bims-medebr 2024-10-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–10–27
eleven papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes.
Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.
Role of ACSBG1 in Brain Lipid Metabolism and X-Linked Adrenoleukodystrophy Pathogenesis: Insights from a Knockout Mouse Model.
Lipid Compositions of Liquid-Ordered and Liquid-Disordered Phases in Ternary Membranes of Sphingomyelin, Cholesterol, and Dioleoylphosphatidylcholine Determined by 2H NMR: Stearoyl-Sphingomyelin Compared with Its Palmitoyl Counterpart.
Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease.
Supplemental Oxygen Alters the Pentose Phosphate Pathway in the Developing Mouse Brain Through SIRT Signaling.
Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
Cerebral net uptake of lactate contributes to neurological injury after experimental cardiac arrest in rabbits.
Multiomics approach discloses lipids and metabolites profiles associated to Parkinson's disease stages and applied therapies.
Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.
Glia dysfunction in schizophrenia: evidence of possible therapeutic effects of nervonic acid in a preclinical model.

Cells. 2024 Oct 17. pii: 1714. [Epub ahead of print]13(20):

Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes.

Polina Shichkova, Jay S Coggan, Henry Markram, Daniel Keller.

  The regulation of energy in the brain has garnered substantial attention in recent years due to its significant implications in various disorders and aging. The brain's energy metabolism is a dynamic and tightly regulated network that balances energy demand and supply by engaging complementary molecular pathways. The crosstalk among these pathways enables the system to switch its preferred fuel source based on substrate availability, activity levels, and cell state-related factors such as redox balance. Brain energy production relies on multi-cellular cooperation and is continuously supplied by fuel from the blood due to limited internal energy stores. Astrocytes, which interface with neurons and blood vessels, play a crucial role in coordinating the brain's metabolic activity, and their dysfunction can have detrimental effects on brain health. This review characterizes the major energy substrates (glucose, lactate, glycogen, ketones and lipids) in astrocyte metabolism and their role in brain health, focusing on recent developments in the field.

Keywords:  astrocyte; brain aging; brain energy metabolism; brain glucose; brain glycogen; brain ketones; brain lactate; neurodegeneration

DOI:  https://doi.org/10.3390/cells13201714
Alzheimers Dement. 2024 Oct 22.

Comparative brain metabolomics reveals shared and distinct metabolic alterations in Alzheimer's disease and progressive supranuclear palsy.

Alzheimer's Disease Metabolomics Consortium (ADMC)

   BACKGROUND: Metabolic dysregulation is a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). Although metabolic dysregulation is a common link between these two tauopathies, a comprehensive brain metabolic comparison of the diseases has not yet been performed.
METHODS: We analyzed 342 postmortem brain samples from the Mayo Clinic Brain Bank and examined 658 metabolites in the cerebellar cortex and the temporal cortex between the two tauopathies.
RESULTS: Our findings indicate that both diseases display oxidative stress associated with lipid metabolism, mitochondrial dysfunction linked to lysine metabolism, and an indication of tau-induced polyamine stress response. However, specific to AD, we detected glutathione-related neuroinflammation, deregulations of enzymes tied to purines, and cognitive deficits associated with vitamin B.
DISCUSSION: Our findings underscore vast alterations in the brain's metabolome, illuminating shared neurodegenerative pathways and disease-specific traits in AD and PSP.
HIGHLIGHTS: First high-throughput metabolic comparison of Alzheimer's diesease (AD) versus progressive supranuclear palsy (PSP) in brain tissue. Cerebellar cortex (CER) shows substantial AD-related metabolic changes, despite limited proteinopathy. AD impacts both CER and temporal cortex (TCX); PSP's changes are primarily in CER. AD and PSP share metabolic alterations despite major pathological differences.

Keywords:  Alzheimer's disease; brain; cognitive deficit; metabolism; mitochondrial dysfunction; neuroinflammation; oxidative stress; progressive supranuclear palsy; tau‐mediated stress

DOI:  https://doi.org/10.1002/alz.14249
Cells. 2024 Oct 12. pii: 1687. [Epub ahead of print]13(20):

Role of ACSBG1 in Brain Lipid Metabolism and X-Linked Adrenoleukodystrophy Pathogenesis: Insights from a Knockout Mouse Model.

Xiaoli Ye, Yuanyuan Li, Domingo González-Lamuño, Zhengtong Pei, Ann B Moser, Kirby D Smith, Paul A Watkins.

  "Bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during mouse brain development, facilitating the activation of long-chain fatty acids (LCFA) and their incorporation into lipid species that are crucial for brain function. ACSBG1 converts LCFA into acyl-CoA derivatives, supporting vital metabolic processes. Fruit fly mutants lacking ACSBG1 exhibited neurodegeneration and had elevated levels of very long-chain fatty acids (VLCFA), characteristics of human X-linked adrenoleukodystrophy (XALD). To explore ACSBG1's function and potential as a therapeutic target in XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse and examined the effects on brain FA metabolism during development. Phenotypically, Acsbg1-/- mice resembled wild type (w.t.) mice. ACSBG1 expression was found mainly in tissue affected pathologically in XALD, namely the brain, adrenal gland and testis. ACSBG1 depletion did not significantly reduce the total ACS enzyme activity in these tissue types. In adult mouse brain, ACSBG1 expression was highest in the cerebellum; the low levels detected during the first week of life dramatically increased thereafter. Unexpectedly, lower, rather than higher, saturated VLCFA levels were found in cerebella from Acsbg1-/- vs. w.t. mice, especially after one week of age. Developmental changes in monounsaturated ω9 FA and polyunsaturated ω3 FA levels also differed between w.t. and Acsbg1-/- mice. ACSBG1 deficiency impacted the developmental expression of several cerebellar FA metabolism enzymes, including those required for the synthesis of ω3 polyunsaturated FA, precursors of bioactive signaling molecules like eicosanoids and docosanoids. These changes in membrane lipid FA composition likely affect membrane fluidity and may thus influence the body's response to inflammation. We conclude that, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD, decreasing its potential as a therapeutic target. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

Keywords:  ACSBG1; X-linked adrenoleukodystrophy; brain fatty acid levels; bubblegum; eicosanoids and docosanoids; inflammation; membrane fluidity; very long-chain fatty acid

DOI:  https://doi.org/10.3390/cells13201687
Langmuir. 2024 Oct 21.

Lipid Compositions of Liquid-Ordered and Liquid-Disordered Phases in Ternary Membranes of Sphingomyelin, Cholesterol, and Dioleoylphosphatidylcholine Determined by 2H NMR: Stearoyl-Sphingomyelin Compared with Its Palmitoyl Counterpart.

Shinya Hanashima, Ayana Yamanaka, Yuki Ibata, Tomokazu Yasuda, Yuichi Umegawa, Michio Murata.

Sphingomyelin (SM) and cholesterol are the major lipids in the signaling platforms of cell membranes, known as lipid rafts. In particular, SM with a stearoyl chain (C18-SM) is abundant in specific tissues such as the brain, the most cholesterol-rich organ, whereas the distribution of palmitoyl (C16)-SM is ubiquitous. Here, we reveal the differences between palmitoyl- and stearoyl-SM in lipid-lipid interactions based on the tie lines obtained from the 2H solid-state NMR spectra of bilayer systems composed of SM/dioleoylphosphatidylcholine/cholesterol 33:33:33 and 40:40:20. Lipid probes carrying position-selective deuterations, 10',10'-d2-SM, 24-d1-cholesterol, and 6″,6″-d2-dioleoyl-phosphatidylcholine, were incorporated into the membranes. 2H NMR peaks from these probes in the membranes directly provide the lipid compositions of the liquid-ordered (Lo) and liquid-disordered (Ld) regions. Without using bulky fluorescent groups, these probes allow us to obtain the end points of the tie lines in a ternary phase diagram based on the lever rule. Consequently, the tie lines of the stearoyl-SM membranes were steeper than those of the palmitoyl-SM membranes, indicating that cholesterol content was higher in the Lo domains of stearoyl-SM, regardless of the total concentration of unsaturated phospholipids. When comparing the content of unsaturated lipids in the Lo domain, the stearoyl-SM membranes had a higher content than palmitoyl-SM membranes. These results revealed that stearoyl-SM is suitable for stabilizing biologically functional microdomains in cholesterol-rich organs, whereas palmitoyl-SM may be better suited for stabilizing domains in tissue membranes with normal cholesterol content. The small but significant differences in the lipid interactions between stearoyl-SM and palmitoyl-SM may be related to the spatiotemporal formation of functional domains in biological environments.

DOI: https://doi.org/10.1021/acs.langmuir.4c03104
Neurobiol Dis. 2024 Oct 22. pii: S0969-9961(24)00315-2. [Epub ahead of print] 106713

Sphingosine 1-phosphate receptor subtype 1 (S1P1) activity in the course of Alzheimer's disease.

Jonatan Martínez-Gardeazabal, Gorka Pereira-Castelo, Marta Moreno-Rodríguez, Alberto Llorente-Ovejero, Manuel Fernández, Iván Fernández-Vega, Iván Manuel, Rafael Rodríguez-Puertas.

  Some specific lipid molecules in the brain act as signaling molecules, neurotransmitters, or neuromodulators, by binding to specific G protein-coupled receptors (GPCR) for neurolipids. One such receptor, sphingosine 1-phosphate receptor subtype 1 (S1P1), is coupled to Gi/o proteins and is involved in cell proliferation, growth, and neuroprotection. S1P1 constitutes an interesting target for neurodegenerative diseases like multiple sclerosis and Alzheimer's disease (AD), in which changes in the sphingolipid metabolism have been observed. This study analyzes S1P1 receptor-mediated activity in healthy brains and during AD progression using postmortem samples from controls and patients at different Braak's stages. Additionally, the distribution of S1P1 receptor activity in human brains is compared to that in commonly used rodent models, rats and mice, through functional autoradiography, measuring [35S]GTPγS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to obtain the distribution of functional activity of S1P1 receptors. S1P1 receptor-mediated activity, along with that of the cannabinoid CB1 receptor, is one of the highest recorded for any GPCR in many gray matter areas of the brain, reaching maximum values in the cerebellar cortex, specific areas of the hippocampus and the basal forebrain. S1P1 signaling is crucial in areas that regulate learning, memory, motor control, and nociception, such as the basal forebrain and basal ganglia. In AD, S1P1 receptor activity is increased in the inner layers of the frontal cortex and underlying cortical white matter at early stages, but decreases in the hippocampus in advanced stages, indicating ongoing brain impairment. Importantly, we identified significant correlations between S1P1 receptor activity and Braak stages, suggesting that S1P1 receptor dysfunction is associated to disease progression, particularly in memory-related regions. The S1P signaling via S1P1 receptor is a promising neurological target due to its role in key neurophysiological functions and its potential to modify the progression of neurodegenerative diseases. Finally, rats are suggested as a preferred experimental model for studying S1P1 receptor-mediated responses in the human brain.

Keywords:  Alzheimer's disease; Brain; Human; Mapping; Rodents; S1P(1) receptor; [(35)S]GTPγS

DOI:  https://doi.org/10.1016/j.nbd.2024.106713
Neurochem Int. 2024 Oct 20. pii: S0197-0186(24)00213-4. [Epub ahead of print] 105886

Supplemental Oxygen Alters the Pentose Phosphate Pathway in the Developing Mouse Brain Through SIRT Signaling.

Defne Engur, Serap Cilaker Micili, Sila Soy, Gökcen Bilici, Kemal Ugur Tufekci, Cagla Kiser, İlkcan Ercan, Abdullah Kumral, Sermin Genc.

  Oxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood. PURPOSE: of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out. Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.

Keywords:  Hyperoxia; Newborn; Oxygen; Pentose phosphate pathway; SIRT

DOI:  https://doi.org/10.1016/j.neuint.2024.105886
Commun Biol. 2024 Oct 22. 7(1): 1373

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.

Seda Yasa, Elisabeth S Butz, Alessio Colombo, Uma Chandrachud, Luca Montore, Sarah Tschirner, Matthias Prestel, Steven D Sheridan, Stephan A Müller, Janos Groh, Stefan F Lichtenthaler, Sabina Tahirovic, Susan L Cotman.

Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.

DOI: https://doi.org/10.1038/s42003-024-07057-w
Sci Rep. 2024 10 19. 14(1): 24600

Cerebral net uptake of lactate contributes to neurological injury after experimental cardiac arrest in rabbits.

Faucher Estelle, Demelos Alexandra, Boissady Emilie, Abi Zeid Daou Yara, Fanny Lidouren, Bernard Vigué, Rodrigues Aurore, Ghaleh Bijan, Tissier Renaud, Matthias Kohlhauer.

  During focal ischemia, neurons can use lactate as an alternative source of energy through its oxidation into pyruvate by the lactate dehydrogenase (LDH). After cardiac arrest, the neurological consequences of this phenomenon are unknown. Experimental study. Experimental laboratory. Male New-Zealand rabbits. Animals were surgically instrumented and randomly divided into five groups receiving short infusion duration of either lactate or pyruvate or a pre-cardiac arrest infusion of oxamate (an inhibitor of the lactate dehydrogenase) or injection of fluorocitrate (an inhibitor of astrocytic tricarboxylic acid), or Saline (lactate, pyruvate, Oxa, FC and Control groups, respectively). After randomization, animals were submitted to 10 min of ventricular fibrillation and subsequent resuscitation. All animals were then either followed during 4 h, for the evaluation of the cerebral net uptake and concentrations of metabolites by microdialysis (n = 6 in each experimental group, n = 12 in control group), or during 48 h for the evaluation of their neurological outcome (n = 7 in each groups and n = 14 in control group). Cardiac arrest was associated with a dramatic increase in cerebral net uptake of lactate during 120 min after resuscitation, which was increased by lactate or pyruvate administration. This was associated with an increase in the mean neurological dysfunction score (66.7 ± 4.7, 79.0 ± 4.5 vs 57.7 ± 1.5 in Lactate, Pyruvate and Control group respectively) at 48 h after cardiac arrest. Oxamate and FC administration were associated with a lower lactate cerebral uptake after cardiac arrest and with an improvement of the neurological recovery (28.85 ± 9.4, 23.86 ± 6.2 vs 57.7 ± 1.5 in Oxa, FC and Control group respectively). After cardiac arrest, immediate isotonic lactate or pyruvate administration is deleterious. Pre-cardiac arrest LDH inhibition was potently neuroprotective in this setting.

Keywords:  Astrocytes; Cardiac arrest; Fluorocitrate; Lactate; Neuroprotection; Oxamate

DOI:  https://doi.org/10.1038/s41598-024-74660-6
Neurobiol Dis. 2024 Oct 18. pii: S0969-9961(24)00298-5. [Epub ahead of print]202 106698

Multiomics approach discloses lipids and metabolites profiles associated to Parkinson's disease stages and applied therapies.

Federica Carrillo, Nicole Piera Palomba, Marco Ghirimoldi, Camilla Didò, Giorgio Fortunato, Shahzaib Khoso, Tiziana Giloni, Marco Santilli, Tommaso Bocci, Alberto Priori, Sara Pietracupa, Nicola Modugno, Elettra Barberis, Marcello Manfredi, Paola Signorelli, Teresa Esposito.

  Profiling circulating lipids and metabolites in Parkinson's disease (PD) patients could be useful not only to highlight new pathways affected in PD condition but also to identify sensitive and effective biomarkers for early disease detection and potentially effective therapeutic interventions. In this study we adopted an untargeted omics approach in three groups of patients (No L-Dopa, L-Dopa and DBS) to disclose whether long-term levodopa treatment with or without deep brain stimulation (DBS) could reflect a characteristic lipidomic and metabolomic signature at circulating level. Our findings disclosed a wide up regulation of the majority of differentially regulated lipid species that increase with disease progression and severity. We found a relevant modulation of triacylglycerols and acyl-carnitines, together with an altered profile in adiponectin and leptin, that can differentiate the DBS treated group from the others PD patients. We found a highly significant increase of exosyl ceramides (Hex2Cer) and sphingoid bases (SPB) in PD patients mainly in DBS group (p < 0.0001), which also resulted in a highly accurate diagnostic performance. At metabolomic level, we found a wide dysregulation of pathways involved in the biosynthesis and metabolism of several amino acids. The most interesting finding was the identification of a specific modulation of L-glutamic acid in the three groups of patients. L-glutamate levels increased slightly in No L-Dopa and highly in L-Dopa patients while decreased in DBS, suggesting that DBS therapy might have a beneficial effect on the glutamatergic cascade. All together, these data provide novel insights into the molecular and metabolic alterations underlying PD therapy and might be relevant for PD prediction, diagnosis and treatment.

Keywords:  Circulating biomarkers; Deep brain stimulation (DBS); Mass spectrometry; Multi-omics analysis; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2024.106698
Curr Neuropharmacol. 2024 Oct 21.

Oxidative Stress-mediated Lipid Peroxidation-derived Lipid Aldehydes in the Pathophysiology of Neurodegenerative Diseases.

Kieran Allowitz, Justin Taylor, Kyra Harames, John Yoo, Omar Baloch, Kota V Ramana.

  Neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis cause damage and gradual loss of neurons affecting the central nervous system. Neurodegenerative diseases are most commonly seen in the ageing process. Ageing causes increased reactive oxygen species and decreased mitochondrial ATP generation, resulting in redox imbalance and oxidative stress. Oxidative stress-generated free radicals cause damage to membrane lipids containing polyunsaturated fatty acids, leading to the formation of toxic lipid aldehyde products such as 4- hydroxynonenal and malondialdehyde. Several studies have shown that lipid peroxidation-derived aldehyde products form adducts with cellular proteins, altering their structure and function. Thus, these lipid aldehydes could act as secondary signaling intermediates, modifying important metabolic pathways, and contributing to the pathophysiology of several human diseases, including neurodegenerative disorders. Additionally, they could serve as biomarkers for disease progression. This narrative review article discusses the biological and clinical significance of oxidative stress-mediated lipid peroxidation-derived lipid aldehydes in the pathophysiology of various neurodegenerative diseases.

Keywords:  Alzheimer’s; Oxidative stress; Parkinson’s; hydroxynonenal; lipid peroxidation; malondialdehyde; neurodegenerative disorders.

DOI:  https://doi.org/10.2174/011570159X342720241014164650
Psychopharmacology (Berl). 2024 Oct 21.

Glia dysfunction in schizophrenia: evidence of possible therapeutic effects of nervonic acid in a preclinical model.

Xiaona Wang, Jiacheng Fu, Huiying Wang, Cong Liu, Yongping Zhang, Cai Song, Changhong Wang.

   RATIONALE: Neuroinflammation may inhibit oligodendrocyte and astrocyte differentiation, which causes demyelination and synaptic degeneration. The myelin component nervonic acid (NA) may improve demyelinating and neurodegenerative diseases.
OBJECTIVES: This study firstly explored relationships between glial cell dysfunction and demyelination or synaptic degeneration in schizophrenia patients, and secondly determined nervonic acid therapeutic effects in a preclinical schizophrenia model of mice.
METHODS: Plasma samples were collected from 18 male healthy controls and 18 male schizophrenic patients (diagnosed by DSM-V) at aged 18-55. Mouse brain samples were collected from a maternal immune activation (MIA) model of schizophrenia via injecting 5 mg/kg polyinosinic-polycytidylic acid. Male mouse offspring (age 2.5 months, n = 12) were treated by clozapine (15 mg/kg/day) or fed 0.5% NA for 6 weeks. Cytokine and dopamine (DA) concentrations, and glial phenotypes and myelin markers were measured in both human plasma and mouse brain samples.
RESULTS: In patient plasma, increased proinflammatory cytokines were associated with reactive microglia (Iba-1) up-regulation, while decreased anti-inflammatory cytokines were related to microglia (CD206) downregulation. Decreased astrocyte marker (p11) concentrations were accompanied by reduced concentrations of oligodendrocyte and synaptic markers. However, NA and DA contents were increased. Compared with control mice, SZ-like behaviors appeared in MIA male mice. Changes in microglia and astrocytes markers, and cytokine concentrations in the frontal cortex were consistent with those observed in patients' plasma. Hippocampal oligodendrocyte and synaptic marker expression were also decreased. DA content and DA/metabolite (DAPOC) were increased in MIA mouse brains. Most of these changes were normalized by both clozapine and NA. Even though some NA effects were more pronounced than clozapine, only clozapine restored cytokine function.
CONCLUSION: The data suggest a possible therapeutic route for schizophrenia patients.

Keywords:  Glial cells; Myelin sheath; Nervonic acid; Schizophrenia; Synaptic

DOI:  https://doi.org/10.1007/s00213-024-06632-7