwei Huang, Antonisamy William James, Victor Escobar, Ashwag Mokbe, Adam M Brickman, José A Luchsinger, Kezhi Dai, Herman Moreno, M Mahmood Hussain.

  Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer's disease (LOAD) across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with wild type (WT), had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical layer II/III lateral entorhinal cortex synapse but not in the hippocampal synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation, but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and LOAD.

Keywords:  ABCA7; Alzheimer disease; lipids; sphingolipids; sphingomyelin

DOI:  https://doi.org/10.1016/j.jbc.2022.102411
Front Aging Neurosci. 2022 ;14 975176

Phosphatidylserine, inflammation, and central nervous system diseases.

Xiaohua Ma, Xiaojing Li, Wenjuan Wang, Meng Zhang, Bo Yang, Zhigang Miao.

  Phosphatidylserine (PS) is an anionic phospholipid in the eukaryotic membrane and is abundant in the brain. Accumulated studies have revealed that PS is involved in the multiple functions of the brain, such as activation of membrane signaling pathways, neuroinflammation, neurotransmission, and synaptic refinement. Those functions of PS are related to central nervous system (CNS) diseases. In this review, we discuss the metabolism of PS, the anti-inflammation function of PS in the brain; the alterations of PS in different CNS diseases, and the possibility of PS to serve as a therapeutic agent for diseases. Clinical studies have showed that PS has no side effects and is well tolerated. Therefore, PS and PS liposome could be a promising supplementation for these neurodegenerative and neurodevelopmental diseases.

Keywords:  central nervous system disease; neurotransmission; phosphatidylserine; phosphatidylserine liposomes; synaptic refinement

DOI:  https://doi.org/10.3389/fnagi.2022.975176
Metabolites. 2022 Jul 29. pii: 712. [Epub ahead of print]12(8):

Glucose Metabolism Disorders: Challenges and Opportunities for Diagnosis and Treatment.

Jelena Vekic, José Silva-Nunes, Manfredi Rizzo.

Alterations of glucose metabolism are recognized as one of the most important risk factors for the development and complications of cardiometabolic diseases [...].

DOI: https://doi.org/10.3390/metabo12080712
Life (Basel). 2022 Jul 30. pii: 1164. [Epub ahead of print]12(8):

Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild-Moderate Neonatal Hypoxia-Ischemia Brain Injury Model.

Anne Ehlting, Margit Zweyer, Elke Maes, Yvonne Schleehuber, Hardik Doshi, Hemmen Sabir, Maria Eugenia Bernis.

  Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2-3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3-10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate-severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild-moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild-moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild-moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild-moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild-moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

Keywords:  BrdU; MRI; behavior testing; hypothermia; hypoxia-ischemia; mild HIE; neonatal; neurogenesis

DOI:  https://doi.org/10.3390/life12081164
Nutrients. 2022 Aug 10. pii: 3273. [Epub ahead of print]14(16):

Relevance of ω-6 GLA Added to ω-3 PUFAs Supplements for ADHD: A Narrative Review.

Jelle D'Helft, Riccardo Caccialanza, Emma Derbyshire, Michael Maes.

  The use of polyunsaturated fatty acids in Attention-Deficit/Hyperactivity Disorder (ADHD) and developmental disorders has been gaining interest with preparations containing different dosages and combinations. Gamma-linolenic acid (GLA) is an ω-6 fatty acid of emerging interest with potential roles as an adjuvant anti-inflammatory agent that could be used with ω-3 PUFAs in the treatment of ADHD and associated symptoms. A narrative review was undertaken to examine the potential role(s) of the ω-6 fatty acid GLA. PubMed, Google Scholar, and Scopus were searched to examine the potential role(s) of the ω-6 fatty acid GLA as (1) an antioxidant and anti-inflammatory agent, (2) a synergistic nutrient when combined with ω-3 PUFAs, and (3) a potential etiological factor in ADHD and its treatment. The results show that GLA exerts anti-inflammatory effects by increasing dihomo-gamma-linolenic acid in immune cells. ω-3 PUFAs, such as EPA and DHA, are often co-administered with GLA because these ω-3 PUFAs may prevent the accumulation of serum arachidonic acid in response to GLA administration without limiting the storage of DGLA in immune cells. The administration of ω-3 PUFAs alone might not be sufficient to effectively treat patients with ADHD and developmental disorders. Overall studies point towards a combination of EPA and DHA with GLA in a 9:3:1 ratio appearing to be associated with ADHD symptom improvement. A combination of PUFAs may lead to better outcomes.

Keywords:  attention deficit hyperactivity disorder (ADHD); brain function; brain structure; cognition; developmental; difference; gamma-linolenic acid (GLA); hyperactivity; neuro-immune; neuroinflammatory; oxidative stress; wellbeing; ω-3 PUFAs

DOI:  https://doi.org/10.3390/nu14163273