bims-medebr 2023-03-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒03‒19
34 papers selected by
Regina F. Fernández
Johns Hopkins University

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission - The essential roles of astrocytes.
A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies.
The role of sphingosine 1-phosphate metabolism in brain health and disease.
Single-nucleus transcriptional profiling uncovers the reprogrammed metabolism of astrocytes in Alzheimer's disease.
Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes.
A diet rich in docosahexaenoic acid enhances reactive astrogliosis and ramified microglia morphology in apolipoprotein E epsilon 4-targeted replacement mice.
Brain-wide transcriptome-based metabolic alterations in Parkinson's disease: human inter-region and human-experimental model correlations.
Emerging Promise of the Therapeutic Approaches of Mitochondria for Neurodegenerative Disorders.
Role of amino acid metabolism in mitochondrial homeostasis.
Oxidative stress, dysfunctional energy metabolism, and destabilizing neurotransmitters altered the cerebral metabolic profile in a rat model of simulated heliox saturation diving to 4.0 MPa.
Post-translational palmitoylation of metabolic proteins.
18 F-FDG PET Brain Findings in a Case of Idiopathic Benign Rolandic Epilepsy of Childhood.
Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy.
Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains.
HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.
Sex differences in brain metabolic connectivity architecture in probable dementia with Lewy bodies.
Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.
Impact of two ketogenic diet types in refractory childhood epilepsy.
Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in hippocampal neurogenesis of the offspring.
Neuroprotective mechanisms of OXCT1 via the SIRT3-SOD2 pathway after traumatic brain injury.
Lactate and Lactylation in the Brain: Current Progress and Perspectives.
Genetic Aberration Analysis of Mitochondrial Respiratory Complex I Implications in the Development of Neurological Disorders and Their Clinical Significance.
Prediction of voluntary movements of the upper extremities by resting state-brain regional glucose metabolism in patients with chronic severe brain injury: A pilot study.
Excitatory Amino Acid Transporters: Beyond Their Expected Function.
Neurometabolite alterations in traumatic brain injury and associations with chronic pain.
Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain.
PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats.
Identification and characterization of diacylglycerol kinase ζ as a novel enzyme producing ceramide-1-phosphate.
Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism.
Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways.
PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.
Nutrition and adult neurogenesis in the hippocampus: Does what you eat help you remember?
A Young Female With Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD): A Case Report.
Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.

J Neurochem. 2023 Mar 15.

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission - The essential roles of astrocytes.

Jens V Andersen, Arne Schousboe.

  Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA-glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABA-glutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA-glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism and recycling. We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine-tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis.

Keywords:  Neurotransmitter recycling; anaplerosis; excitotoxicity; fatty acid metabolism; glutamine; ketones; metabolite transfer; neurodegenerative diseases; neuron-glia coupling

DOI:  https://doi.org/10.1111/jnc.15811
J Neurochem. 2023 Mar 16.

A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies.

Gerald A Dienel, Arne Schousboe, Mary C McKenna, Douglas L Rothman.

  Leif Hertz, M.D., D.Sc. (honōris causā) (1930-2018) was one of the original and noteworthy participants in the International Conference on Brain Energy Metabolism (ICBEM) series since its inception in 1993. The biennial ICBEM conferences are organized by neuroscientists interested in energetics and metabolism underlying neural functions; they have had a high impact on conceptual and experimental advances in these fields and on promoting collaborative interactions among neuroscientists. Leif made major contributions to ICBEM discussions and understanding of metabolic and signaling characteristics of astrocytes and their roles in brain function. His studies ranged from uptake of K+ from extracellular fluid and its stimulation of astrocytic respiration, identification and regulation of enzymes specifically or preferentially expressed in astrocytes in the glutamate-glutamine cycle of excitatory neurotransmission, a requirement for astrocytic glycogenolysis for fueling K+ uptake, involvement of glycogen in memory consolidation in the chick, and pharmacology of astrocytes. This tribute to Leif Hertz highlights his major discoveries, the high impact of his work on astrocyte-neuron interactions, and his unparalleled influence on understanding the cellular basis of brain energy metabolism. His work over seven decades has helped integrate the roles of astrocytes into neurotransmission where oxidative and glycogenolytic metabolism during neurotransmitter glutamate turnover are key aspects of astrocytic energetics. Leif recognized that brain astrocytic metabolism is greatly underestimated unless the volume fraction of astrocytes is taken into account. Adjustment for pathway rates expressed per gram tissue for volume fraction indicates that astrocytes have much higher oxidative rates than neurons and astrocytic glycogen concentrations and glycogenolytic rates during sensory stimulation in vivo are similar to those in resting and exercising muscle, respectively. These novel insights are typical of Leif's astute contributions to the energy metabolism field, and his publications have identified unresolved topics that provide the neuroscience community with challenges and opportunities for future research.

Keywords:  Glu/GABA-Gln cycle; astrocyte and neuron cell culture; astrocytic metabolism and energetics; astrocytic pharmacology; cellular maturation in vitro; glycogen

DOI:  https://doi.org/10.1111/jnc.15812
Pharmacol Ther. 2023 Mar 10. pii: S0163-7258(23)00045-1. [Epub ahead of print] 108381

The role of sphingosine 1-phosphate metabolism in brain health and disease.

Gerhild van Echten-Deckert.

  Lipids are essential structural and functional components of the central nervous system (CNS). Sphingolipids are ubiquitous membrane components which were discovered in the brain in the late 19th century. In mammals, the brain contains the highest concentration of sphingolipids in the body. Sphingosine 1-phosphate (S1P) derived from membrane sphingolipids evokes multiple cellular responses which, depending on its concentration and localization, make S1P a double-edged sword in the brain. In the present review we highlight the role of S1P in brain development and focus on the often contrasting findings regarding its contributions to the initiation, progression and potential recovery of different brain pathologies, including neurodegeneration, multiple sclerosis (MS), brain cancers, and psychiatric illnesses. A detailed understanding of the critical implications of S1P in brain health and disease may open the door for new therapeutic options. Thus, targeting S1P-metabolizing enzymes and/or signaling pathways might help overcome, or at least ameliorate, several brain illnesses.

Keywords:  Fingolimod/FTY720; Neurodegeneration; S1P-lyase (SGPL1); Sphingosine 1-phosphate (S1P); Sphingosine 1-phosphate receptor (S1P(1-5)); Sphingosine kinase

DOI:  https://doi.org/10.1016/j.pharmthera.2023.108381
Front Mol Neurosci. 2023 ;16 1136398

Single-nucleus transcriptional profiling uncovers the reprogrammed metabolism of astrocytes in Alzheimer's disease.

Li-Yuan Fan, Jing Yang, Ming-Li Li, Ruo-Yu Liu, Ying Kong, Su-Ying Duan, Guang-Yu Guo, Jing-Hua Yang, Yu-Ming Xu.

  Astrocytes play an important role in the pathogenesis of Alzheimer's disease (AD). It is widely involved in energy metabolism in the brain by providing nutritional and metabolic support to neurons; however, the alteration in the metabolism of astrocytes in AD remains unknown. Through integrative analysis of single-nucleus sequencing datasets, we revealed metabolic changes in various cell types in the prefrontal cortex of patients with AD. We found the depletion of some important metabolites (acetyl-coenzyme A, aspartate, pyruvate, 2-oxoglutarate, glutamine, and others), as well as the inhibition of some metabolic fluxes (glycolysis and tricarbocylic acid cycle, glutamate metabolism) in astrocytes of AD. The abnormality of glutamate metabolism in astrocytes is unique and important. Downregulation of GLUL (GS) and GLUD1 (GDH) may be the cause of glutamate alterations in astrocytes in AD. These results provide a basis for understanding the characteristic changes in astrocytes in AD and provide ideas for the study of AD pathogenesis.

Keywords:  Alzheimer’s disease; astrocyte; glutamate; glutamine; metabolism; neurodegenerative disease; single-nucleus transcriptome

DOI:  https://doi.org/10.3389/fnmol.2023.1136398
Neurochem Res. 2023 Mar 14.

Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes.

Antonia Regina Harders, Christian Arend, Sadhbh Cynth Denieffe, Julius Berger, Ralf Dringen.

  Adenosine triphosphate (ATP) is the central energy currency of all cells. Cultured primary rat astrocytes contain a specific cellular ATP content of 27.9 ± 4.7 nmol/mg. During incubation in a glucose- and amino acid-free incubation buffer, this high cellular ATP content was maintained for at least 6 h, while within 24 h the levels of ATP declined to around 30% of the initial value without compromising cell viability. In contrast, cells exposed to 1 mM and 5 mM glucose maintained the initial high cellular ATP content for 24 and 72 h, respectively. The loss in cellular ATP content observed during a 24 h glucose-deprivation was fully prevented by the presence of glucose, fructose or mannose as well as by the mitochondrial substrates lactate, pyruvate, β-hydroxybutyrate or acetate. The high initial specific ATP content in glucose-starved astrocytes, was almost completely abolished within 30 min after application of the respiratory chain inhibitor antimycin A or the mitochondrial uncoupler BAM-15, while these inhibitors lowered in glucose-fed cells the ATP content only to 60% (BAM-15) and 40% (antimycin A) within 5 h. Inhibition of the mitochondrial pyruvate carrier by UK5099 alone or of mitochondrial fatty acid uptake by etomoxir alone hardly affected the high ATP content of glucose-deprived astrocytes during an incubation for 8 h, while the co-application of both inhibitors depleted cellular ATP levels almost completely within 5 h. These data underline the importance of mitochondrial metabolism for the ATP regeneration of astrocytes and demonstrate that the mitochondrial oxidation of pyruvate and fatty acids strongly contributes to the maintenance of a high ATP concentration in glucose-deprived astrocytes.

Keywords:  ATP; Astrocytes; Fatty acids; Glucose; Metabolism; Mitochondria

DOI:  https://doi.org/10.1007/s11064-023-03903-1
Aging Brain. 2022 ;2 100046

A diet rich in docosahexaenoic acid enhances reactive astrogliosis and ramified microglia morphology in apolipoprotein E epsilon 4-targeted replacement mice.

Hillary Chappus-McCendie, Marc-Antoine Poulin, Raphaël Chouinard-Watkins, Milène Vandal, Frédéric Calon, Marc-Antoine Lauzon, Mélanie Plourde.

  Docosahexaenoic acid (DHA) consumption reduces spatial memory impairment in mice carrying the human apolipoprotein E ε4 (APOE4) allele. The current study evaluated whether astrocyte and microglia morphology contribute to the mechanism of this result. APOE3 and APOE4 mice were fed either a DHA-enriched diet or a control diet from 4 to 12 months of age. Coronal brain sections were immunostained for GFAP, Iba1, and NeuN. Astrocytes from APOE4 mice exhibited signs of reactive astrogliosis compared to APOE3 mice. Consumption of DHA exacerbated reactive astrocyte morphology in APOE4 carriers. Microglia from APOE4-control mice exhibited characteristics of amoeboid morphology and other characteristics of ramified morphology (more processes, greater process complexity, and greater distance between neighboring microglia). DHA enhanced ramified microglia morphology in APOE4 mice. In addition, APOE4 mice fed the DHA diet had lower hippocampal concentrations of interleukin-7, lipopolysaccharide-induced CXC chemokine and monocyte chemoattractant protein 1, and higher concentration of interferon-gamma compared to APOE4-control mice. Our results indicate that a diet rich in DHA enhances reactive astrogliosis and ramified microglia morphology in APOE4 mice.

Keywords:  APOE2, apolipoprotein E epsilon 2 allele; APOE3, apolipoprotein E epsilon 3 allele; APOE4, apolipoprotein E epsilon 4 allele; Apolipoprotein E epsilon 4; Astrocyte; DHA, docosahexaenoic acid; Docosahexaenoic acid; EPA, eicosapentaenoic acid; Microglia; Neuroinflammation; PUFA, polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.nbas.2022.100046
Mol Omics. 2023 Mar 17.

Brain-wide transcriptome-based metabolic alterations in Parkinson's disease: human inter-region and human-experimental model correlations.

Regan Odongo, Orhan Bellur, Ecehan Abdik, Tunahan Çakır.

Alterations in brain metabolism are closely associated with the molecular hallmarks of Parkinson's disease (PD). A clear understanding of the main metabolic perturbations in PD is therefore important. Here, we retrospectively analysed the expression of metabolic genes from 34 PD-control post-mortem human brain transcriptome data comparisons from literature, spanning multiple brain regions. We found high metabolic correlations between the Substantia nigra (SN)- and cerebral cortex-derived tissues. Moreover, three clusters of PD patient cohorts were identified based on perturbed metabolic processes in the SN - each characterised by perturbations in (a) bile acid metabolism (b) omega-3 fatty acid metabolism, and (c) lipoic acid and androgen metabolism - metabolic themes not comprehensively addressed in PD. These perturbations were supported by concurrence between transcriptome and proteome changes in the expression patterns for CBR1, ECI2, BDH2, CYP27A1, ALDH1B1, ALDH9A1, ADH5, ALDH7A1, L1CAM, and PLXNB3 genes, providing a valuable resource for drug targeting and diagnosis. Also, we analysed 58 PD-control transcriptome data comparisons from in vivo/in vitro disease models and identified experimental PD models with significant correlations to matched human brain regions. Collectively, our findings suggest metabolic alterations in several brain regions, heterogeneity in metabolic alterations between study cohorts for the SN tissues and the need to optimize current experimental models to advance research on metabolic aspects of PD.

DOI: https://doi.org/10.1039/d2mo00343k
Curr Neuropharmacol. 2023 Mar 16.

Emerging Promise of the Therapeutic Approaches of Mitochondria for Neurodegenerative Disorders.

Md Mominur Rahman, Afroza Alam Tumpa, Md Saidur Rahaman, Fahadul Islam, Popy Rani Sutradhar, Muniruddin Ahmed, Badrah S Alghamdi, Abdul Hafeez, Athanasios Alexiou, Asma Perveen, Ghulam Md Ashraf.

  Mitochondria are critical for homeostasis and metabolism in all cellular eukaryotes. Brain mitochondria are the primary source of fuel that supports many brain functions, including intracellular energy supply, cellular calcium regulation, regulation of limited cellular oxidative capacity, and control of cell death. Much evidence suggests that mitochondria play a central role in neurodegenerative disorders (NDDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Ongoing studies of NDDs have revealed that mitochondrial pathology is mainly found in inherited or irregular NDDs and is thought to be associated with the pathophysiological cycle of these disorders. Typical mitochondrial disturbances in NDDs include increased free radical production, decreased ATP synthesis, alterations in mitochondrial permeability, and mitochondrial DNA damage. The main objective of this review is to highlight the basic mitochondrial problems that occur in NDDs and discuss the use mitochondrial drugs, especially mitochondrial antioxidants, mitochondrial permeability transition blockade, and mitochondrial gene therapy, for the treatment and control of NDDs.

Keywords:  Alzheimer’s disease; Mitochondria; Parkinson’s disease; antioxidants; gene therapy; neurodegenerative disorders

DOI:  https://doi.org/10.2174/1570159X21666230316150559
Front Cell Dev Biol. 2023 ;11 1127618

Role of amino acid metabolism in mitochondrial homeostasis.

Qiaochu Li, Thorsten Hoppe.

  Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic processes that provide energy in the cell is amino acid metabolism. Almost all of the 20 amino acids that serve as the building blocks of proteins are produced or degraded in the mitochondria. The synthesis of the amino acids aspartate and arginine depends on the activity of the respiratory chain, which is essential for cell proliferation. The degradation of branched-chain amino acids mainly occurs in the mitochondrial matrix, contributing to energy metabolism, mitochondrial biogenesis, as well as protein quality control in both mitochondria and cytosol. Dietary supplementation or restriction of amino acids in worms, flies and mice modulates lifespan and health, which has been associated with changes in mitochondrial biogenesis, antioxidant response, as well as the activity of tricarboxylic acid cycle and respiratory chain. Consequently, impaired amino acid metabolism has been associated with both primary mitochondrial diseases and diseases with mitochondrial dysfunction such as cancer. Here, we present recent observations on the crosstalk between amino acid metabolism and mitochondrial homeostasis, summarise the underlying molecular mechanisms to date, and discuss their role in cellular functions and organismal physiology.

Keywords:  TCA cycle; amino acid metabolism; amino acid recycling; lifespan; mitochondrial homeostasis; proteasome; respiratory chain

DOI:  https://doi.org/10.3389/fcell.2023.1127618
PLoS One. 2023 ;18(3): e0282700

Oxidative stress, dysfunctional energy metabolism, and destabilizing neurotransmitters altered the cerebral metabolic profile in a rat model of simulated heliox saturation diving to 4.0 MPa.

Xia Liu, Yiqun Fang, Jiajun Xu, Tao Yang, Ji Xu, Jia He, Wenwu Liu, Xuhua Yu, Yukun Wen, Naixia Zhang, Ci Li.

The main objective of the present study was to determine metabolic profile changes in the brains of rats after simulated heliox saturated diving (HSD) to 400 meters of sea water compared to the blank controls. Alterations in the polar metabolome in the rat brain due to HSD were investigated in cortex, hippocampus, and striatum tissue samples by applying an NMR-based metabolomic approach coupled with biochemical detection in the cortex. The reduction in glutathione and taurine levels may hypothetically boost antioxidant defenses during saturation diving, which was also proven by the increased malondialdehyde level, the decreased superoxide dismutase, and the decreased glutathione peroxidase in the cortex. The concomitant decrease in aerobic metabolic pathways and anaerobic metabolic pathways comprised downregulated energy metabolism, which was also proven by the biochemical quantification of the metabolic enzymes Na-K ATPase and LDH in cerebral cortex tissue. The significant metabolic abnormalities of amino acid neurotransmitters, such as GABA, glycine, and aspartate, decreased aromatic amino acids, including tyrosine and phenylalanine, both of which are involved in the metabolism of dopamine and noradrenaline, which are downregulated in the cortex. Particularly, a decline in the level of N-acetyl aspartate is associated with neuronal damage. In summary, hyperbaric decompression of a 400 msw HSD affected the brain metabolome in a rat model, potentially including a broad range of disturbing amino acid homeostasis, metabolites related to oxidative stress and energy metabolism, and destabilizing neurotransmitter components. These disturbances may contribute to the neurochemical and neurological phenotypes of HSD.

DOI: https://doi.org/10.1371/journal.pone.0282700
Front Physiol. 2023 ;14 1122895

Post-translational palmitoylation of metabolic proteins.

Kaitlyn M J H Dennis, Lisa C Heather.

  Numerous cellular proteins are post-translationally modified by addition of a lipid group to their structure, which dynamically influences the proteome by increasing hydrophobicity of proteins often impacting protein conformation, localization, stability, and binding affinity. These lipid modifications include myristoylation and palmitoylation. Palmitoylation involves a 16-carbon saturated fatty acyl chain being covalently linked to a cysteine thiol through a thioester bond. Palmitoylation is unique within this group of modifications, as the addition of the palmitoyl group is reversible and enzyme driven, rapidly affecting protein targeting, stability and subcellular trafficking. The palmitoylation reaction is catalyzed by a large family of Asp-His-His-Cys (DHHCs) motif-containing palmitoyl acyltransferases, while the reverse reaction is catalyzed by acyl-protein thioesterases (APTs), that remove the acyl chain. Palmitoyl-CoA serves an important dual purpose as it is not only a key metabolite fueling energy metabolism, but is also a substrate for this PTM. In this review, we discuss protein palmitoylation in regulating substrate metabolism, focusing on membrane transport proteins and kinases that participate in substrate uptake into the cell. We then explore the palmitoylation of mitochondrial proteins and the palmitoylation regulatory enzymes, a less explored field for potential lipid metabolic regulation.

Keywords:  fatty acid signalling; membrane transporter; metabolism; mitochondria; palmitoylation

DOI:  https://doi.org/10.3389/fphys.2023.1122895
World J Nucl Med. 2023 Mar;22(1): 52-54

18 F-FDG PET Brain Findings in a Case of Idiopathic Benign Rolandic Epilepsy of Childhood.

Kousik Vankadari, Rajender Kumar, Bhagwant Rai Mittal, Naveen Sankhyan.

  Idiopathic benign rolandic epilepsy, also known as benign childhood epilepsy with centrotemporal spikes (BCECTS), is one of the commonly seen electroclinical epilepsy syndromes of childhood with a generally favorable long-term prognosis. We describe a 5-year-old female child who presented with recurrent focal seizures involving right side of face since the age of 6 months. She had no perinatal or postnatal insults, had normal development, and her neurological examination was unremarkable. Electroencephalogram showed rolandic spikes, suggesting BCETCS. Her seizures remained refractory to two appropriately dosed antiepileptic drugs. Magnetic resonance imaging of the brain did not reveal any structural lesion. Interictal fluorodeoxyglucose 18 F-positron emission tomography brain showed hypometabolism in the left lower rolandic region.

Keywords:  18 F-FDG ; BCECTS; centrotemporal spikes; childhood epilepsy; rolandic epilepsy

DOI:  https://doi.org/10.1055/s-0042-1757287
Mol Neurodegener. 2023 Mar 16. 18(1): 17

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy.

Monica Xiong, Chao Wang, Maud Gratuze, Fareeha Saadi, Xin Bao, Megan E Bosch, Choonghee Lee, Hong Jiang, Javier Remolina Serrano, Ernesto R Gonzales, Michal Kipnis, David M Holtzman.

  BACKGROUND: Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.METHODS: We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity.
RESULTS: Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.
CONCLUSION: In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

Keywords:  APOE; Amyloid-β; Astrocyte; Cerebral amyloid angiopathy; Cerebrovasculature

DOI:  https://doi.org/10.1186/s13024-023-00610-x
Biomed Pharmacother. 2023 Feb;pii: S0753-3322(22)01595-5. [Epub ahead of print]158 114206

Metabolic perspective of astrocyte dysfunction in Alzheimer's disease and type 2 diabetes brains.

Zheng Shen, Zheng-Yang Li, Meng-Ting Yu, Kai-Leng Tan, Si Chen.

  The term type III diabetes (T3DM) has been proposed for Alzheimer's disease (AD) due to the shared molecular and cellular features between type 2 diabetes (T2DM) and insulin resistance-associated memory deficits and cognitive decline in elderly individuals. Astrocytes elicit neuroprotective or deleterious effects in AD progression and severity. Patients with T2DM are at a high risk of cognitive impairment, and targeting astrocytes might be promising in alleviating neurodegeneration in the diabetic brain. Recent studies focusing on cell-specific activities in the brain have revealed the important role of astrocytes in brain metabolism (e.g., glucose metabolism, lipid metabolism), neurovascular coupling, synapses, and synaptic plasticity. In this review, we discuss how astrocytes and their dysfunction result in multiple pathological and clinical features of AD and T2DM from a metabolic perspective and the potential comorbid mechanism in these two diseases from the perspective of astrocytes.

Keywords:  Alzheimer’s disease; Astrocyte; Metabolic disorder; Metabolism; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.biopha.2022.114206
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00149-1. [Epub ahead of print]83(6): 829-831

HK2: Gatekeeping microglial activity by tuning glucose metabolism and mitochondrial functions.

Jing Fang, Shudi Luo, Zhimin Lu.

Hexokinase 2 (HK2) plays a multifaceted role in the regulation of cellular activities. A new study by Hu et al.1 delineated a critical role of HK2 in governing glycolytic flux and mitochondrial activity, thereby modulating microglial functions in maladaptive inflammation in brain diseases.

DOI: https://doi.org/10.1016/j.molcel.2023.02.022
Neurobiol Aging. 2023 Feb 17. pii: S0197-4580(23)00036-2. [Epub ahead of print]126 14-24

Sex differences in brain metabolic connectivity architecture in probable dementia with Lewy bodies.

Alzheimer's Disease Neuroimaging Initiative

  We investigated how sex modulates metabolic connectivity alterations in probable dementia with Lewy bodies (pDLB). We included 131 pDLB patients (males/females: 58/73) and similarly aged healthy controls (HC) (male/female: 59/75) with available (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. We assessed (1) sex differences in the whole-brain connectivity, identifying pathological hubs, (2) connectivity alterations in functional pathways of the neurotransmitter systems, (3) Resting State Networks (RSNs) integrity. Both pDLBM (males) and pDLBF (females) shared dysfunctional hubs in the insula, Rolandic operculum, and inferior parietal lobule, but the pDLBM group showed more severe and diffuse whole-brain connectivity alterations. Neurotransmitters connectivity analysis revealed common alterations in dopaminergic and noradrenergic pathways. Sex differences emerged particularly in the Ch4-perisylvian division, with pDLBM showing more severe alterations than pDLBF. The RSNs analysis showed no sex differences, with decreased connectivity strength in the primary visual, posterior default mode, and attention networks in both groups. Extensive connectivity changes characterize both males and females in the dementia stage, with a major vulnerability of cholinergic neurotransmitter systems in males, possibly contributing to the observed different clinical phenotypes.

Keywords:  Alpha-synuclein; Brain Hypometabolism; Neurodegeneration; Sex; Vulnerability

DOI:  https://doi.org/10.1016/j.neurobiolaging.2023.02.004
Neuron. 2023 Mar 03. pii: S0896-6273(23)00123-X. [Epub ahead of print]

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.

Dylan V Neel, Himanish Basu, Georgia Gunner, Matthew D Bergstresser, Richard M Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong-Jie Zhang, Leonard Petrucelli, Tracey L Young-Pearse, Alice S Chen-Plotkin, Lee L Rubin, Judy Lieberman, Isaac M Chiu.

  Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neurodegeneration.

Keywords:  ALS; FTD; axon degeneration; cell death; gasdermins; innate immunity; mitochondria; neurodegeneration; neuroimmunology; pyroptosis

DOI:  https://doi.org/10.1016/j.neuron.2023.02.019
Pediatr Res. 2023 Mar 11.

Impact of two ketogenic diet types in refractory childhood epilepsy.

Ali M El-Shafie, Wael A Bahbah, Sameh A Abd El Naby, Zein A Omar, Elsayedamr M Basma, Aya A A Hegazy, Heba M S El Zefzaf.

BACKGROUND: Ketogenic diet (KD) refers to any diet in which food composition induces a ketogenic state of human metabolism.OBJECTIVE: To assess short- and long-term efficacy, safety, and tolerability of KD [classic KD and modified Atkins diet (MAD)] in childhood drug-resistant epilepsy (DRE) and to investigate the effect of KD on electroencephalographic (EEG) features of children with DRE.
METHODS: Forty patients diagnosed with DRE according to International League Against Epilepsy were included and randomly assigned into classic KD or MAD groups. KD was initiated after clinical, lipid profile and EEG documentation, and regular follow-up was done for 24 months.
RESULTS: Out of 40 patients with DRE, 30 completed this study. Both classic KD and MAD were effective in seizure control as 60% in classic KD group and 53.33% in MAD group became seizure free, and the remaining showed ≥50% seizure reduction. Lipid profile remained within acceptable levels throughout the study period in both groups. Adverse effects were mild and managed medically with an improvement of growth parameters and EEG during the study period.
CONCLUSIONS: KD is an effective and safe non-pharmacologic, non-surgical therapy for the management of DRE with a positive impact on growth and EEG.
IMPACT: Both common types of KD (classic KD and MAD) are effective for DRE, but unfortunately, nonadherence and dropout rates are frequent. High serum lipid profile (cardiovascular AE) is often suspected in children following a high-fat diet, but lipid profile remained in the acceptable level up to 24 months. Therefore, KD constitutes a safe treatment. KD had a positive impact on growth, despite inconsistent results of the KD's effect on growth. In addition to showing strong clinical effectiveness, KD also considerably decreased the frequency of interictal epileptiform discharges and enhanced the EEG background rhythm.

DOI: https://doi.org/10.1038/s41390-023-02554-w
Prostaglandins Leukot Essent Fatty Acids. 2023 Mar 11. pii: S0952-3278(23)00035-2. [Epub ahead of print]191 102566

Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in hippocampal neurogenesis of the offspring.

Vilasagaram Srinivas, Saikanth Varma, Suryam Reddy Kona, Ahamed Ibrahim, Asim K Duttaroy, Sanjay Basak.

  Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment.

Keywords:  Breast milk; DHA; Desaturase; Hippocampus; Neurogenesis; n-3 PUFA deficiency

DOI:  https://doi.org/10.1016/j.plefa.2023.102566
Brain Res. 2023 Mar 13. pii: S0006-8993(23)00094-X. [Epub ahead of print] 148324

Neuroprotective mechanisms of OXCT1 via the SIRT3-SOD2 pathway after traumatic brain injury.

Yun-Song Zhuang, Xue-Wang, Sheng-Qing Gao, Shu-Hao Miao, Tao-Li, Chao-Chao Gao, Yan-Ling Han, Jia-Yin Qiu, Meng-Liang Zhou, Han-Dong Wang.

  BACKGROUND: Ketones are not only utilized to produce energy but also play a neuroprotective role in many neurodegenerative diseases. However, whether this process has an impact on secondary brain damage after traumatic brain injury (TBI) remains unknown. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme in the intra-neuronal utilization of ketones. In this study, we investigated whether reduced expression of OXCT1 after TBI could impact neuroprotective mechanisms and exacerbate neurological dysfunction.MATERIALS AND METHODS: Experimental TBI was induced by a modified version of the weight drop model, it is a model of severe head trauma. Expression of OXCT1 in the injured hippocampus of mice was measured at different time points using immunoblotting assays. The release of abnormal mitochondrial cytochrome c from neurons of the mouse injured lateral hippocampus was measured 1 week after TBI using immunoblotting assays. Neuronal death was assessed by Nissl staining and the level of reactive oxygen species (ROS) within the neurons of the injured lateral hippocampus was assessed by Dihydroethidium staining. Results OXCT1 was overexpressed in hippocampal neurons by injection of adeno-associated virus into the lateral ventricle. OXCT1 expression levels decreased significantly 1 week post-TBI. After comparing the data obtained from different groups of mice, OXCT1 was found to significantly increase the expression of SIRT3 and reduce the proportion of acetylated SOD2, thus decreasing the production of ROS in the injured hippocampal neurons, reducing neuronal death, and improving cognitive function. Conclusions OXCT1 has a critical previously unappreciated protective role in neurological impairment following TBI via the SIR3-SOD2 pathway. These findings highlight the potential of OXCT1 as a simple treatment for patients with TBI.

Keywords:  3-Oxoacid CoA-Transferase 1; Sirtuin 3; Superoxide Dismutase 2; Traumatic brain injury; deacetylation; reactive oxygen species

DOI:  https://doi.org/10.1016/j.brainres.2023.148324
Cell Mol Neurobiol. 2023 Mar 16.

Lactate and Lactylation in the Brain: Current Progress and Perspectives.

Ruobing Li, Yi Yang, Haoyu Wang, Tingting Zhang, Fangfang Duan, Kaidi Wu, Siyu Yang, Ke Xu, Xicheng Jiang, Xiaowei Sun.

  As the final product of glycolysis, lactate features not only as an energy substrate, a metabolite, and a signaling molecule in a variety of diseases-such as cancer, inflammation, and sepsis-but also as a regulator of protein lactylation; this is a newly proposed epigenetic modification that is considered to be crucial for energy metabolism and signaling in brain tissues under both physiological and pathological conditions. In this review, evidence on lactylation from studies on lactate metabolism and disease has been summarized, revealing the function of lactate and its receptors in the regulation of brain function and summarizing the levels of lactylation expression in various brain diseases. Finally, the function of lactate and lactylation in the brain and the potential mechanisms of intervention in brain diseases are presented and discussed, providing optimal perspectives for future research on the role of lactylation in the brain.

Keywords:  Brain diseases; Epigenetic modification; Lactate; Protein lactylation

DOI:  https://doi.org/10.1007/s10571-023-01335-7
Ageing Res Rev. 2023 Mar 09. pii: S1568-1637(23)00065-X. [Epub ahead of print] 101906

Genetic Aberration Analysis of Mitochondrial Respiratory Complex I Implications in the Development of Neurological Disorders and Their Clinical Significance.

Ghulam Mehdi Dar, Ejaj Ahmad, Asgar Ali, Bhawna Mahajan, Ghulam Md Ashraf, Sundeep Singh Saluja.

  Growing neurological diseases pose difficult challenges for modern medicine to diagnose and manage them effectively. Many neurological disorders mainly occur due to genetic alteration in genes encoding mitochondrial proteins. Moreover, mitochondrial genes exhibit a higher rate of mutation due to the generation of Reactive oxygen species (ROS) during oxidative phosphorylation operating in their vicinity. Among the different complexes of Electron transport chain (ETC), NADH: Ubiquinone oxidoreductase (Mitochondrial complex I) is the most important. This multimeric enzyme, composed of 44 subunits, is encoded by both nuclear and mitochondrial genes. It often exhibits mutations resulting in development of various neurological diseases. The most prominent diseases include leigh syndrome (LS), leber hereditary optic neuropathy (LHON), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy associated with ragged-red fibers (MERRF), idiopathic Parkinson's disease (PD) and, Alzheimer's disease (AD). Preliminary data suggest that mitochondrial complex I subunit genes mutated are frequently of nuclear origin; however, most of the mtDNA gene encoding subunits are also primarily involved. In this review, we have discussed the genetic origins of neurological disorders involving mitochondrial complex I and signified recent approaches to unravel the diagnostic and therapeutic potentials and their management.

Keywords:  Complex I; Electron Transport Chain (ETC); Mitochondrial DNA (mtDNA); Neurological disorders; Oxidative Phosphorylation

DOI:  https://doi.org/10.1016/j.arr.2023.101906
Hum Brain Mapp. 2023 Mar 16.

Prediction of voluntary movements of the upper extremities by resting state-brain regional glucose metabolism in patients with chronic severe brain injury: A pilot study.

Tomohiro Yamaki, Naoya Hatakeyama, Takemi Murayama, Mika Funakura, Takuya Hara, Shinji Onodera, Daisuke Ito, Maidinamu Yakufujiang, Masaru Odaki, Nobuo Oka, Shigeki Kobayashi.

  Confirmation of the exact voluntary movements of patients with disorder of consciousness following severe traumatic brain injury (TBI) is difficult because of the associated communication disturbances. In this pilot study, we investigated whether regional brain glucose metabolism assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) at rest could predict voluntary movement in severe TBI patients, particularly those with sufficient upper limb capacity to use communication devices. We visually and verbally instructed patients to clasp or open their hands. After video capture, three independent rehabilitation therapists determined whether the patients' movements were voluntary or involuntary. The results were compared with the standardized uptake value in the primary motor cortex, referring to the Penfield's homunculus, by resting state by FDG-PET imaged 1 year prior. Results showed that glucose uptake in the left (p = 0.0015) and right (p = 0.0121) proximal limb of the primary motor cortex, based on Penfield's homunculus on cerebral cartography, may reflect contralateral voluntary movement. Receiver operating characteristic curve analysis showed that a mean cutoff standardized uptake value of 5.47 ± 0.08 provided the best sensitivity and specificity for differentiating between voluntary and involuntary movements in each area. FDG-PET may be a useful and robust biomarker for predicting long-term recovery of motor function in severe TBI patients with disorders of consciousness.

Keywords:  FDG-PET; brain injury; disorder of consciousness; traumatic brain injury

DOI:  https://doi.org/10.1002/hbm.26270
J Neurochem. 2023 Mar 15.

Excitatory Amino Acid Transporters: Beyond Their Expected Function.

Zila Martinez-Lozada, Arturo Ortega.

Glutamate is the major excitatory neurotransmitter in the vertebrate brain, it is critically involved in the function and dysfunction of the central nervous system. The molecular cloning of its ionotropic receptors in the last decade of the past century increased exponentially the interest in this neurotransmitter system. Since then, a plethora of knowledge of the structure, function, and regulation of its receptors and transporters has advanced our understanding of glutamate-mediated neurochemical transactions. Moreover, the characterization of glial glutamate receptors together with the compulsory participation of surrounding astrocytes in glutamate turnover and in the known metabolic coupling with neurons has supported what is now known as the tripartite synapses. The molecular characterization of the various glutamate transporters has also been fundamental for the involvement of glial cells in glutamatergic synapses. Using radial glial cultures, we have demonstrated an alternative glutamate-mediated signaling system triggered by the sodium-dependent glutamate transporters over the years. A detailed account of these findings and the signaling through other glutamate transporters are presented here. The role of this signaling system in the context of glutamatergic transmission is discussed, as well as the future directions in the field.

DOI: https://doi.org/10.1111/jnc.15809
Front Neurosci. 2023 ;17 1125128

Neurometabolite alterations in traumatic brain injury and associations with chronic pain.

Linda E Robayo, Varan Govind, Teddy Salan, Nicholas P Cherup, Sulaiman Sheriff, Andrew A Maudsley, Eva Widerström-Noga.

  Traumatic brain injury (TBI) can lead to a variety of comorbidities, including chronic pain. Although brain tissue metabolite alterations have been extensively examined in several chronic pain populations, it has received less attention in people with TBI. Thus, the primary aim of this study was to compare brain tissue metabolite levels in people with TBI and chronic pain (n = 16), TBI without chronic pain (n = 17), and pain-free healthy controls (n = 31). The metabolite data were obtained from participants using whole-brain proton magnetic resonance spectroscopic imaging (1H-MRSI) at 3 Tesla. The metabolite data included N-acetylaspartate, myo-inositol, total choline, glutamate plus glutamine, and total creatine. Associations between N-acetylaspartate levels and pain severity, neuropathic pain symptom severity, and psychological variables, including anxiety, depression, post-traumatic stress disorder (PTSD), and post-concussive symptoms, were also explored. Our results demonstrate N-acetylaspartate, myo-inositol, total choline, and total creatine alterations in pain-related brain regions such as the frontal region, cingulum, postcentral gyrus, and thalamus in individuals with TBI with and without chronic pain. Additionally, NAA levels in the left and right frontal lobe regions were positively correlated with post-concussive symptoms; and NAA levels within the left frontal region were also positively correlated with neuropathic pain symptom severity, depression, and PTSD symptoms in the TBI with chronic pain group. These results suggest that neuronal integrity or density in the prefrontal cortex, a critical region for nociception and pain modulation, is associated with the severity of neuropathic pain symptoms and psychological comorbidities following TBI. Our data suggest that a combination of neuronal loss or dysfunction and maladaptive neuroplasticity may contribute to the development of persistent pain following TBI, although no causal relationship can be determined based on these data.

Keywords:  N-acetylaspartate; brain metabolite; chronic pain; magnetic resonance spectroscopic imaging; traumatic brain injury

DOI:  https://doi.org/10.3389/fnins.2023.1125128
J Med Chem. 2023 Mar 16.

Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain.

Lin Qiu, Hao Jiang, Charles Zhou, Jinzhi Wang, Yanbo Yu, Haiyang Zhao, Tianyu Huang, Robert Gropler, Joel S Perlmutter, Tammie L S Benzinger, Zhude Tu.

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01752
J Pharm Anal. 2023 Feb;13(2): 187-200

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats.

Ya Zhao, Yanwei Wang, Yuying Wu, Cimin Tao, Rui Xu, Yong Chen, Linghui Qian, Tengfei Xu, Xiaoyuan Lian.

  Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

Keywords:  Hyperglycolysis; Mitochondrial fusion; Neuronal vulnerability; PKM2; Parkinson's disease; Type 1 diabetes mellitus

DOI:  https://doi.org/10.1016/j.jpha.2022.11.006
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Mar 09. pii: S1388-1981(23)00031-8. [Epub ahead of print] 159307

Identification and characterization of diacylglycerol kinase ζ as a novel enzyme producing ceramide-1-phosphate.

Ayako Yamazaki, Ayane Kawashima, Takuya Honda, Takafumi Kohama, Chiaki Murakami, Fumio Sakane, Toshihiko Murayama, Hiroyuki Nakamura.

  Ceramide-1-phosphate (C1P) is a sphingolipid formed by the phosphorylation of ceramide; it regulates various physiological functions, including cell survival, proliferation, and inflammatory responses. In mammals, ceramide kinase (CerK) is the only C1P-producing enzyme currently known. However, it has been suggested that C1P is also produced by a CerK-independent pathway, although the identity of this CerK-independent C1P was unknown. Here, we identified human diacylglycerol kinase (DGK) ζ as a novel C1P-producing enzyme and demonstrated that DGKζ catalyzes the phosphorylation of ceramide to produce C1P. Analysis using fluorescently labeled ceramide (NBD-ceramide) demonstrated that only DGKζ among ten kinds of DGK isoforms increased C1P production by transient overexpression of the DGK isoforms. Furthermore, an enzyme activity assay using purified DGKζ revealed that DGKζ could directly phosphorylate ceramide to produce C1P. Furthermore, genetic deletion of DGKζ decreased the formation of NBD-C1P and the levels of endogenous C18:1/24:1- and C18:1/26:0-C1P. Interestingly, the levels of endogenous C18:1/26:0-C1P were not decreased by the knockout of CerK in the cells. These results suggest that DGKζ is also involved in the formation of C1P under physiological conditions.

Keywords:  Ceramide kinase (CerK); Ceramide-1-phosphate (C1P); Diacylglycerol kinase (DGK); Sphingolipids

DOI:  https://doi.org/10.1016/j.bbalip.2023.159307
Cell Metab. 2023 Mar 07. pii: S1550-4131(23)00050-5. [Epub ahead of print]

Organelle-selective click labeling coupled with flow cytometry allows pooled CRISPR screening of genes involved in phosphatidylcholine metabolism.

Masaki Tsuchiya, Nobuhiko Tachibana, Kohjiro Nagao, Tomonori Tamura, Itaru Hamachi.

  Cellular lipid synthesis and transport are governed by intricate protein networks. Although genetic screening should contribute to deciphering the regulatory networks of lipid metabolism, technical challenges remain-especially for high-throughput readouts of lipid phenotypes. Here, we coupled organelle-selective click labeling of phosphatidylcholine (PC) with flow cytometry-based CRISPR screening technologies to convert organellar PC phenotypes into a simple fluorescence readout for genome-wide screening. This technique, named O-ClickFC, was successfully applied in genome-scale CRISPR-knockout screens to identify previously reported genes associated with PC synthesis (PCYT1A, ACACA), vesicular membrane trafficking (SEC23B, RAB5C), and non-vesicular transport (PITPNB, STARD7). Moreover, we revealed previously uncharacterized roles of FLVCR1 as a choline uptake facilitator, CHEK1 as a post-translational regulator of the PC-synthetic pathway, and CDC50A as responsible for the translocation of PC to the outside of the plasma membrane bilayer. These findings demonstrate the versatility of O-ClickFC as an unprecedented platform for genetic dissection of cellular lipid metabolism.

Keywords:  CRISPR screens; flow cytometry; lipid metabolism; organelle-selective labeling: click chemistry; phosphatidylcholine

DOI:  https://doi.org/10.1016/j.cmet.2023.02.014
Front Pharmacol. 2023 ;14 1113966

Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways.

Mariam A Elgamal, Dina M Khodeer, Basel A Abdel-Wahab, Ibrahim Abdel Aziz Ibrahim, Abdullah R Alzahrani, Yasser M Moustafa, Azza A Ali, Norhan M El-Sayed.

  Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against the valproic acid (VPA)-induced model of autism. VPA was injected subcutaneously (SC) into rat pups at a dose of 300 mg/kg, twice daily on postnatal day-2 (PD-2) and PD-3, and once on PD-4 to induce an autism-like syndrome. Graded doses of Cana were administered (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, P.O.) starting from the first day of VPA injections and continued for 21 days. At the end of the experiment, behavioral tests and histopathological alterations were assessed. In addition, the gene expression of peroxisome proliferator-activated receptor γ (PPAR γ), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase (PDK), cellular myeloctomatosis (c-Myc) with protein expression of glucose transporter-1 (GLUT-1), phosphatase and tensin homolog (PTEN), and level of acetylcholine (ACh) were determined. Treatment with Cana significantly counteracted histopathological changes in the cerebellum tissues of the brain induced by VPA. Cana (5 mg/kg, 7.5 mg/kg, and 10 mg/kg) improved sociability and social preference, enhanced stereotypic behaviors, and decreased hyperlocomotion activity, in addition to its significant effect on the canonical Wnt/β-catenin pathway via the downregulation of gene expression of LDHA (22%, 64%, and 73% in cerebellum tissues with 51%, 60%, and 75% in cerebrum tissues), PDK (27%, 50%, and 67% in cerebellum tissues with 34%, 66%, and 77% in cerebrum tissues), c-Myc (35%, 44%, and 72% in cerebellum tissues with 19%, 58%, and 79% in cerebrum tissues), protein expression of GLUT-1 (32%, 48%, and 49% in cerebellum tissues with 30%, 50%, and 54% in cerebrum tissues), and elevating gene expression of PPAR-γ (2, 3, and 4 folds in cerebellum tissues with 1.5, 3, and 9 folds in cerebrum tissues), protein expression of PTEN (2, 5, and 6 folds in cerebellum tissues with 6, 6, and 10 folds in cerebrum tissues), and increasing the ACh levels (4, 5, and 7 folds) in brain tissues. The current study confirmed the ameliorating effect of Cana against neurochemical and behavioral alterations in the VPA-induced model of autism in rats.

Keywords:  PDK; PPAR γ; Pten; autism; canagliflozin; valproic acid

DOI:  https://doi.org/10.3389/fphar.2023.1113966
Res Sq. 2023 Mar 02. pii: rs.3.rs-2614714. [Epub ahead of print]

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Zheng-Xiong Xi, Briana Hempel, Madeline Crissman, Sruti Pari, Benjamin Klein, Guo-Hua Bi, Hannah Alton.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is a PPARg agonist and some endocannabinoids are natural activators of PPAR a and PPARg. Therefore, both the receptors are putative cannabinoid receptors. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are highly expressed in ~70% midbrain dopamine (DA) neurons and in ~50% GABAergic and ~50% glutamatergic neurons in the amygdala. However, no PPARα/γ signal was detected in GABAergic neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ 9 -THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ 9 -THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS, suggesting that dopaminergic PPARγ modulates DA-dependent behavior. Surprisingly, pretreatment with PPARα or PPARγ antagonists dose-dependently attenuated the Δ 9 -THC-induced reduction in oICSS and anxiogenic effects. In addition, a PPARγ agonist increased, while PPARa or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARa or PPARγ antagonists potentiated Δ 9 -THC-induced hypoactivity and catalepsy but failed to alter Δ 9 -THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARa/g in DA-dependent behavior and cannabinoid action.

DOI: https://doi.org/10.21203/rs.3.rs-2614714/v1
Front Neurosci. 2023 ;17 1147269

Nutrition and adult neurogenesis in the hippocampus: Does what you eat help you remember?

Sonia Melgar-Locatelli, Marialuisa de Ceglia, M Carmen Mañas-Padilla, Celia Rodriguez-Pérez, Estela Castilla-Ortega, Adriana Castro-Zavala, Patricia Rivera.

  Neurogenesis is a complex process by which neural progenitor cells (NPCs)/neural stem cells (NSCs) proliferate and differentiate into new neurons and other brain cells. In adulthood, the hippocampus is one of the areas with more neurogenesis activity, which is involved in the modulation of both emotional and cognitive hippocampal functions. This complex process is affected by many intrinsic and extrinsic factors, including nutrition. In this regard, preclinical studies performed in rats and mice demonstrate that high fats and/or sugars diets have a negative effect on adult hippocampal neurogenesis (AHN). In contrast, diets enriched with bioactive compounds, such as polyunsaturated fatty acids and polyphenols, as well as intermittent fasting or caloric restriction, can induce AHN. Interestingly, there is also growing evidence demonstrating that offspring AHN can be affected by maternal nutrition in the perinatal period. Therefore, nutritional interventions from early stages and throughout life are a promising perspective to alleviate neurodegenerative diseases by stimulating neurogenesis. The underlying mechanisms by which nutrients and dietary factors affect AHN are still being studied. Interestingly, recent evidence suggests that additional peripheral mediators may be involved. In this sense, the microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could act as a link between nutritional factors and AHN. The aim of this mini-review is to summarize, the most recent findings related to the influence of nutrition and diet in the modulation of AHN. The importance of maternal nutrition in the AHN of the offspring and the role of the microbiota-gut-brain axis in the nutrition-neurogenesis relationship have also been included.

Keywords:  adult neurogenesis; diet; gut microbiota; hippocampus; nutrients; perinatal programming

DOI:  https://doi.org/10.3389/fnins.2023.1147269
Cureus. 2023 Mar;15(3): e36018

A Young Female With Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD): A Case Report.

Ibidapo Q Yusuf, Aadithiyavikram Venkatesan, Faith C Okafor, Athar Yasin, Samson O Oyibo.

  Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is a rare autosomal recessive inborn error of mitochondrial fatty acid oxidation. MCAD is essential for fatty acid β-oxidation during hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores are exhausted during extended fasting and periods of increased energy demand. The inability to metabolize these fatty acids results in hypoketotic hypoglycemia and the accumulation of toxic partially metabolized fatty acids. Intercurrent infection, extended fasting, excessive alcohol intake, vomiting, or diarrhea can lead to serious illness, including encephalopathy and even sudden death. Young people with MCADD are followed up on a regular basis by their metabolic disease specialist, and they are informed about risk factors as they advance through adolescence and adulthood. They should also carry along a written emergency management plan and relevant contact numbers. We describe a case of a 17-year-old female who attended her local emergency care center complaining of severe abdominal pain, vomiting, muscle ache, and poor oral intake. She was known to have MCADD; however, her emergency care plan had a date from eight years ago. She made a rapid recovery after receiving intravenous glucose and other therapies. The patient's concerns and knowledge about MCADD were not fully appreciated at the initial stage due to the rare nature of the disease. This in combination with the absence of current notes on the system, an emergency care plan dated from eight years ago, and the need to obtain specialist advice led to a slight delay in commencing specific therapy. This case report serves as a reminder of the emergency presentation of young people with MCADD, emphasizing the importance of effective communication between the patient, their parents, and the treating clinicians, obtaining the emergency care plan and recommendations, and communicating with the metabolic disease specialist.

Keywords:  acyl-coa dehydrogenase; emergency care plan; exercise training; hypoketotic hypoglycemia; mcadd; medium-chain acyl-coa dehydrogenase; medium-chain acyl-coa dehydrogenase deficiency; metabolic crisis; rhabdomyolysis; sports injury surgery

DOI:  https://doi.org/10.7759/cureus.36018
Neuroglia. 2022 Jun;3(2): 73-83

Fabp7 Is Required for Normal Sleep Suppression and Anxiety-Associated Phenotype following Single-Prolonged Stress in Mice.

William M Vanderheyden, Micah Lefton, Carlos C Flores, Yuji Owada, Jason R Gerstner.

  Humans with post-traumatic stress disorder (PTSD) exhibit sleep disturbances that include insomnia, nightmares, and enhanced daytime sleepiness. Sleep disturbances are considered a hallmark feature of PTSD; however, little is known about the cellular and molecular mechanisms regulating trauma-induced sleep disorders. Using a rodent model of PTSD called "Single Prolonged Stress" (SPS) we examined the requirement of the brain-type fatty acid binding protein Fabp7, an astrocyte expressed lipid-signaling molecule, in mediating trauma-induced sleep disturbances. We measured baseline sleep/wake parameters and then exposed Fabp7 knock-out (KO) and wild-type (WT) C57BL/6N genetic background control animals to SPS. Sleep and wake measurements were obtained immediately following the initial trauma exposure of SPS, and again 7 days later. We found that active-phase (dark period) wakefulness was similar in KO and WT at baseline and immediately following SPS; however, it was significantly increased after 7 days. These effects were opposite in the inactive-phase (light period), where KOs exhibited increased wake in baseline and following SPS, but returned to WT levels after 7 days. To examine the effects of Fabp7 on unconditioned anxiety following trauma, we exposed KO and WT mice to the light-dark box test before and after SPS. Prior to SPS, KO and WT mice spent similar amounts of time in the lit compartment. Following SPS, KO mice spent significantly more time in the lit compartment compared to WT mice. These results demonstrate that mutations in an astrocyte-expressed gene (Fabp7) influence changes in stress-dependent sleep disturbances and associated anxiety behavior.

Keywords:  anxiolytic; blbp; fear; glia; lipid signaling; stress

DOI:  https://doi.org/10.3390/neuroglia3020005