bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024‒01‒14
twenty papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Brain energy metabolism: A roadmap for future research.
  2. Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
  3. Contribution of changes in the orexin system and energy sensors in the brain in depressive disorder - a study in an animal model.
  4. Local and dynamic regulation of neuronal glycolysis in vivo.
  5. Lipids as Emerging Biomarkers in Neurodegenerative Diseases.
  6. Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.
  7. Cell type-specific roles of APOE4 in Alzheimer disease.
  8. Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
  9. Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.
  10. Effects of aging on glucose and lipid metabolism in mice.
  11. Protocol for the isolation and culture of microglia, astrocytes, and neurons from the same mouse brain.
  12. Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease.
  13. Nicotinamide mononucleotide alleviates seizures via modulating SIRT1-PGC-1α mediated mitochondrial fusion and fission.
  14. Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes.
  15. OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3β/β-catenin pathway after subarachnoid hemorrhage.
  16. Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer's Disease.
  17. Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.
  18. Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.
  19. Repeated Ketamine Anesthesia during the Neonatal Period Impairs Hippocampal Neurogenesis and Long-Term Neurocognitive Function by Inhibiting Mfn2-Mediated Mitochondrial Fusion in Neural Stem Cells.
  20. Prediction of clinical progression in nervous system diseases: plasma glial fibrillary acidic protein (GFAP).
  1. J Neurochem. 2024 Jan 06.
    Brain energy metabolism: A roadmap for future research.
    Caroline D Rae, Joseph A Baur, Karin Borges, Gerald Dienel, Carlos Manlio Díaz-García, Starlette R Douglass, Kelly Drew, João M N Duarte, Jordi Duran, Oliver Kann, Tibor Kristian, Dasfne Lee-Liu, Britta E Lindquist, Ewan C McNay, Michael B Robinson, Douglas L Rothman, Benjamin D Rowlands, Timothy A Ryan, Joseph Scafidi, Susanna Scafidi, C William Shuttleworth, Raymond A Swanson, Gökhan Uruk, Nina Vardjan, Robert Zorec, Mary C McKenna.
      Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.
    Keywords:  GLUT4; acetate; aerobic glycolysis; insulin; noradrenaline
    DOI:  https://doi.org/10.1111/jnc.16032
  2. Int J Mol Sci. 2023 Dec 21. pii: 124. [Epub ahead of print]25(1):
    Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases.
    Jiwon Jang, Su Rim Kim, Jo Eun Lee, Seoyeon Lee, Hyeong Jig Son, Wonchae Choe, Kyung-Sik Yoon, Sung Soo Kim, Eui-Ju Yeo, Insug Kang.
      Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; cerebral ischemia; ketogenic diet; ketone bodies; mitochondrial dysfunction; neurodegenerative disease; neuroinflammation; oxidative stress; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/ijms25010124
  3. Pharmacol Rep. 2024 Jan 09.
    Contribution of changes in the orexin system and energy sensors in the brain in depressive disorder - a study in an animal model.
    Katarzyna Głombik, Magdalena Kukla-Bartoszek, Katarzyna Curzytek, Agnieszka Basta-Kaim, Bogusława Budziszewska.
      BACKGROUND: Maternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression.MATERIALS: The study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14-21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries.
    RESULTS: We revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported.
    CONCLUSIONS: Our study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies.
    Keywords:  Brain; Depression; Dexamethasone; Metabolism; Orexins
    DOI:  https://doi.org/10.1007/s43440-023-00559-0
  4. Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2314699121
    Local and dynamic regulation of neuronal glycolysis in vivo.
    Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Ian J Gonzalez, Marc Hammarlund, Anthony A Hyman, Philip J S Stork, Richard H Goodman, Daniel A Colón-Ramos.
      Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.
    Keywords:  C. elegans; biosensor; energy metabolism; glycolysis; neurons
    DOI:  https://doi.org/10.1073/pnas.2314699121
  5. Int J Mol Sci. 2023 Dec 21. pii: 131. [Epub ahead of print]25(1):
    Lipids as Emerging Biomarkers in Neurodegenerative Diseases.
    Justin Wei, Li Chin Wong, Sebastian Boland.
      Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic.
    Keywords:  Alzheimer’s disease; Gaucher disease; Niemann–Pick disease; Parkinson’s disease; Tay–Sachs disease; amyotrophic lateral sclerosis; biomarkers; bis(monoacylglycero)phosphate (BMP); frontotemporal dementia; gangliosides; glycosphingolipids; lipids; multiple sclerosis; neurodegenerative diseases; progranulin; sphingolipids
    DOI:  https://doi.org/10.3390/ijms25010131
  6. Anat Cell Biol. 2024 Jan 09.
    Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma.
    Hassan Azari, Angela Poff, Dominic D'Agostino, Brent Reynolds.
      Heavy reliance on glucose metabolism and a reduced capacity to use ketone bodies makes glioblastoma (GBM) a promising candidate for ketone-based therapies. Ketogenic diet (KD) is well-known for its promising effects in controlling tumor growth in GBM. Moreover, synthetic ketone ester (KE) has demonstrated to increase blood ketone levels and enhance animal survival in a metastatic VM-M3 murine tumor model. Here, we compared the efficacy of a KE-supplemented Atkins-type diet (ATD-KE) to a classic KD in controlling tumor progression and enhancing survival in a clinically relevant orthotopic patient-derived xenograft GBM model. Our findings demonstrate that ATD-KE preserves body weight (percent change from the baseline; 112±2.99 vs. 116.9±2.52 and 104.8±3.67), decreases blood glucose (80.55±0.86 vs. 118.6±9.51 and 52.35±3.89 mg/dl), and increases ketone bodies in blood (1.15±0.03 mM vs. 0.55±0.04 and 2.66±0.21 mM) and brain tumor tissue (3.35±0.30 mM vs. 2.04±0.3 and 4.25±0.25 mM) comparable to the KD (results presented for ATD-KE vs. standard diet [STD] and KD, respectively). Importantly, the ATD-KE treatment significantly enhanced survival compared to the STD and was indistinguishable from the KD (47 days in STD vs. 56 days in KD and ATD-KE), suggesting that a nutritionally balanced low carbohydrate ATD combined with KE may be as effective as the KD alone in reducing brain tumor progression. Overall, these data support the rationale for clinical testing of KE-supplemented low-carb diet as an adjunct treatment for brain tumor patients.
    Keywords:  Glioblastoma; Ketone bodies; Ketone ester; Survival; Tumor progression
    DOI:  https://doi.org/10.5115/acb.23.158
  7. Nat Rev Neurosci. 2024 Jan 08.
    Cell type-specific roles of APOE4 in Alzheimer disease.
    Jessica Blumenfeld, Oscar Yip, Min Joo Kim, Yadong Huang.
      The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell - including astrocytes, neurons, microglia, oligodendrocytes and vascular cells - has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD.
    DOI:  https://doi.org/10.1038/s41583-023-00776-9
  8. J Biol Chem. 2024 Jan 08. pii: S0021-9258(24)00002-4. [Epub ahead of print] 105626
    Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
    Gaganvir Parmar, Claire Fong-McMaster, Chantal Pileggi, David A Patten, Alexanne Cuillerier, Stephanie Myers, Ying Wang, Siegfried Hekimi, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.
      Mitochondrial electron transport chain (ETC) complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SC remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in TCA cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.
    Keywords:  Mitochondria; NDUFB4; electron transport chain; oxidative phosphorylation; respirasome; steady-state metabolomics; supercomplexes
    DOI:  https://doi.org/10.1016/j.jbc.2024.105626
  9. JIMD Rep. 2024 Jan;65(1): 10-16
    Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin.
    I Bernhardt, L Van Dorp, M Dixon, M McSweeney, C Gan, J Baruteau, A Chakrapani.
      Pyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty-acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life-limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd-chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood-brain-barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal-onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI-brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up-titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long-chain triglycerides were restricted, with fat-soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post-exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well-tolerated and appeared efficacious during 2 years' follow-up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.
    DOI:  https://doi.org/10.1002/jmd2.12405
  10. bioRxiv. 2023 Dec 18. pii: 2023.12.17.572088. [Epub ahead of print]
    Effects of aging on glucose and lipid metabolism in mice.
    Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.
      Aging is accompanied by multiple molecular changes that contribute to aging-associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part because mitochondria are central to cellular metabolism. Moreover, the co-factor NAD+, which is reported to decline across multiple tissue types during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and Diversity Outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of up-regulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. Because mitochondrial respiration, a major source of NAD+ regeneration, is reported to decline with age, our data supports a model where NAD+-generating lipid metabolism reactions may buffer against changes in NAD+/NADH during healthy aging.
    DOI:  https://doi.org/10.1101/2023.12.17.572088
  11. STAR Protoc. 2024 Jan 10. pii: S2666-1667(23)00771-2. [Epub ahead of print]5(1): 102804
    Protocol for the isolation and culture of microglia, astrocytes, and neurons from the same mouse brain.
    Elvira P Leites, Vanessa A Morais.
      Studying the intrinsic properties of microglia, astrocytes, and neurons is essential to our understanding of brain function. Here, we present a protocol to isolate and culture these neural cells from the same mouse brain. Using immunocapture magnetic beads, we describe steps for dissociating, cleaning, and sequentially separating brains from 9-day-old mice into microglia, astrocytes, and neurons. Following these detailed procedures for seeding and culturing of isolated cells, we can address critical questions related to brain function.
    Keywords:  Cell culture; Cell isolation; Cell-based Assays; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2023.102804
  12. Sci Rep. 2024 01 09. 14(1): 870
    Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease.
    Laura Ferré-González, Ángel Balaguer, Marta Roca, Artemis Ftara, Ana Lloret, Consuelo Cháfer-Pericás.
      Lipids are the major component of the brain with important structural and functional properties. Lipid disruption could play a relevant role in Alzheimer's disease (AD). Some brain lipidomic studies showed significant differences compared to controls, but few studies have focused on different brain areas related to AD. Furthermore, AD is more prevalent in females, but there is a lack of studies focusing on this sex. This work aims to perform a lipidomic study in selected brain areas (cerebellum, amygdala, hippocampus, entire cortex) from wild-type (WT, n = 10) and APPswe/PS1dE9 transgenic (TG, n = 10) female mice of 5 months of age, as a model of early AD, to identify alterations in lipid composition. A lipidomic mass spectrometry-based method was optimized and applied to brain tissue. As result, some lipids showed statistically significant differences between mice groups in cerebellum (n = 68), amygdala (n = 49), hippocampus (n = 48), and the cortex (n = 22). In addition, some lipids (n = 15) from the glycerolipid, phospholipid, and sphingolipid families were statistically significant in several brain areas simultaneously between WT and TG. A selection of lipid variables was made to develop a multivariate approach to assess their discriminant potential, showing high diagnostic indexes, especially in cerebellum and amygdala (sensitivity 70-100%, sensibility 80-100%).
    DOI:  https://doi.org/10.1038/s41598-024-51463-3
  13. J Neurochem. 2024 Jan 09.
    Nicotinamide mononucleotide alleviates seizures via modulating SIRT1-PGC-1α mediated mitochondrial fusion and fission.
    Yahong Cheng, Puxin Huang, Qixian Zou, Hui Tian, Qingzhou Cheng, Hong Ding.
      Both human and animal experiments have demonstrated that energy metabolism dysfunction in neurons after seizures is associated with an imbalance in mitochondrial fusion/fission dynamics. Effective neuronal mitochondrial dynamics regulation strategies remain elusive. Nicotinamide mononucleotide (NMN) can ameliorate mitochondrial functional and oxidative stress in age-related diseases. But whether NMN improves mitochondrial energy metabolism to exert anti-epileptic effects is unclear. This study aims to clarify if NMN can protect neurons from pentylenetetrazole (PTZ) or Mg2+ -free-induced mitochondrial disorder and apoptosis via animal and cell models. We established a continuous 30-day PTZ (37 mg/kg) intraperitoneal injection-induced epileptic mouse model and a cell model induced by Mg2+ -free solution incubation to explore the neuroprotective effects of NMN. We found that NMN treatment significantly reduced the seizure intensity of PTZ-induced epileptic mice, improved their learning and memory ability, and enhanced their motor activity and exploration desire. At the same time, in vitro and in vivo experiments showed that NMN can inhibit neuronal apoptosis and improve the mitochondrial energy metabolism function of neurons. In addition, NMN down-regulated the expression of mitochondrial fission proteins (Drp1 and Fis1) and promoted the expression of mitochondrial fusion proteins (Mfn1 and Mfn2) by activating the SIRT1-PGC-1α pathway, thereby inhibiting PTZ or Mg2+ -free extracellular solution-induced mitochondrial dysfunction, cell apoptosis, and oxidative stress. However, combined intervention of SIRT1 inhibitor, Selisistat, and PGC-1α inhibitor, SR-18292, eliminated the regulatory effect of NMN pre-treatment on mitochondrial fusion and fission proteins and apoptosis-related proteins. Therefore, NMN intervention may be a new potential treatment for cognitive impairment and behavioral disorders induced by epilepsy, and targeting the SIRT1-PGC-1α pathway may be a promising therapeutic strategy for seizures.
    Keywords:  SIRT1/PGC-1α pathway; epilepsy; mitochondrial fission; mitochondrial fusion; nicotinamide mononucleotide
    DOI:  https://doi.org/10.1111/jnc.16041
  14. Biol Sex Differ. 2024 Jan 08. 15(1): 4
    Sex-dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes.
    Marlene Zubillaga, Julia Tau, Diana Rosa, M José Bellini, Nathalie Arnal.
      BACKGROUND: Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer's disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis.METHODS: We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts.
    RESULTS: Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males.
    CONCLUSIONS: Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.
    Keywords:  Astrocytes; Cholesterol; Copper; Neurons; Sexual differences
    DOI:  https://doi.org/10.1186/s13293-023-00578-9
  15. Brain Res. 2024 Jan 08. pii: S0006-8993(24)00012-X. [Epub ahead of print]1827 148758
    OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3β/β-catenin pathway after subarachnoid hemorrhage.
    Jia-Yin Qiu, Sheng-Qing Gao, Yu-Sheng Chen, Xue Wang, Yun-Song Zhuang, Shu-Hao Miao, Xiao-Bo Zheng, Ran Zhao, Yan Sun, Meng-Liang Zhou.
      BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening neurological disease that usually has a poor prognosis. Neurogenesis is a potential therapeutic target for brain injury. Ketone metabolism also plays neuroprotective roles in many neurological disorders. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme of ketone body oxidation. In this study, we explored whether increasing ketone oxidation by upregulating OXCT1 in neurons could promote neurogenesis after SAH, and evaluated the potential mechanism involved in this process.METHODS: The β-hydroxybutyrate content was measured using an enzymatic colorimetric assay. Adeno-associated virus targeting neurons was injected to overexpress OXCT1, and the expression and localization of proteins were evaluated by western blotting and immunofluorescence staining. Adult hippocampal neurogenesis was evaluated by dual staining with doublecortin and 5-Ethynyl-2'-Deoxyuridine. LY294002 was intracerebroventricularly administered to inhibit Akt activity. The Morris water maze and Y-maze tests were employed to assess cognitive function after SAH.
    RESULTS: The results showed that OXCT1 expression and hippocampal neurogenesis significantly decreased in the early stage of SAH. Overexpression of OXCT1 successfully increased hippocampal neurogenesis via activation of Akt/GSK-3β/β-catenin signaling and improved cognitive function, both of which were reversed by administration of LY294002.
    CONCLUSIONS: OXCT1 regulated hippocampal ketone body metabolism and increased neurogenesis through mechanisms mediated by the Akt/GSK-3β/β-catenin pathway, improving cognitive impairment after SAH.
    Keywords:  3-Oxoacid CoA-Transferase 1; Akt/GSK-3β/β-catenin pathway; Ketone body metabolism; Neurogenesis; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1016/j.brainres.2024.148758
  16. Int J Mol Sci. 2023 Dec 22. pii: 170. [Epub ahead of print]25(1):
    Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer's Disease.
    Xun Zhou, Xiaolang Wu, Rui Wang, Lu Han, Huilin Li, Wei Zhao.
      Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer's disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment.
    Keywords:  Alzheimer’s disease; HMGCR; lipid mediators; lipid metabolism; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms25010170
  17. Prog Lipid Res. 2024 Jan 07. pii: S0163-7827(24)00001-8. [Epub ahead of print]94 101268
    Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.
    Vijay Aditya Mavuduru, Lavanya Vadupu, Krishna Kanta Ghosh, Sabyasachi Chakrabortty, Balázs Gulyás, Parasuraman Padmanabhan, Writoban Basu Ball.
      One of the major constituents of mitochondrial membranes is the phospholipids, which play a key role in maintaining the structure and the functions of the mitochondria. However, mitochondria do not synthesize most of the phospholipids in situ, necessitating the presence of phospholipid import pathways. Even for the phospholipids, which are synthesized within the inner mitochondrial membrane (IMM), the phospholipid precursors must be imported from outside the mitochondria. Therefore, the mitochondria heavily rely on the phospholipid transport pathways for its proper functioning. Since, mitochondria are not part of a vesicular trafficking network, the molecular mechanisms of how mitochondria receive its phospholipids remain a relevant question. One of the major ways that hydrophobic phospholipids can cross the aqueous barrier of inter or intraorganellar spaces is by apposing membranes, thereby decreasing the distance of transport, or by being sequestered by lipid transport proteins (LTPs). Therefore, with the discovery of LTPs and membrane contact sites (MCSs), we are beginning to understand the molecular mechanisms of phospholipid transport pathways in the mitochondria. In this review, we will present a brief overview of the recent findings on the molecular architecture and the importance of the MCSs, both the intraorganellar and interorganellar contact sites, in facilitating the mitochondrial phospholipid transport. In addition, we will also discuss the role of LTPs for trafficking phospholipids through the intermembrane space (IMS) of the mitochondria. Mechanistic insights into different phospholipid transport pathways of mitochondria could be exploited to vary the composition of membrane phospholipids and gain a better understanding of their precise role in membrane homeostasis and mitochondrial bioenergetics.
    Keywords:  ERMES; Mitochondria; Mitochondrial contact sites; Phospholipid biosynthesis; Phospholipid transport; vCLAMP
    DOI:  https://doi.org/10.1016/j.plipres.2024.101268
  18. Clin Genet. 2024 Jan 09.
    Further delineation of the phenotypic and metabolomic profile of ALDH1L2-related neurodevelopmental disorder.
    Mikyoung You, Hanan E Shamseldin, Halle M Fogle, Blake R Rushing, Reem H AlMalki, Amal Jaafar, Mais Hashem, Firdous Abdulwahab, Anas M Abdel Rahman, Natalia I Krupenko, Fowzan S Alkuraya, Sergey A Krupenko.
      ALDH1L2, a mitochondrial enzyme in folate metabolism, converts 10-formyl-THF (10-formyltetrahydrofolate) to THF (tetrahydrofolate) and CO2 . At the cellular level, deficiency of this NADP+ -dependent reaction results in marked reduction in NADPH/NADP+ ratio and reduced mitochondrial ATP. Thus far, a single patient with biallelic ALDH1L2 variants and the phenotype of a neurodevelopmental disorder has been reported. Here, we describe another patient with a neurodevelopmental disorder associated with a novel homozygous missense variant in ALDH1L2, Pro133His. The variant caused marked reduction in the ALDH1L2 enzyme activity in skin fibroblasts derived from the patient as probed by 10-FDDF, a stable synthetic analog of 10-formyl-THF. Additional associated abnormalities in these fibroblasts include reduced NADPH/NADP+ ratio and pool of mitochondrial ATP, upregulated autophagy and dramatically altered metabolomic profile. Overall, our study further supports a link between ALDH1L2 deficiency and abnormal neurodevelopment in humans.
    Keywords:  ALDH1L2; folate metabolism; metabolomics; missense mutation; neurodevelopmental disorder
    DOI:  https://doi.org/10.1111/cge.14479
  19. Mol Neurobiol. 2024 Jan 10.
    Repeated Ketamine Anesthesia during the Neonatal Period Impairs Hippocampal Neurogenesis and Long-Term Neurocognitive Function by Inhibiting Mfn2-Mediated Mitochondrial Fusion in Neural Stem Cells.
    He Huang, Ning Wang, Jia-Tao Lin, Yong-Kang Qiu, Wei-Feng Wu, Qiang Liu, Chen Chen, Hai-Bi Wang, Yan-Ping Liu, Wei Dong, Jie Wan, Hui Zheng, Cheng-Hua Zhou, Yu-Qing Wu.
      The mechanism of ketamine-induced neurotoxicity development remains elusive. Mitochondrial fusion/fission dynamics play a critical role in regulating neurogenesis. Therefore, this study was aimed to evaluate whether mitochondrial dynamics were involved in ketamine-induced impairment of neurogenesis in neonatal rats and long-term synaptic plasticity dysfunction. In the in vivo study, postnatal day 7 (PND-7) rats received intraperitoneal (i.p.) injection of 40 mg/kg ketamine for four consecutive times at 1 h intervals. The present findings revealed that ketamine induced mitochondrial fusion dysfunction in hippocampal neural stem cells (NSCs) by downregulating Mitofusin 2 (Mfn2) expression. In the in vitro study, ketamine treatment at 100 μM for 6 h significantly decreased the Mfn2 expression, and increased ROS generation, decreased mitochondrial membrane potential and ATP levels in cultured hippocampal NSCs. For the interventional study, lentivirus (LV) overexpressing Mfn2 (LV-Mfn2) or control LV vehicle was microinjected into the hippocampal dentate gyrus (DG) 4 days before ketamine administration. Targeted Mfn2 overexpression in the DG region could restore mitochondrial fusion in NSCs and reverse the inhibitory effect of ketamine on NSC proliferation and its faciliatory effect on neuronal differentiation. In addition, synaptic plasticity was evaluated by transmission electron microscopy, Golgi-Cox staining and long-term potentiation (LTP) recordings at 24 h after the end of the behavioral test. Preconditioning with LV-Mfn2 improved long-term cognitive dysfunction after repeated neonatal ketamine exposure by reversing the inhibitory effect of ketamine on synaptic plasticity in the hippocampal DG. The present findings demonstrated that Mfn2-mediated mitochondrial fusion dysfunction plays a critical role in the impairment of long-term neurocognitive function and synaptic plasticity caused by repeated neonatal ketamine exposure by interfering with hippocampal neurogenesis. Thus, Mfn2 might be a novel therapeutic target for the prevention of the developmental neurotoxicity of ketamine.
    Keywords:  Ketamine; Mfn2; Mitochondrial dynamics; Neurocognition; Neurogenesis; Synaptic plasticity
    DOI:  https://doi.org/10.1007/s12035-024-03921-2
  20. Eur J Med Res. 2024 Jan 12. 29(1): 51
    Prediction of clinical progression in nervous system diseases: plasma glial fibrillary acidic protein (GFAP).
    Xiaoxiao Zheng, Jingyao Yang, Yiwei Hou, Xinye Shi, Kangding Liu.
      Glial fibrillary acidic protein (GFAP), an intracellular type III intermediate filament protein, provides structural support and maintains the mechanical integrity of astrocytes. It is predominantly found in the astrocytes which are the most abundant subtypes of glial cells in the brain and spinal cord. As a marker protein of astrocytes, GFAP may exert a variety of physiological effects in neurological diseases. For example, previous published literatures showed that autoimmune GFAP astrocytopathy is an inflammatory disease of the central nervous system (CNS). Moreover, the studies of GFAP in brain tumors mainly focus on the predictive value of tumor volume. Furthermore, using biomarkers in the early setting will lead to a simplified and standardized way to estimate the poor outcome in traumatic brain injury (TBI) and ischemic stroke. Recently, observational studies revealed that cerebrospinal fluid (CSF) GFAP, as a valuable potential diagnostic biomarker for neurosyphilis, had a sensitivity of 76.60% and specificity of 85.56%. The reason plasma GFAP could serve as a promising biomarker for diagnosis and prediction of Alzheimer's disease (AD) is that it effectively distinguished AD dementia from multiple neurodegenerative diseases and predicted the individual risk of AD progression. In addition, GFAP can be helpful in differentiating relapsing-remitting multiple sclerosis (RRMS) versus progressive MS (PMS). This review article aims to provide an overview of GFAP in the prediction of clinical progression in neuroinflammation, brain tumors, TBI, ischemic stroke, genetic disorders, neurodegeneration and other diseases in the CNS and to explore the potential therapeutic methods.
    Keywords:  Alexander disease; Alzheimer's disease; Astrocytes; Creutzfeldt–Jakob disease; Down syndrome; GFAP; GFAP astrocytopathy; Gliomas; Ischemic stroke; Traumatic brain injury
    DOI:  https://doi.org/10.1186/s40001-023-01631-4
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