bims-medebr 2023-09-10 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒09‒10
27 papers selected by
Regina F. Fernández, Johns Hopkins University

What is good for the heart is good for brain glucose metabolism.
Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.
Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.
Impaired glucose utilization in the brain of patients with delirium following hip fracture.
Local and dynamic regulation of neuronal glycolysis in vivo.
D - β -hydroxybutyrate stabilizes the hippocampal CA3-CA1 circuit during acute insulin resistance.
Memantine Improves the Disturbed Glutamine and γ-Amino Butyric Acid Homeostasis in the Brain of Rats Subjected to Experimental Autoimmune Encephalomyelitis.
Metabolic Brain Changes Can Predict the Underlying Pathology in Neurodegenerative Brain Disorders: A Case Report of Sporadic Creutzfeldt-Jakob Disease with Concomitant Parkinson's Disease.
Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination.
Lipid metabolism in malignant tumor brain metastasis: reprogramming and therapeutic potential.
Brain-derived neurotrophic factor protects neurons by stimulating mitochondrial function through protein kinase A.
SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats.
Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis.
Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.
Nicotinamide enhances myelin production after demyelination through reduction of astrogliosis and microgliosis.
Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease.
Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.
The impact of ketogenic diet on the onset and progression of multiple sclerosis.
Lipid and glucose metabolism in senescence.
Longitudinal transcriptomic analysis of human cortical spheroids identifies axonal dysregulation in the prenatal brain as a mediator of genetic risk for schizophrenia.
Spatial multimodal analysis of transcriptomes and metabolomes in tissues.
Lipid metabolism transcriptomics of murine microglia in Alzheimer's disease and neuroinflammation.
N-palmitoylethanolamine modulates hippocampal neuroplasticity in rats with stress-induced depressive behavior phenotype.
Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA.
Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism.
Regulatory Effects and Mechanisms of L-Theanine on Neurotransmitters via Liver-Brain Axis Under a High Protein Diet.
Suppressive Effects of Docosahexaenoic Acid Intake on Increased Seizure Susceptibility after Growth Due to Febrile Seizures in Infancy.

Lancet Healthy Longev. 2023 Sep;pii: S2666-7568(23)00167-8. [Epub ahead of print]4(9): e448-e449

What is good for the heart is good for brain glucose metabolism.

Makoto Ishii.

DOI: https://doi.org/10.1016/S2666-7568(23)00167-8
Int J Mol Sci. 2023 Aug 29. pii: 13398. [Epub ahead of print]24(17):

Lactate Metabolism, Signaling, and Function in Brain Development, Synaptic Plasticity, Angiogenesis, and Neurodegenerative Diseases.

Anika Wu, Daehoon Lee, Wen-Cheng Xiong.

  Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous influx of metabolic substrates from the blood. Disruption of this process can lead to impairment of neurological functions, loss of consciousness, and coma within minutes. Intricate neurovascular networks permit both spatially and temporally appropriate metabolic substrate delivery. Lactate is the end product of anaerobic or aerobic glycolysis, converted from pyruvate by lactate dehydrogenase-5 (LDH-5). Although abundant in the brain, it was traditionally considered a byproduct or waste of glycolysis. However, recent evidence indicates lactate may be an important energy source as well as a metabolic signaling molecule for the brain and astrocytes-the most abundant glial cell-playing a crucial role in energy delivery, storage, production, and utilization. The astrocyte-neuron lactate-shuttle hypothesis states that lactate, once released into the extracellular space by astrocytes, can be up-taken and metabolized by neurons. This review focuses on this hypothesis, highlighting lactate's emerging role in the brain, with particular emphasis on its role during development, synaptic plasticity, angiogenesis, and disease.

Keywords:  development; dysmetabolism; energy; lactate; neurodegeneration; neuroprotective; synaptic plasticity

DOI:  https://doi.org/10.3390/ijms241713398
Front Aging Neurosci. 2023 ;15 1230467

Potential benefits of medium chain fatty acids in aging and neurodegenerative disease.

Ella Dunn, Biqin Zhang, Virender K Sahota, Hrvoje Augustin.

  Neurodegenerative diseases are a large class of neurological disorders characterized by progressive dysfunction and death of neurones. Examples include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Aging is the primary risk factor for neurodegeneration; individuals over 65 are more likely to suffer from a neurodegenerative disease, with prevalence increasing with age. As the population ages, the social and economic burden caused by these diseases will increase. Therefore, new therapies that address both aging and neurodegeneration are imperative. Ketogenic diets (KDs) are low carbohydrate, high-fat diets developed initially as an alternative treatment for epilepsy. The classic ketogenic diet provides energy via long-chain fatty acids (LCFAs); naturally occurring medium chain fatty acids (MCFAs), on the other hand, are the main components of the medium-chain triglyceride (MCT) ketogenic diet. MCT-based diets are more efficient at generating the ketone bodies that are used as a secondary energy source for neurones and astrocytes. However, ketone levels alone do not closely correlate with improved clinical symptoms. Recent findings suggest an alternative mode of action for the MCFAs, e.g., via improving mitochondrial biogenesis and glutamate receptor inhibition. MCFAs have been linked to the treatment of both aging and neurodegenerative disease via their effects on metabolism. Through action on multiple disease-related pathways, MCFAs are emerging as compounds with notable potential to promote healthy aging and ameliorate neurodegeneration. MCFAs have been shown to stimulate autophagy and restore mitochondrial function, which are found to be disrupted in aging and neurodegeneration. This review aims to provide insight into the metabolic benefits of MCFAs in neurodegenerative disease and healthy aging. We will discuss the use of MCFAs to combat dysregulation of autophagy and mitochondrial function in the context of "normal" aging, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease.

Keywords:  Alzheimer’s disease; Parkinson’ s disease; ageing; amyotrophic lateral sclerosis; autophagy; ketogenic diet (KD); medium chain fatty acid (MCFA); mitochondria

DOI:  https://doi.org/10.3389/fnagi.2023.1230467
Brain. 2023 Sep 02. pii: awad296. [Epub ahead of print]

Impaired glucose utilization in the brain of patients with delirium following hip fracture.

Irit Titlestad, Leiv Otto Watne, Gideon A Caplan, Adrian McCann, Per Magne Ueland, Bjørn Erik Neerland, Marius Myrstad, Nathalie Bodd Halaas, Christian Thomas Pollmann, Kristi Henjum, Anette Hylen Ranhoff, Lene B Solberg, Wender Figved, Colm Cunningham, Lasse M Giil.

  Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there is limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (SD 10), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate, and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

Keywords:  3-hydroxyisobutyrate; acetoacetate; branched-chain amino acids; lactate; β-hydroxybutyrate

DOI:  https://doi.org/10.1093/brain/awad296
bioRxiv. 2023 Aug 26. pii: 2023.08.25.554774. [Epub ahead of print]

Local and dynamic regulation of neuronal glycolysis in vivo.

Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Marc Hammarlund, Anthony Hyman, Philip Js Stork, Richard 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 C. elegans to image dynamic changes in glycolysis within individual neurons and in vivo . We determined that neurons perform glycolysis cell-autonomously, 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 new relationships between neuronal identities and metabolic landscapes in vivo .Significance statement: While it is generally accepted that energy metabolism underpins neuronal function, how it is distributed and dynamically regulated in different tissues of the brain to meet varying energy demands is not well understood. Here we utilized a fluorescent biosensor, HYlight, to observe glycolytic metabolism at cellular and subcellular scales in vivo . By leveraging both the stereotyped identities of individual neurons in C. elegans, and genetic tools for manipulating glycolytic metabolism, we determined that neurons perform and dynamically regulate glycolysis to match changing cellular demands for energy. Our findings support a model whereby glycolytic states should be considered distinct and related to individual neuron identities in vivo , and introduce new questions about the interconnected nature of metabolism and neuronal function.

DOI: https://doi.org/10.1101/2023.08.25.554774
bioRxiv. 2023 Aug 24. pii: 2023.08.23.554428. [Epub ahead of print]

D - β -hydroxybutyrate stabilizes the hippocampal CA3-CA1 circuit during acute insulin resistance.

Bartosz Kula, Botond Antal, Corey Weistuch, Florian Gackière, Alexander Barre, Victor Velado, Jeffrey M Hubbard, Maria Kukley, Lilianne R Mujica-Parodi, Nathan A Smith.

The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KB) during low glucose availability. Neuronal KB uptake, which does not rely on the glucose transporter 4 (GLUT4) and insulin, has shown promising clinical applications in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of the exogenous KB D-β-hydroxybutyrate (D-βHb) on mouse brain metabolism during acute insulin resistance (AIR). We found the impacts of AIR and D-βHb to be qualitatively distinct across neuronal compartments: AIR decreased synaptic activity and LTP, and impaired axonal conduction, synchronization, and action potential (AP) properties. D-βHb rescued neuronal functions connected to axonal conduction and synchronization but did not rescue synaptic activity. While D-βHB failed to rescue synaptic activity, it successfully rescued neuronal functions associated with axonal conduction and synchronization. Teaser: D-βHb reverses detrimental effects of acute insulin resistance in the hippocampus, with distinct effects on soma, dendrites, and axons.

DOI: https://doi.org/10.1101/2023.08.23.554428
Int J Mol Sci. 2023 Aug 24. pii: 13149. [Epub ahead of print]24(17):

Memantine Improves the Disturbed Glutamine and γ-Amino Butyric Acid Homeostasis in the Brain of Rats Subjected to Experimental Autoimmune Encephalomyelitis.

Beata Dąbrowska-Bouta, Lidia Strużyńska, Marta Sidoryk-Węgrzynowicz, Grzegorz Sulkowski.

  Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate-glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron-astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA.

Keywords:  EAE; GABA; PAG; amino acid transport; glutamine synthase

DOI:  https://doi.org/10.3390/ijms241713149
Int J Mol Sci. 2023 Aug 23. pii: 13081. [Epub ahead of print]24(17):

Metabolic Brain Changes Can Predict the Underlying Pathology in Neurodegenerative Brain Disorders: A Case Report of Sporadic Creutzfeldt-Jakob Disease with Concomitant Parkinson's Disease.

Tomaž Rus, Jernej Mlakar, Jan Jamšek, Maja Trošt.

  The co-occurrence of multiple proteinopathies is being increasingly recognized in neurodegenerative disorders and poses a challenge in differential diagnosis and patient selection for clinical trials. Changes in brain metabolism captured by positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) allow us to differentiate between different neurodegenerative disorders either by visual exploration or by studying disease-specific metabolic networks in individual patients. However, the impact of multiple proteinopathies on brain metabolism and metabolic networks remains unknown due to the absence of pathological studies. In this case study, we present a 67-year-old patient with rapidly progressing dementia clinically diagnosed with probable sporadic Creutzfeldt-Jakob disease (sCJD). However, in addition to the expected pronounced cortical and subcortical hypometabolism characteristic of sCJD, the brain FDG PET revealed an intriguing finding of unexpected relative hypermetabolism in the bilateral putamina, raising suspicions of coexisting Parkinson's disease (PD). Additional investigation of disease-specific metabolic brain networks revealed elevated expression of both CJD-related pattern (CJDRP) and PD-related pattern (PDRP) networks. The patient eventually developed akinetic mutism and passed away seven weeks after symptom onset. Neuropathological examination confirmed neuropathological changes consistent with sCJD and the presence of Lewy bodies confirming PD pathology. Additionally, hyperphosphorylated tau and TDP-43 pathology were observed, a combination of four proteinopathies that had not been previously reported. Overall, this case provides valuable insights into the complex interplay of neurodegenerative pathologies and their impact on metabolic brain changes, emphasizing the role of metabolic brain imaging in evaluating potential presence of multiple proteinopathies.

Keywords:  Creutzfeldt–Jakob disease; FDG PET; Parkinson’s disease; brain networks analysis; multiple co-proteinopathy

DOI:  https://doi.org/10.3390/ijms241713081
Proc Natl Acad Sci U S A. 2023 Sep 12. 120(37): e2301030120

Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination.

Aida V Garcia Corrales, Sanne G S Verberk, Mansour Haidar, Elien Grajchen, Jonas Dehairs, Sam Vanherle, Melanie Loix, Tine Weytjens, Pascal Gervois, Takashi Matsuzaka, Ivo Lambrichts, Johannes V Swinnen, Jeroen F J Bogie, Jerome J A Hendriks.

  A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and monounsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of Elovl6 induced a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway. Elovl6-deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases.

Keywords:  fatty acid metabolism; macrophage; multiple sclerosis; remyelination

DOI:  https://doi.org/10.1073/pnas.2301030120
Expert Opin Ther Targets. 2023 Sep 08. 1-18

Lipid metabolism in malignant tumor brain metastasis: reprogramming and therapeutic potential.

Yan-Jie Cheng, Fan Fan, Zhong Zhang, Hai-Jun Zhang.

  INTRODUCTION: Brain metastasis is a highly traumatic event in the progression of malignant tumors, often symbolizing higher mortality. Metabolic alterations are hallmarks of cancer, and the mask of lipid metabolic program rearrangement in cancer progression is gradually being unraveled.AREAS COVERED: In this work, we reviewed clinical and fundamental studies related to lipid expression and activity changes in brain metastases originating from lung, breast, and cutaneous melanomas, respectively. Novel roles of lipid metabolic reprogramming in the development of brain metastasis from malignant tumors were identified and its potential as a therapeutic target was evaluated. Published literature and clinical studies in databases consisting of PubMed, Embase, Scopus and www.ClinicalTrials.gov from 1990 to 2022 were searched.
EXPERT OPINION: Lipid metabolic reprogramming in brain metastasis is involved in de novo lipid synthesis within low lipid availability environments, regulation of lipid uptake and storage, metabolic interactions between brain tumors and the brain microenvironment, and membrane lipid remodeling, in addition to being a second messenger for signal transduction. Although some lipid metabolism modulators work efficiently in preclinical models, there is still a long way to go from laboratory to clinic. This area of research holds assurance for the organ-targeted treatment of brain metastases through drug-regulated metabolic targets and dietary interventions.

Keywords:  Brain metastasis; de novo lipogenesis; fatty acid synthase; lipid metabolism; malignant tumor; membrane lipid remodeling; microenvironment

DOI:  https://doi.org/10.1080/14728222.2023.2255377
J Neurochem. 2023 Sep 09.

Brain-derived neurotrophic factor protects neurons by stimulating mitochondrial function through protein kinase A.

Maryann Swain, Smijin K Soman, Kylea Tapia, Raul Y Dagda, Ruben K Dagda.

  Brain-derived neurotrophic factor (BDNF) stimulates dendrite outgrowth and synaptic plasticity by activating downstream protein kinase A (PKA) signaling. Recently, BDNF has been shown to modulate mitochondrial respiration in isolated brain mitochondria, suggesting that BDNF can modulate mitochondrial physiology. However, the molecular mechanisms by which BDNF stimulates mitochondrial function in neurons remain to be elucidated. In this study, we surmised that BDNF binds to the TrkB receptor and translocates to mitochondria to govern mitochondrial physiology in a PKA-dependent manner. Confocal microscopy and biochemical subcellular fractionation assays confirm the localization of the TrkB receptor in mitochondria. The translocation of the TrkB receptor to mitochondria was significantly enhanced upon treating primary cortical neurons with exogenous BDNF, leading to rapid PKA activation. Showing a direct role of BDNF in regulating mitochondrial structure/function, time-lapse confocal microscopy in primary cortical neurons showed that exogenous BDNF enhances mitochondrial fusion, anterograde mitochondrial trafficking, and mitochondrial content within dendrites, which led to increased basal and ATP-linked mitochondrial respiration and glycolysis as assessed by an XF24e metabolic analyzer. BDNF-mediated regulation of mitochondrial structure/function requires PKA activity as treating primary cortical neurons with a pharmacological inhibitor of PKA or transiently expressing constructs that target an inhibitor peptide of PKA (PKI) to the mitochondrion abrogated BDNF-mediated mitochondrial fusion and trafficking. Mechanistically, western/Phos-tag blots show that BDNF stimulates PKA-mediated phosphorylation of Drp1 and Miro-2 to promote mitochondrial fusion and elevate mitochondrial content in dendrites, respectively. Effects of BDNF on mitochondrial function were associated with increased resistance of neurons to oxidative stress and dendrite retraction induced by rotenone. Overall, this study revealed new mechanisms of BDNF-mediated neuroprotection, which entails enhancing mitochondrial health and function of neurons.

Keywords:  BDNF; PKA; TrkB; bioenergetics; mitochondrial dynamics; mitochondrial trafficking

DOI:  https://doi.org/10.1111/jnc.15945
Mol Neurobiol. 2023 Sep 05.

SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats.

Junke Jia, Wanjiang Tao, Ting Chen, Qi Zhong, Jiahui Sun, Yutong Xu, Xiaokai Sui, Chang Chen, Zongze Zhang.

  OBJECTIVE: Prolonged sleep deprivation is known to have detrimental effects on the hippocampus during development or in adulthood. Furthermore, it is well-established that sleep deprivation disrupts energy metabolism broadly. SIRT6 is a critical regulator of energy metabolism in both central and peripheral tissues. This study aims to investigate the role of SIRT6 in modulating hippocampal neurogenesis following sleep deprivation during development, and elucidate the underlying mechanism.METHODS: Male Sprague-Dawley rats, aged three weeks, were subjected to 2 weeks of sleep deprivation using the modified multiple platform method. Metabolomic profiling was carried out using the liquid chromatography-electrospray ionization-tandem mass spectrometry (LC‒ESI‒MS/MS). To investigate the role of SIRT6 in energy metabolism, the rats were administered with either the SIRT6-specific inhibitor, OSS128167, or SIRT6-overexpressing adeno-associated virus (AAV). Hippocampal neurogenesis was assessed by immunostaining with markers for neural stem cells (SOX2), immature neurons [doublecortin (DCX)] and newborn cells (BrdU). Sparse labeling of adult neurons was used to determine the density of dendritic spines in the dentate gyrus (DG). The Y-maze and novel object recognition (NOR) tests were performed to evaluate the spatial and recognition memory. SIRT6 expression was examined using immunofluorescence and western blotting (WB). The inhibition of SIRT6 was confirmed by assessing the acetylation of histone 3 lysine 9 (aceH3K9), a well-known substrate of SIRT6, through WB.
RESULTS: Sleep deprivation for a period of two weeks leads to inhibited hippocampal neurogenesis, reduced density of dendritic spines in the DG, and impaired memory, accompanied by decreased SIRT6 expression and disrupted energy metabolism. Similar to sleep deprivation, administration of OSS128167 significantly decreased energy metabolism, leading to reduced neurogenesis and memory dysfunction. Notably, the abnormal hippocampal energy metabolism, neurogenetic pathological changes and memory dysfunction caused by sleep deprivation were alleviated by SIRT6 overexpression in the DG.
CONCLUSION: Our results suggest that SIRT6 plays a critical role in maintaining energy metabolism homeostasis in the hippocampus after sleep deprivation, promoting hippocampal neurogenesis and enhancing memory during development.

Keywords:  Development; Energy metabolism; Neurogenesis; SIRT6; Sleep deprivation

DOI:  https://doi.org/10.1007/s12035-023-03585-4
Glia. 2023 Sep 05.

Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis.

Takahiro Fuchigami, Yutaka Itokazu, Robert K Yu.

  The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia-like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogeneous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent on their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3-synthase knockout (GD3S-KO) mouse brains. The specific roles of GD3 in determining the stage and cell-lineage determination of NSCs remain unclear, since global GD3S-KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here, we show that inducible GD3 deletion in postnatal radial glia-like NSCs promotes NSC activation, resulting in the loss of the long-term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S-conditional-knockout mice led to the impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia-like NSCs in the adult NSC niche.

Keywords:  GD3 ganglioside; adult neurogenesis; memory; neural stem cell; olfaction; quiescence; radial glia

DOI:  https://doi.org/10.1002/glia.24468
J Physiol. 2023 Sep 05.

Enhanced mitochondrial buffering prevents Ca2+ overload in naked mole-rat brain.

Hang Cheng, Guy A Perkins, Saeyeon Ju, Keunyoung Kim, Mark H Ellisman, Matthew E Pamenter.

  Deleterious Ca2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia-mediated increases in cytosolic Ca2+ are retarded in hypoxia-tolerant naked mole-rat brain. We hypothesized that naked mole-rat brain mitochondria have an enhanced capacity to buffer exogenous Ca2+ and examined Ca2+ handling in naked mole-rat cortical tissue. We report that naked mole-rat brain mitochondria buffer >2-fold more exogenous Ca2+ than mouse brain mitochondria, and that the half-maximal inhibitory concentration (IC50 ) at which Ca2+ inhibits aerobic oxidative phosphorylation is >2-fold higher in naked mole-rat brain. The primary driving force of Ca2+ uptake is the mitochondrial membrane potential (Δψm ), and the IC50 at which Ca2+ decreases Δψm is ∼4-fold higher in naked mole-rat than mouse brain. The ability of naked mole-rat brain mitochondria to safely retain large volumes of Ca2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca2+ in mitochondria. Specifically, and relative to mouse brain, naked mole-rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca2+ management. We propose that excessive Ca2+ influx into naked mole-rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca2+ overload and may thus contribute to the hypoxia and ischaemia-tolerance of naked mole-rat brain. KEY POINTS: Unregulated Ca2+ influx is a hallmark of hypoxic brain death; however, hypoxia-mediated Ca2+ influx into naked mole-rat brain is markedly reduced relative to mice. This is important because naked mole-rat brain is robustly tolerant against in vitro hypoxia, and because Ca2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole-rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca2+ stress. This is due to mitochondrial buffering of exogenous Ca2+ and is driven by a mitochondrial membrane potential-dependant mechanism. The unique ultrastructure of naked mole-rat brain mitochondria, as a large physical storage space, may support increased Ca2+ buffering and thus hypoxia-tolerance.

Keywords:  electron transport system; membrane potential; mitochondrial permeability transition pore; oxidative phosphorylation

DOI:  https://doi.org/10.1113/JP285002
Front Cell Neurosci. 2023 ;17 1201317

Nicotinamide enhances myelin production after demyelination through reduction of astrogliosis and microgliosis.

Stefanos Ioannis Kaplanis, Despoina Kaffe, Niki Ktena, Andriani Lygeraki, Ourania Kolliniati, Maria Savvaki, Domna Karagogeos.

  Caloric restriction is the chronic reduction of total caloric intake without malnutrition and has attracted a lot of attention as, among multiple other effects, it attenuates demyelination and stimulates remyelination. In this study we have evaluated the effect of nicotinamide (NAM), a well-known caloric restriction mimetic, on myelin production upon demyelinating conditions. NAM is the derivative of nicotinic acid (vitamin B3) and a precursor of nicotinamide adenine dinucleotide (NAD+), a ubiquitous metabolic cofactor. Here, we use cortical slices ex vivo subjected to demyelination or cultured upon normal conditions, a lysolecithin (LPC)-induced focal demyelination mouse model as well as primary glial cultures. Our data show that NAM enhances both myelination and remyelination ex vivo, while it also induces myelin production after LPC-induced focal demyelination ex vivo and in vivo. The increased myelin production is accompanied by reduction in both astrogliosis and microgliosis in vivo. There is no direct effect of NAM on the oligodendrocyte lineage, as no differences are observed in oligodendrocyte precursor cell proliferation or differentiation or in the number of mature oligodendrocytes. On the other hand, NAM affects both microglia and astrocytes as it decreases the population of M1-activated microglia, while reducing the pro-inflammatory phenotype of astrocytes as assayed by the reduction of TNF-α. Overall, we show that the increased myelin production that follows NAM treatment in vivo is accompanied by a decrease in both astrocyte and microglia accumulation at the lesion site. Our data indicate that NAM influences astrocytes and microglia directly, in favor of the remyelination process by promoting a less inflammatory environment.

Keywords:  astrocytes; caloric restriction; microglia; myelin; nicotinamide (NAM); remyelination

DOI:  https://doi.org/10.3389/fncel.2023.1201317
Dis Model Mech. 2023 Sep 08. pii: dmm.050238. [Epub ahead of print]

Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease.

Akanksha Onkar, Deepashree Sheshadri, Anupama Rai, Arjit Kant Gupta, Nitin Gupta, Subramaniam Ganesh.

  Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal glycogen and glycogen synthase in the context of Huntington's disease. To gain insight into the role of brain glycogen in regulating proteotoxicity, we utilized a Drosophila model of Huntington's disease in which glycogen synthase was either knocked down or expressed ectopically. Enhancing glycogen synthesis in the brains of flies with Huntington's disease decreased mutant Huntingtin aggregation and reduced oxidative stress by activating auto-lysosomal functions. Further, the overexpression of glycogen synthase in the brain rescues photoreceptor degeneration, improves locomotor deficits, and increases fitness traits in Huntington's disease model. We thus provide in vivo evidence for the neuroprotective functions of glycogen synthase and glycogen in neurodegenerative conditions and their role in the neuronal autophagy process.

Keywords:  Aging; Autophagy; Glycogen synthase; Neurodegenerative disorders; Oxidative stress

DOI:  https://doi.org/10.1242/dmm.050238
Redox Biol. 2023 Aug 29. pii: S2213-2317(23)00266-5. [Epub ahead of print]66 102865

Emerging role of metabolic reprogramming in hyperoxia-associated neonatal diseases.

Tong Sun, Haiyang Yu, Danni Li, He Zhang, Jianhua Fu.

  Oxygen therapy is common during the neonatal period to improve survival, but it can increase the risk of oxygen toxicity. Hyperoxia can damage multiple organs and systems in newborns, commonly causing lung conditions such as bronchopulmonary dysplasia and pulmonary hypertension, as well as damage to other organs, including the brain, gut, and eyes. These conditions are collectively referred to as newborn oxygen radical disease to indicate the multi-system damage caused by hyperoxia. Hyperoxia can also lead to changes in metabolic pathways and the production of abnormal metabolites through a process called metabolic reprogramming. Currently, some studies have analyzed the mechanism of metabolic reprogramming induced by hyperoxia. The focus has been on mitochondrial oxidative stress, mitochondrial dynamics, and multi-organ interactions, such as the lung-gut, lung-brain, and brain-gut axes. In this article, we provide an overview of the major metabolic pathway changes reported in hyperoxia-associated neonatal diseases and explore the potential mechanisms of metabolic reprogramming. Metabolic reprogramming induced by hyperoxia can cause multi-organ metabolic disorders in newborns, including abnormal glucose, lipid, and amino acid metabolism. Moreover, abnormal metabolites may predict the occurrence of disease, suggesting their potential as therapeutic targets. Although the mechanism of metabolic reprogramming caused by hyperoxia requires further elucidation, mitochondria and the gut-lung-brain axis may play a key role in metabolic reprogramming.

Keywords:  Bronchopulmonary dysplasia; Hyperoxia; Metabolic reprogramming; Mitochondria; Neonate

DOI:  https://doi.org/10.1016/j.redox.2023.102865
Eur J Microbiol Immunol (Bp). 2023 Sep 04.

The impact of ketogenic diet on the onset and progression of multiple sclerosis.

Jurij D Brockhoff, Stefan Bereswill, Markus M Heimesaat.

  Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by inflammation and neurodegeneration. Current research suggests that diet may influence disease course, severity of symptoms, and quality of life in MS patients. The ketogenic diet (KD) has been used for more than a century as a therapeutic approach for various medical conditions. It was originally developed in the 1920s as a treatment option for epilepsy, and especially in the last 30 years, has gained popularity for its potential benefits in a variety of neurological conditions other than epilepsy. This prompted us to perform a literature survey regarding the effect of KD on the onset and progression of MS. The here reviewed 15 original research articles including in vitro, preclinical, and clinical studies provide evidence for the safety and feasibility of the KD in MS, showing potential neuroprotective effects and positive impacts on cellular metabolism and disease outcome. Since the literature is limited and most studies were conducted with low numbers of MS patients and rather exploratory in nature, further studies with larger cohorts are needed to gain a better understanding of the mechanisms by which the improvements of the MS disease course are achieved.

Keywords:  Ketogenic diet; cuprizone (CPZ) model; demyelinating autoimmune diseases in CNS; experimental autoimmune encephalomyelitis (EAE) model; multiple sclerosis; neuroprotective effects

DOI:  https://doi.org/10.1556/1886.2023.00020
Front Nutr. 2023 ;10 1157352

Lipid and glucose metabolism in senescence.

Bin Liu, Qingfei Meng, Xin Gao, Huihui Sun, Zhixiang Xu, Yishu Wang, Honglan Zhou.

  Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.

Keywords:  ACC; ACOX1; CPT1; PPP; TCA; glycolysis; lipid metabolism; senescence

DOI:  https://doi.org/10.3389/fnut.2023.1157352
Biol Psychiatry. 2023 Sep 01. pii: S0006-3223(23)01529-9. [Epub ahead of print]

Longitudinal transcriptomic analysis of human cortical spheroids identifies axonal dysregulation in the prenatal brain as a mediator of genetic risk for schizophrenia.

Ibrahim A Akkouh, Thor Ueland, Attila Szabo, Timothy Hughes, Olav B Smeland, Ole A Andreassen, Jordi Requena Osete, Srdjan Djurovic.

  BACKGROUND: Schizophrenia (SCZ) has a known neurodevelopmental etiology, but limited access to human prenatal brain tissue hampers the investigation of basic disease mechanisms in early brain development. Here, we elucidate the molecular mechanisms contributing to SCZ risk in a disease-relevant model of the prenatal human brain.METHODS: We generated induced pluripotent stem cell-derived cortical spheroids (hCSs) from a large and genetically stratified sample of 14 SCZ patients and 14 age and sex-matched controls (CTRL). The hCSs were differentiated for 150 days, and comprehensive molecular characterization across four time points was carried out.
RESULTS: The transcriptional and cellular architecture of hCSs closely resembled that of 10-24 post-conception week fetal brain, showing strongest spatial overlap with frontal regions of the cerebral cortex. A total of 3,520 genes were differentially modulated between SCZ and CTRL hCSs across organoid maturation, displaying a significant contribution of genetic loading, an over-representation of risk genes for autism spectrum disorder and SCZ, and strongest enrichment for axonal processes in all hCS stages. The two axon guidance genes SEMA7A and SEMA5A, the first a promoter of synaptic functions and the second a repressor, were down and up-regulated in SCZ hCSs, respectively. This expression pattern was confirmed at the protein level and replicated in a large post-mortem sample.
CONCLUSIONS: Applying a disease-relevant model of the developing fetal brain, we identified consistent dysregulation of axonal genes as an early risk factor for SCZ, providing novel insights into the effects of genetic predisposition on the neurodevelopmental origins of the disorder.

Keywords:  Axonogenesis; Cortical Spheroids; Genetic Risk; Neurodevelopment; Schizophrenia; Transcriptional Profiling

DOI:  https://doi.org/10.1016/j.biopsych.2023.08.017
Nat Biotechnol. 2023 Sep 04.

Spatial multimodal analysis of transcriptomes and metabolomes in tissues.

Marco Vicari, Reza Mirzazadeh, Anna Nilsson, Reza Shariatgorji, Patrik Bjärterot, Ludvig Larsson, Hower Lee, Mats Nilsson, Julia Foyer, Markus Ekvall, Paulo Czarnewski, Xiaoqun Zhang, Per Svenningsson, Lukas Käll, Per E Andrén, Joakim Lundeberg.

We present a spatial omics approach that combines histology, mass spectrometry imaging and spatial transcriptomics to facilitate precise measurements of mRNA transcripts and low-molecular-weight metabolites across tissue regions. The workflow is compatible with commercially available Visium glass slides. We demonstrate the potential of our method using mouse and human brain samples in the context of dopamine and Parkinson's disease.

DOI: https://doi.org/10.1038/s41587-023-01937-y
Sci Rep. 2023 Sep 08. 13(1): 14800

Lipid metabolism transcriptomics of murine microglia in Alzheimer's disease and neuroinflammation.

Daniel C Shippy, Tyler K Ulland.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques followed by intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. An unrestrained immune response by microglia, the resident cells of the central nervous system (CNS), leads to neuroinflammation which can amplify AD pathology. AD pathology is also driven by metabolic dysfunction with strong correlations between dementia and metabolic disorders such as diabetes, hypercholesterolemia, and hypertriglyceridemia. Since elevated cholesterol and triglyceride levels appear to be a major risk factor for developing AD, we investigated the lipid metabolism transcriptome in an AD versus non-AD state using RNA-sequencing (RNA-seq) and microarray datasets from N9 cells and murine microglia. We identified 52 differentially expressed genes (DEG) linked to lipid metabolism in LPS-stimulated N9 microglia versus unstimulated control cells using RNA-seq, 86 lipid metabolism DEG in 5XFAD versus wild-type mice by microarray, with 16 DEG common between both datasets. Functional enrichment and network analyses identified several biological processes and molecular functions, such as cholesterol homeostasis, insulin signaling, and triglyceride metabolism. Furthermore, therapeutic drugs targeting lipid metabolism DEG found in our study were identified. Focusing on drugs that target genes associated with lipid metabolism and neuroinflammation could provide new targets for AD drug development.

DOI: https://doi.org/10.1038/s41598-023-41897-6
Eur J Pharmacol. 2023 Sep 04. pii: S0014-2999(23)00553-8. [Epub ahead of print] 176041

N-palmitoylethanolamine modulates hippocampal neuroplasticity in rats with stress-induced depressive behavior phenotype.

Luwen Zhang, Wenjuan Tang, Yinan Ouyang, Miao Zhang, Ruirui Li, Lianping Sun, Chao Liu, Hailing Yu.

  Bioactive lipid mediator N-palmitoylethanolamide (PEA) is an endocannabinoid-like molecule. Based on our previous data, this study aimed to further investigate the antidepressant property of PEA via the peroxisome proliferator-activated receptor alpha (PPARα) pathway, focusing on the intervention of PEA on hippocampal neuroplasticity. Behavioral tests were performed in rats induced by unpredictable chronic mild stress (uCMS) in the last week of the experiment, and then the brain tissue samples were retained for subsequent immunohistochemical detection and Western blot analysis. In vitro, the apoptosis of HT22 cells induced by CORT and apoptosis-related proteins were detected by Hoechst staining and Western blot, respectively. The results showed that PEA ameliorated the depression-like phenotype in rats induced by uCMS, prevented the uCMS-induced reduction in the number of BrdU-positive cells, and increased BrdU/NeuN co-localization in the hippocampus, and upregulated the levels of synapse associated protein NCAM, MAP2, SYN and PSD95 in the hippocampus. Hoechst staining results showed that PEA significantly increased the CORT-induced reduction in the number of hippocampal neurons. Western blot analysis showed that PEA decreased the expression of caspase-3 and c-caspase-3, and increased the ratio of Bcl-2/Bax in CORT-induced HT22 cells. MK886, a PPARα antagonist, partially or completely reversed these effects. In conclusion, the therapeutic potential of PEA for depressive mood disorders may be through targeting the hippocampal neuroplasticity, including increasing adult neurogenesis and synaptic plasticity, as well as down-regulated neuronal apoptosis, to remodel hippocampal circuitries upon functional integration and PPARα pathway may be involved in this process.

Keywords:  Apoptosis; Hippocampus; N-Palmitoylethanolamide; Neurogenesis; Neuroplasticity; Rats

DOI:  https://doi.org/10.1016/j.ejphar.2023.176041
Cells. 2023 Aug 25. pii: 2143. [Epub ahead of print]12(17):

Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA.

Joel P Wiener, Sindy Desire, Viktor Garliyev, Nicholas Lyssenko Iii, Domenico Praticò, Nicholas N Lyssenko.

  Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) is a major risk factor for Alzheimer's disease. Human neural cell lines were used to investigate the regulation of ABCA7 expression by cholesterol and pro-inflammatory cytokines. Cholesterol was depleted by methyl-β-cyclodextrin, followed by treatment with rosuvastatin to suppress de novo synthesis, while the cells underwent adjustment to low cholesterol. Cholesterol depletion by 50-76% decreased ABCA7 expression by ~40% in C20 microglia and ~21% in A172 astrocytes but had no effect on the protein in SK-N-SH neurons. Cholesterol depletion also suppressed ABCA7 in HMC3 microglia. Previously, cholesterol loss was reported to up-regulate ABCA7 in murine macrophages. ABCA7 was down-regulated during PMA-induced differentiation of human THP-1 monocytes to macrophages. But, cholesterol depletion in THP-1 macrophages by ~71% had no effect on ABCA7. IL-1β and TNFα reduced ABCA7 expression in C20 and HMC3 microglia but not in A172 astrocytes or SK-N-SH neurons. IL-6 did not affect ABCA7 in the neural cells. These findings suggest that ABCA7 is active in regular homeostasis in human neural cells, is regulated by cholesterol in a cell type-dependent manner, i.e., cholesterol depletion down-regulates it in human neuroglia but not neurons, and is incompatible with IL-1β and TNFα inflammatory responses in human microglia.

Keywords:  ABC transporter; Alzheimer’s disease; THP-1 cells; astrocytes; cholesterol metabolism; cyclodextrin; cytokines; inflammation; microglia; rosuvastatin

DOI:  https://doi.org/10.3390/cells12172143
Mol Genet Genomic Med. 2023 Sep 08. e2283

Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism.

Anisha Verma, April N Lehman, Hatice Gokcan, Lorna Cropcho, Danielle Black, Steven F Dobrowolski, Jerry Vockley, Jirair K Bedoyan.

  BACKGROUND: Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually in the USA. The median and mean ages of diagnosis of PDCD are about 12 and 31 months, respectively. PDCD is a major cause of primary lactic acidosis with concomitant elevation in blood alanine (Ala) and proline (Pro) concentrations depending on phenotypic severity. Alanine/Leucine (Ala/Leu) ≥4.0 and Proline/Leucine (Pro/Leu) ≥3.0 combination cutoff from dried blood spot specimens was used as a biomarker for early identification of neonates/infants with PDCD. Further investigations were needed to evaluate the sensitivity (SN), specificity (SP), and clinical utility of such amino acid (AA) ratio combination cutoffs in discriminating PDCD from other inborn errors of metabolism (IEM) for early identification of such patients.METHODS: We reviewed medical records of patients seen at UPMC in the past 11 years with molecularly or enzymatically confirmed diagnosis. We collected plasma AA analysis data from samples prior to initiation of therapeutic interventions such as total parenteral nutrition and/or ketogenic diet. Conditions evaluated included organic acidemias, primary mitochondrial disorders (MtDs), fatty acid oxidation disorders (FAOD), other IEMs on current newborn screening panels, congenital cardiac great vessel anomalies, renal tubular acidosis, and non-IEMs. The utility of specific AA ratio combinations as biomarkers were evaluated using receiver operating characteristic curves, correlation analysis, principal component analysis, and cutoff SN, SP, and positive predictive value determined from 201 subjects with broad age range.
RESULTS: Alanine/Lysine (Ala/Lys) and Ala/Leu as well as (Ala + Pro)/(Leu + Lys) and Ala/Leu ratio combinations effectively discriminated subjects with PDCD from those with other MtDs and IEMs on current newborn screening panels. Specific AA ratio combinations were significantly more sensitive in identifying PDCD than Ala alone or combinations of Ala and/or Pro in the evaluated cohort of subjects. Ala/Lys ≥3.0 and Ala/Leu ≥5.0 as well as (Ala + Pro)/(Leu + Lys) ≥2.5 and Ala/Leu ≥5.0 combination cutoffs identified patients with PDCD with 100% SN and ~85% SP.
CONCLUSIONS: With the best predictor of survival and positive cognitive outcome in PDCD being age of diagnosis, PDCD patients would benefit from use of such highly SN and SP AA ratio combination cutoffs as biomarkers for early identification of at-risk newborns, infants, and children, for early intervention(s) with known and/or novel therapeutics for this disorder.

Keywords:  amino acid ratio combinations; biomarkers; inborn errors of metabolism; pyruvate dehydrogenase complex deficiency

DOI:  https://doi.org/10.1002/mgg3.2283
Mol Neurobiol. 2023 Sep 02.

Regulatory Effects and Mechanisms of L-Theanine on Neurotransmitters via Liver-Brain Axis Under a High Protein Diet.

Wei Xu, Yuxin Song, Wenjun Xiao, Zhihua Gong.

  Excessive protein intake causes liver and brain damage and neurotransmitter disorders, thereby inducing cognitive dysfunction. L-theanine can regulate the neurotransmitter content and show great potential in liver and brain protection. However, it remains unclear whether l-theanine effectively regulates neurotransmitter content under high-protein diet. A 40-day feeding experiment was performed in Sprague Dawley rats to investigate the regulatory effects and mechanisms of l-theanine on neurotransmitters via liver-brain axis in high-protein diets. The results showed that a 30% protein diet increased the liver and brain neurotransmitter content while maintaining the normal structure of liver and the hippocampal CA1 of brain and improving the autonomous behavior of rats. In contrast, 40% and 50% protein diets decreased the content of neurotransmitters, affected autonomous behavior, destroyed the hippocampal CA1 of brain structure, increased hepatic inflammatory infiltration, lipid degeneration, and hepatocyte eosinophilic change in liver, increased liver AST, ALT, MDA, CRP, and blood ammonia level, and decreased liver SOD and CAT level. However, l-theanine improved liver and brain neurotransmitter content, autonomous behavior, liver and hippocampal brain structure, and liver biochemical indicators in 40% and 50% protein diets. To explore how LTA can eliminate the adverse effects of a high-protein diet, we analyzed different metabolites and proteomes and using western blotting for validate quantitatively. We found that l-theanine regulates the activity of PF4 and G protein subunit alpha i2, increases the content of brain-derived neurotrophic factor and dopamine under a 20% protein diet. In addition, l-theanine can activate the adenylate cyclase-protein kinase A pathway through the protein alpha/beta-hydrolase domain protein 12 to regulate the content of neurotransmitters under a 40% protein diet, thereby exerting a neuroprotective effect.

Keywords:  High protein diet; L-Theanine; Neurotransmitters; Nutritional intervention

DOI:  https://doi.org/10.1007/s12035-023-03608-0
Biol Pharm Bull. 2023 ;46(9): 1184-1193

Suppressive Effects of Docosahexaenoic Acid Intake on Increased Seizure Susceptibility after Growth Due to Febrile Seizures in Infancy.

Shinji Kawano, Kouichi Itoh, Yasuhiro Ishihara.

  Febrile seizures are seizures accompanied by a fever and frequently occur in children six months to five years of age. Febrile seizures are classified as simple or complex, and complex febrile seizures increase the risk of temporal lobe epilepsy after growth. Therefore, it is important to interfere with epileptogenesis after febrile seizures to prevent post-growth epilepsy. The present study challenged nutritional intervention using docosahexaenoic acid (DHA). Febrile seizures were induced in mice at the age of 10 d using a heat chamber, and seizure sensitivity was examined using pentylenetetrazol (PTZ) administration after growth. PTZ increased the seizure score and shortened the latency in the complex febrile seizure group compared to the control, hyperthermia and simple febrile seizure groups. Mice in the complex febrile seizure group showed abnormal electroencephalograms pre- and post-PTZ administration. Therefore, seizure susceptibility increases the episodes of complex febrile seizures. DHA supplementation after febrile seizures clearly suppressed the increased seizure susceptibility due to complex febrile seizures experienced in infancy. DHA also attenuated microglial activation after complex febrile seizures. Taken together, DHA suppressed microglial activation following complex febrile seizures, which may contribute to protecting the brain from post-growth seizures. The intake of DHA in infancy may protect children from high fever-induced developmental abnormalities.

Keywords:  docosahexaenoic acid (DHA); estradiol; febrile seizure; microglia; recurrent seizure

DOI:  https://doi.org/10.1248/bpb.b23-00015