bims-medebr 2023-07-09 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒07‒09
twenty-two papers selected by
Regina F. Fernández
Johns Hopkins University

A spatially distributed model of brain metabolism highlights the role of diffusion in brain energy metabolism.
Mitochondrial regulation of local supply of energy in neurons.
Cognitive dysfunction in diabetes: abnormal glucose metabolic regulation in the brain.
LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.
The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer's Disease.
Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct (2H) and indirect (1H) detection of deuterium labeled compounds at 7T and clinical 3T.
Synthetic GM1 improves motor and memory dysfunctions in mice with monoallelic or biallelic disruption of GM3 synthase.
Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.
The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.
Meta-analytic evidence of elevated choline, reduced N-acetylaspartate, and normal creatine in schizophrenia and their moderation by measurement quality, echo time, and medication status.
A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult.
ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.
FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function.
Metabolism changes during direct revascularization in moyamoya disease: illustrative case.
Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.
G6PDi-1 is a Potent Inhibitor of G6PDH and of Pentose Phosphate pathway-dependent Metabolic Processes in Cultured Primary Astrocytes.
Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives.
Autoradiographic characterization of [18 F]PSMA-1007 binding in rat brain.
Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration.
Mitochondrial calcium uniporter deficiency in dentate granule cells remodels neuronal metabolism and impairs reversal learning.
Mechanism of cAMP response element-binding protein 1/death-associated protein kinase 1 axis-mediated hippocampal neuron apoptosis in rat brain injury after cardiopulmonary resuscitation.
Case report: Tackling the complexities of an extremely premature newborn with intrauterine growth restriction and congenital metabolic disorders through a multidisciplinary approach.

J Theor Biol. 2023 Jun 30. pii: S0022-5193(23)00164-9. [Epub ahead of print] 111567

A spatially distributed model of brain metabolism highlights the role of diffusion in brain energy metabolism.

Gideon Idumah, Erkki Somersalo, Daniela Calvetti.

  The different active roles of neurons and astrocytes during neuronal activation are associated with the metabolic processes necessary to supply the energy needed for their respective tasks at rest and during neuronal activation. Metabolism, in turn, relies on the delivery of metabolites and removal of toxic byproducts through diffusion processes and the cerebral blood flow. A comprehensive mathematical model of brain metabolism should account not only for the biochemical processes and the interaction of neurons and astrocytes, but also the diffusion of metabolites. In the present article, we present a computational methodology based on a multidomain model of the brain tissue and a homogenization argument for the diffusion processes. In our spatially distributed compartment model, communication between compartments occur both through local transport fluxes, as is the case within local astrocyte-neuron complexes, and through diffusion of some substances in some of the compartments. The model assumes that diffusion takes place in the extracellular space (ECS) and in the astrocyte compartment. In the astrocyte compartment, the diffusion across the syncytium network is implemented as a function of gap junction strength. The diffusion process is implemented numerically by means of a finite element method (FEM) based spatial discretization, and robust stiff solvers are used to time integrate the resulting large system. Computed experiments show the effects of ECS tortuosity, gap junction strength and spatial anisotropy in the astrocyte network on the brain energy metabolism.

Keywords:  Astrocyte syncytium; Brain energy metabolism; Diffusion process; Gap junction strength; Oxygen-Glucose index; Tortuosity

DOI:  https://doi.org/10.1016/j.jtbi.2023.111567
Curr Opin Neurobiol. 2023 Jun 29. pii: S0959-4388(23)00072-7. [Epub ahead of print]81 102747

Mitochondrial regulation of local supply of energy in neurons.

Guillermo López-Doménech, Josef T Kittler.

Brain computation is metabolically expensive and requires the supply of significant amounts of energy. Mitochondria are highly specialized organelles whose main function is to generate cellular energy. Due to their complex morphologies, neurons are especially dependent on a set of tools necessary to regulate mitochondrial function locally in order to match energy provision with local demands. By regulating mitochondrial transport, neurons control the local availability of mitochondrial mass in response to changes in synaptic activity. Neurons also modulate mitochondrial dynamics locally to adjust metabolic efficiency with energetic demand. Additionally, neurons remove inefficient mitochondria through mitophagy. Neurons coordinate these processes through signalling pathways that couple energetic expenditure with energy availability. When these mechanisms fail, neurons can no longer support brain function giving rise to neuropathological states like metabolic syndromes or neurodegeneration.

DOI: https://doi.org/10.1016/j.conb.2023.102747
Front Endocrinol (Lausanne). 2023 ;14 1192602

Cognitive dysfunction in diabetes: abnormal glucose metabolic regulation in the brain.

Shan Zhang, Yueying Zhang, Zhige Wen, YaNan Yang, Tianjie Bu, Xiangwei Bu, Qing Ni.

  Cognitive dysfunction is increasingly recognized as a complication and comorbidity of diabetes, supported by evidence of abnormal brain structure and function. Although few mechanistic metabolic studies have shown clear pathophysiological links between diabetes and cognitive dysfunction, there are several plausible ways in which this connection may occur. Since, brain functions require a constant supply of glucose as an energy source, the brain may be more susceptible to abnormalities in glucose metabolism. Glucose metabolic abnormalities under diabetic conditions may play an important role in cognitive dysfunction by affecting glucose transport and reducing glucose metabolism. These changes, along with oxidative stress, inflammation, mitochondrial dysfunction, and other factors, can affect synaptic transmission, neural plasticity, and ultimately lead to impaired neuronal and cognitive function. Insulin signal triggers intracellular signal transduction that regulates glucose transport and metabolism. Insulin resistance, one hallmark of diabetes, has also been linked with impaired cerebral glucose metabolism in the brain. In this review, we conclude that glucose metabolic abnormalities play a critical role in the pathophysiological alterations underlying diabetic cognitive dysfunction (DCD), which is associated with multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, inflammation, and others. Brain insulin resistance is highly emphasized and characterized as an important pathogenic mechanism in the DCD.

Keywords:  cerebral glucose metabolism; cognitive dysfunction; diabetes; insulin signal; molecular mechanism

DOI:  https://doi.org/10.3389/fendo.2023.1192602
Cells. 2023 May 22. pii: 1445. [Epub ahead of print]12(10):

LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.

Gopal V Velmurugan, W Brad Hubbard, Paresh Prajapati, Hemendra J Vekaria, Samir P Patel, Alexander G Rabchevsky, Patrick G Sullivan.

  The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases.

Keywords:  LDL receptor-related protein 1 (LRP1); Traumatic Brain Injury (TBI); mitochondria; mitochondrial morphology; mitochondrial network; mitostasis; oxidative stress

DOI:  https://doi.org/10.3390/cells12101445
J Alzheimers Dis. 2023 Jun 27.

The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer's Disease.

Neeraj Chhimpa, Neha Singh, Nikkita Puri, Hanuman Prasad Kayath.

  Citrate synthase is a key mitochondrial enzyme that utilizes acetyl-CoA and oxaloacetate to form citrate in the mitochondrial membrane, which participates in energy production in the TCA cycle and linked to the electron transport chain. Citrate transports through a citrate malate pump and synthesizes acetyl-CoA and acetylcholine (ACh) in neuronal cytoplasm. In a mature brain, acetyl-CoA is mainly utilized for ACh synthesis and is responsible for memory and cognition. Studies have shown low citrate synthase in different regions of brain in Alzheimer's disease (AD) patients, which reduces mitochondrial citrate, cellular bioenergetics, neurocytoplasmic citrate, acetyl-CoA, and ACh synthesis. Reduced citrate mediated low energy and favors amyloid-β (Aβ) aggregation. Citrate inhibits Aβ25-35 and Aβ1-40 aggregation in vitro. Hence, citrate can be a better therapeutic option for AD by improving cellular energy and ACh synthesis, and inhibiting Aβ aggregation, which prevents tau hyperphosphorylation and glycogen synthase kinase-3 beta. Therefore, we need to study if citrate reverses Aβ deposition by balancing mitochondrial energy pathway and neurocytoplasmic ACh production. Furthermore, in AD's silent phase pathophysiology, when neuronal cells are highly active, they shift ATP utilization from oxidative phosphorylation to glycolysis and prevent excessive generation of hydrogen peroxide and reactive oxygen species (oxidative stress) as neuroprotective action, which upregulates glucose transporter-3 (GLUT3) and pyruvate dehydrogenase kinase-3 (PDK3). PDK3 inhibits pyruvate dehydrogenase, which decreases mitochondrial-acetyl-CoA, citrate, and cellular bioenergetics, and decreases neurocytoplasmic citrate, acetyl-CoA, and ACh formation, thus initiating AD pathophysiology. Therefore, GLUT3 and PDK3 can be biomarkers for silent phase of AD.

Keywords:  APOEɛ4; Acetyl-CoA; Alzheimer’s disease; GLUT3; acetylcholine; amyloid-beta; cellular bioenergetics; citrate; citrate synthase

DOI:  https://doi.org/10.3233/JAD-220514
Neuroimage. 2023 Jul 04. pii: S1053-8119(23)00401-9. [Epub ahead of print] 120250

Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct (2H) and indirect (1H) detection of deuterium labeled compounds at 7T and clinical 3T.

Fabian Niess, Bernhard Strasser, Lukas Hingerl, Eva Niess, Stanislav Motyka, Gilbert Hangel, Martin Krššák, Stephan Gruber, Benjamin Spurny-Dworak, Siegfried Trattnig, Thomas Scherer, Rupert Lanzenberger, Wolfgang Bogner.

  INTRODUCTION: Deuterium metabolic imaging (DMI) and quantitative exchange label turnover (QELT) are novel MR spectroscopy techniques for non-invasive imaging of human brain glucose and neurotransmitter metabolism with high clinical potential. Following oral or intravenous administration of non-ionizing [6,6'-2H2]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using 2H MRSI (DMI) and 1H MRSI (QELT), respectively. The purpose of this study was to compare the dynamics of spatially resolved brain glucose metabolism, i.e., estimated concentration enrichment of deuterium labeled Glx (glutamate+glutamine) and Glc (glucose) acquired repeatedly in the same cohort of subjects using DMI at 7T and QELT at clinical 3T.METHODS: Five volunteers (4m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8g/kg oral [6,6'-2H2]-glucose administration using time-resolved 3D 2H FID-MRSI with elliptical phase encoding at 7T and 3D 1H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T.
RESULTS: One hour after oral tracer administration regionally averaged deuterium labeled Glx4 concentrations and the dynamics were not significantly different over all participants between 7T 2H DMI and 3T 1H QELT data for GM (1.29±0.15 vs. 1.38±0.26 mM, p=0.65 & 21±3 vs. 26±3 µM/min, p=0.22) and WM (1.10±0.13 vs. 0.91±0.24 mM, p=0.34 & 19±2 vs. 17±3 µM/min, p=0.48). Also, the observed time constants of dynamic Glc6 data in GM (24±14 vs. 19±7 min, p=0.65) and WM (28±19 vs. 18±9 min, p=0.43) dominated regions showed no significant differences. Between individual 2H and 1H data points a weak to moderate negative correlation was observed for Glx4 concentrations in GM (r=-0.52, p<0.001), and WM (r=-0.3, p<0.001) dominated regions, while a strong negative correlation was observed for Glc6 data GM (r=-0.61, p<0.001) and WM (r=-0.70, p<0.001).
CONCLUSION: This study demonstrates that indirect detection of deuterium labeled compounds using 1H QELT MRSI at widely available clinical 3T without additional hardware is able to reproduce absolute concentration estimates of downstream glucose metabolites and the dynamics of glucose uptake compared to 2H DMI data acquired at 7T. This suggests significant potential for widespread application in clinical settings especially in environments with limited access to ultra-high field scanners and dedicated RF hardware.

Keywords:  Deuterium metabolic Imaging; MR spectroscopy; Quantitative exchange label turnover; clinical 3T; deuterium labeled glucose

DOI:  https://doi.org/10.1016/j.neuroimage.2023.120250
FEBS Open Bio. 2023 Jul 04.

Synthetic GM1 improves motor and memory dysfunctions in mice with monoallelic or biallelic disruption of GM3 synthase.

Suman Chowdhury, Ranjeet Kumar, Evelyn Zepeda, Shawn DeFrees, Robert Ledeen.

  This study attempts to answer the question of whether mice with biallelic and monoallelic disruption of the St3gal5 (GM3 synthase) gene might benefit from GM1 replacement therapy. The GM3 produced by this sialyltransferase gives rise to downstream GD3 and the ganglio-series of gangliosides. The latter includes the a-series (GM1 + GD1a) which has proved most essential for neuron survival and function (especially GM1, for which GD1a provides a reserve pool). These biallelic mice serve as a model for children with this relatively rare autosomal recessive condition (ST3GAL5-/-) who suffer rapid neurological decline including motor loss, intellectual disability, visual and hearing loss, failure to thrive, and other severe conditions leading to an early death by 2-5 years of age without supportive care. Here, we studied both these mice, which serve as a model for the parents and close relatives of these children who are likely to suffer long term disabilities due to partial deficiency of GM1, including Parkinson's disease. We find that the movement and memory disorders manifested by both types of mice can be resolved with GM1 application. This suggests the potential therapeutic value of GM1 for disorders stemming from GM1 deficiency, including GM3 synthase deficiency and Parkinson's disease. It was noteworthy that the GM1 employed in these studies was synthetic rather than animal brain-derived, reaffirming the therapeutic efficacy of the former.

Keywords:  GM1 ganglioside; GM3 synthase; Memory impairment; Motor impairment; Parkinson's disease

DOI:  https://doi.org/10.1002/2211-5463.13669
Front Neurosci. 2023 ;17 1205819

Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs.

Line I Christiansen, Gemma C Ventura, Bo Holmqvist, Karoline Aasmul-Olsen, Sandy E H Lindholm, Matthew D Lycas, Yuki Mori, Jan Bojsen-Møller Secher, Douglas G Burrin, Thomas Thymann, Per T Sangild, Stanislava Pankratova.

  Introduction: Preterm infants have increased risk of impaired neurodevelopment to which reduced systemic levels of insulin-like growth factor 1 (IGF-1) in the weeks after birth may play a role. Hence, we hypothesized that postnatal IGF-1 supplementation would improve brain development in preterm pigs, used as a model for preterm infants.Methods: Preterm pigs delivered by cesarean section received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage and open field activities, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements.
Results: The IGF-1 treatment increased cerebellar protein synthesis rates (both in vivo and ex vivo). Performance in the balance beam test was improved by IGF-1 but not in other neurofunctional tests. The treatment decreased total and relative caudate nucleus weights, without any effects to total brain weight or grey/white matter volumes. Supplementation with IGF-1 reduced myelination in caudate nucleus, cerebellum, and white matter regions and decreased hilar synapse formation, without effects to oligodendrocyte maturation or neuron differentiation. Gene expression analyses indicated enhanced maturation of the GABAergic system in the caudate nucleus (decreased NKCC1:KCC2 ratio) with limited effects in cerebellum or hippocampus.
Conclusion: Supplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.

Keywords:  IGF-1; caudate nucleus; hippocampus; motor function; myelination; preterm neonates

DOI:  https://doi.org/10.3389/fnins.2023.1205819
Nat Commun. 2023 07 05. 14(1): 3964

The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.

Thaddeus J Kunkel, Alice Townsend, Kyle A Sullivan, Jean Merlet, Edward H Schuchman, Daniel A Jacobson, Andrew P Lieberman.

The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1-/- mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1-/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1-/- oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1-/- mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-023-39733-6
Neuroimage Clin. 2023 Jun 27. pii: S2213-1582(23)00150-X. [Epub ahead of print]39 103461

Meta-analytic evidence of elevated choline, reduced N-acetylaspartate, and normal creatine in schizophrenia and their moderation by measurement quality, echo time, and medication status.

Yvonne S Yang, Jason Smucny, Huailin Zhang, Richard J Maddock.

  BACKGROUND: Brain metabolite abnormalities measured with magnetic resonance spectroscopy (MRS) provide insight into pathological processes in schizophrenia. Prior meta-analyses have not yet answered important questions about the influence of clinical and technical factors on neurometabolite abnormalities and brain region differences. To address these gaps, we performed an updated meta-analysis of N-acetylaspartate (NAA), choline, and creatine levels in patients with schizophrenia and assessed the moderating effects of medication status, echo time, measurement quality, and other factors.METHODS: We searched citations from three earlier meta-analyses and the PubMed database after the most recent meta-analysis to identify studies for screening. In total, 113 publications reporting 366 regional metabolite datasets met our inclusion criteria and reported findings in medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex, frontal white matter, hippocampus, thalamus, and basal ganglia from a total of 4445 patient and 3944 control observations.
RESULTS: Patients with schizophrenia had reduced NAA in five of the six brain regions, with a statistically significant sparing of the basal ganglia. Patients had elevated choline in the basal ganglia and both prefrontal cortical regions. Patient creatine levels were normal in all six regions. In some regions, the NAA and choline differences were greater in studies enrolling predominantly medicated patients compared to studies enrolling predominantly unmedicated patients. Patient NAA levels were more reduced in hippocampus and frontal white matter in studies using longer echo times than those using shorter echo times. MPFC choline and NAA abnormalities were greater in studies reporting better metabolite measurement quality.
CONCLUSIONS: Choline is elevated in the basal ganglia and prefrontal cortical regions, suggesting regionally increased membrane turnover or glial activation in schizophrenia. The basal ganglia are significantly spared from the well-established widespread reduction of NAA in schizophrenia suggesting a regional difference in disease-associated factors affecting NAA. The echo time findings agree with prior reports and suggest microstructural changes cause faster NAA T2 relaxation in hippocampus and frontal white matter in schizophrenia. Separating the effects of medication status and illness chronicity on NAA and choline abnormalities will require further patient-level studies. Metabolite measurement quality was shown to be a critical factor in MRS studies of schizophrenia.

Keywords:  Echo time; MRS; Magnetic resonance spectroscopy; Measurement quality; Metabolites; Schizophrenia

DOI:  https://doi.org/10.1016/j.nicl.2023.103461
Front Neurosci. 2023 ;17 1197208

A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult.

Maurizio Ragni, Francesca Fenaroli, Chiara Ruocco, Agnese Segala, Giuseppe D'Antona, Enzo Nisoli, Alessandra Valerio.

  Mitochondrial dysfunction plays a key role in the aging process, and aging is a strong risk factor for neurodegenerative diseases or brain injury characterized by impairment of mitochondrial function. Among these, ischemic stroke is one of the leading causes of death and permanent disability worldwide. Pharmacological approaches for its prevention and therapy are limited. Although non-pharmacological interventions such as physical exercise, which promotes brain mitochondrial biogenesis, have been shown to exert preventive effects against ischemic stroke, regular feasibility is complex in older people, and nutraceutical strategies could be valuable alternatives. We show here that dietary supplementation with a balanced essential amino acid mixture (BCAAem) increased mitochondrial biogenesis and the endogenous antioxidant response in the hippocampus of middle-aged mice to an extent comparable to those elicited by treadmill exercise training, suggesting BCAAem as an effective exercise mimetic on brain mitochondrial health and disease prevention. In vitro BCAAem treatment directly exerted mitochondrial biogenic effects and induced antioxidant enzyme expression in primary mouse cortical neurons. Further, exposure to BCAAem protected cortical neurons from the ischemic damage induced by an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD). BCAAem-mediated protection against OGD was abolished in the presence of rapamycin, Torin-1, or L-NAME, indicating the requirement of both mTOR and eNOS signaling pathways in the BCAAem effects. We propose BCAAem supplementation as an alternative to physical exercise to prevent brain mitochondrial derangements leading to neurodegeneration and as a nutraceutical intervention aiding recovery after cerebral ischemia in conjunction with conventional drugs.

Keywords:  aging; cerebral ischemia; dietary supplementation; endothelial nitric oxide synthase; essential amino acids; mammalian target of rapamycin; mitochondrial biogenesis

DOI:  https://doi.org/10.3389/fnins.2023.1197208
EMBO Rep. 2023 Jul 04. e57499

ER-mitochondria contacts and cholesterol metabolism are disrupted by disease-associated tau protein.

Leonora Szabo, Nadia Cummins, Paolo Paganetti, Alex Odermatt, Andreas Papassotiropoulos, Celeste Karch, Jürgen Götz, Anne Eckert, Amandine Grimm.

  Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.

Keywords:  GSK3β; cholesterol; endoplasmic reticulum; mitochondria; tau protein

DOI:  https://doi.org/10.15252/embr.202357499
Front Syst Neurosci. 2023 ;17 1212213

FABP7: a glial integrator of sleep, circadian rhythms, plasticity, and metabolic function.

Jason R Gerstner, Carlos C Flores, Micah Lefton, Brooke Rogers, Christopher J Davis.

  Sleep and circadian rhythms are observed broadly throughout animal phyla and influence neural plasticity and cognitive function. However, the few phylogenetically conserved cellular and molecular pathways that are implicated in these processes are largely focused on neuronal cells. Research on these topics has traditionally segregated sleep homeostatic behavior from circadian rest-activity rhythms. Here we posit an alternative perspective, whereby mechanisms underlying the integration of sleep and circadian rhythms that affect behavioral state, plasticity, and cognition reside within glial cells. The brain-type fatty acid binding protein, FABP7, is part of a larger family of lipid chaperone proteins that regulate the subcellular trafficking of fatty acids for a wide range of cellular functions, including gene expression, growth, survival, inflammation, and metabolism. FABP7 is enriched in glial cells of the central nervous system and has been shown to be a clock-controlled gene implicated in sleep/wake regulation and cognitive processing. FABP7 is known to affect gene transcription, cellular outgrowth, and its subcellular localization in the fine perisynaptic astrocytic processes (PAPs) varies based on time-of-day. Future studies determining the effects of FABP7 on behavioral state- and circadian-dependent plasticity and cognitive processes, in addition to functional consequences on cellular and molecular mechanisms related to neural-glial interactions, lipid storage, and blood brain barrier integrity will be important for our knowledge of basic sleep function. Given the comorbidity of sleep disturbance with neurological disorders, these studies will also be important for our understanding of the etiology and pathophysiology of how these diseases affect or are affected by sleep.

Keywords:  BBB; astroctye; endocytosis; glycolysis; homeostasis; synaptic plasticity; transcytosis; β-oxidation

DOI:  https://doi.org/10.3389/fnsys.2023.1212213
J Neurosurg Case Lessons. 2023 Jun 26. pii: CASE23104. [Epub ahead of print]5(26):

Metabolism changes during direct revascularization in moyamoya disease: illustrative case.

Fuat Arikan, Ivette Chocron, Helena Calvo-Rubio, Carlos Santos, Dario Gándara.

  BACKGROUND: Cerebral revascularization is recommended for patients with moyamoya disease (MMD) with reduced cerebral perfusion reserve and recurrent or progressive ischemic events. The standard surgical treatment for these patients is a low-flow bypass with or without indirect revascularization. The use of intraoperative monitoring of the metabolic profile using analytes such as glucose, lactate, pyruvate, and glycerol has not yet been described during cerebral artery bypass surgery for MMD-induced chronic cerebral ischemia. The authors aimed to describe an illustrative case using intraoperative microdialysis and brain tissue oxygen partial pressure (PbtO2) probes in a patient with MMD during direct revascularization.OBSERVATIONS: The patient's severe tissue hypoxia situation was confirmed by a PbtO2:partial pressure of oxygen (PaO2) ratio below 0.1 and anaerobic metabolism by a lactate:pyruvate ratio greater than 40. Following bypass, a rapid and sustained increase in PbtO2 up to normal values (PbtO2:PaO2 ratio between 0.1 and 0.35) and the normalization of cerebral energetic metabolism with a lactate/pyruvate ratio less than 20 was observed.
LESSONS: The results show a quick improvement of regional cerebral hemodynamics due to the direct anastomosis procedure, reducing the incidence of subsequent ischemic stroke in pediatric and adult patients immediately.

Keywords:  brain metabolism; cerebrovascular circulation; cerebrovascular physiology; hypoxic ischemia; intraoperative monitoring; moyamoya disease; oximetry

DOI:  https://doi.org/10.3171/CASE23104
Biochim Biophys Acta Mol Basis Dis. 2023 Jun 29. pii: S0925-4439(23)00164-3. [Epub ahead of print]1869(7): 166798

Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.

Jasvinder Singh Bhatti, Satinder Kaur, Jayapriya Mishra, Harikrishnareddy Dibbanti, Arti Singh, Arubala P Reddy, Gurjit Kaur Bhatti, P Hemachandra Reddy.

  Alzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid β (Aβ) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with Aβ and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with Aβ and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology.

Keywords:  Alzheimer's disease; Amyloid beta; Mitochondria; Protein folding; Tau hyperphosphorylation

DOI:  https://doi.org/10.1016/j.bbadis.2023.166798
Neurochem Res. 2023 Jul 02.

G6PDi-1 is a Potent Inhibitor of G6PDH and of Pentose Phosphate pathway-dependent Metabolic Processes in Cultured Primary Astrocytes.

Patrick Watermann, Christian Arend, Ralf Dringen.

  Glucose-6-phosphate dehydrogenase (G6PDH) catalyses the rate limiting first step of the oxidative part of the pentose phosphate pathway (PPP), which has a crucial function in providing NADPH for antioxidative defence and reductive biosyntheses. To explore the potential of the new G6PDH inhibitor G6PDi-1 to affect astrocytic metabolism, we investigated the consequences of an application of G6PDi-1 to cultured primary rat astrocytes. G6PDi-1 efficiently inhibited G6PDH activity in lysates of astrocyte cultures. Half-maximal inhibition was observed for 100 nM G6PDi-1, while presence of almost 10 µM of the frequently used G6PDH inhibitor dehydroepiandrosterone was needed to inhibit G6PDH in cell lysates by 50%. Application of G6PDi-1 in concentrations of up to 100 µM to astrocytes in culture for up to 6 h did not affect cell viability nor cellular glucose consumption, lactate production, basal glutathione (GSH) export or the high basal cellular ratio of GSH to glutathione disulfide (GSSG). In contrast, G6PDi-1 drastically affected astrocytic pathways that depend on the PPP-mediated supply of NADPH, such as the NAD(P)H quinone oxidoreductase (NQO1)-mediated WST1 reduction and the glutathione reductase-mediated regeneration of GSH from GSSG. These metabolic pathways were lowered by G6PDi-1 in a concentration-dependent manner in viable astrocytes with half-maximal effects observed for concentrations between 3 and 6 µM. The data presented demonstrate that G6PDi-1 efficiently inhibits the activity of astrocytic G6PDH and impairs specifically those metabolic processes that depend on the PPP-mediated regeneration of NADPH in cultured astrocytes.

Keywords:  Astrocytes; Glucose; NADPH; Oxidative stress; pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11064-023-03964-2
Mol Med. 2023 Jul 06. 29(1): 93

Roles of protein post-translational modifications in glucose and lipid metabolism: mechanisms and perspectives.

Yu-Hang Yang, Ri Wen, Ni Yang, Tie-Ning Zhang, Chun-Feng Liu.

  The metabolism of glucose and lipids is essential for energy production in the body, and dysregulation of the metabolic pathways of these molecules is implicated in various acute and chronic diseases, such as type 2 diabetes, Alzheimer's disease, atherosclerosis (AS), obesity, tumor, and sepsis. Post-translational modifications (PTMs) of proteins, which involve the addition or removal of covalent functional groups, play a crucial role in regulating protein structure, localization function, and activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation. Emerging evidence indicates that PTMs are significant in modulating glucose and lipid metabolism by modifying key enzymes or proteins. In this review, we summarize the current understanding of the role and regulatory mechanisms of PTMs in glucose and lipid metabolism, with a focus on their involvement in disease progression associated with aberrant metabolism. Furthermore, we discuss the future prospects of PTMs, highlighting their potential for gaining deeper insights into glucose and lipid metabolism and related diseases.

Keywords:  Glucose metabolism; Lipid metabolism; Metabolic disease; Post-translational modification

DOI:  https://doi.org/10.1186/s10020-023-00684-9
Synapse. 2023 Jul 03.

Autoradiographic characterization of [18 F]PSMA-1007 binding in rat brain.

Majken B Thomsen, Anne M Landau, Dirk Bender, Paul Cumming.

  Carboxypeptidase II (CBPII) in brain metabolizes the neuroactive substance N-acetyl-L-aspartyl-L-glutamate (NAGG) to yield the elements of glutamate and N-acetyl-aspartate (NAA). In peripheral organs, CBPII is known as prostrate specific membrane antigen (PSMA), which presents an important target for nuclear medicine imaging in prostate cancer. Available PSMA ligands for PET imaging do not cross the blood-brain barrier, and there is scant knowledge of the neurobiology of CBPII, despite its implication in the regulation of glutamatergic neurotransmission. In this study we used the clinical PET tracer [18 F]-PSMA-1007 ([18 F]PSMA) for an autoradiographic characterization of CGPII in rat brain. Ligand binding and displacement curves indicated a single site in brain, with KD of about 0.5 nM, and Bmax ranging from 9 nM in cortex to 19 nM in white matter (corpus callosum and fimbria) and 24 nM in hypothalamus. The binding properties of [18 F]PSMA in vitro should enable its use for autoradiographic investigations of CBPII expression in animal models of human neuropsychiatric conditions.

Keywords:  PSMA; [18F]-PSMA-1007; autoradiography; brain; carboxypeptidase II

DOI:  https://doi.org/10.1002/syn.22280
Cells. 2023 May 17. pii: 1412. [Epub ahead of print]12(10):

Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration.

Kateryna Murlanova, Yan Jouroukhin, Ksenia Novototskaya-Vlasova, Shovgi Huseynov, Olga Pletnikova, Michael J Morales, Yun Guan, Atsushi Kamiya, Dwight E Bergles, David M Dietz, Mikhail V Pletnikov.

  Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the Oprm1 gene encoding µ opioid receptor 1 was selectively deleted from brain astrocytes in Oprm1 inducible conditional knockout (icKO) mice. These mice did not exhibit changes in locomotor activity, anxiety, or novel object recognition, or in their responses to the acute analgesic effects of morphine. Oprm1 icKO mice displayed increased locomotor activity in response to acute morphine administration but unaltered locomotor sensitization. Oprm1 icKO mice showed normal morphine-induced conditioned place preference but exhibited stronger conditioned place aversion associated with naloxone-precipitated morphine withdrawal. Notably, elevated conditioned place aversion lasted up to 6 weeks in Oprm1 icKO mice. Astrocytes isolated from the brains of Oprm1 icKO mice had unchanged levels of glycolysis but had elevated oxidative phosphorylation. The basal augmentation of oxidative phosphorylation in Oprm1 icKO mice was further exacerbated by naloxone-precipitated withdrawal from morphine and, similar to that for conditioned place aversion, was still present 6 weeks later. Our findings suggest that µ opioid receptors in astrocytes are linked to oxidative phosphorylation and they contribute to long-term changes associated with opioid withdrawal.

Keywords:  astrocytes; morphine withdrawal; oxidative phosphorylation; reward; µ opioid receptor

DOI:  https://doi.org/10.3390/cells12101412
J Neurochem. 2023 Jul 06.

Mitochondrial calcium uniporter deficiency in dentate granule cells remodels neuronal metabolism and impairs reversal learning.

Hadyn M Rose, Beatriz Ferrán, Rojina Ranjit, Anthony M Masingale, Daniel B Owen, Stacy Hussong, Michael T Kinter, Veronica Galvan, Sreemathi Logan, Carlos Manlio Díaz-García.

  The mitochondrial calcium uniporter (MCU) is the main route of calcium (Ca2+ ) entry into neuronal mitochondria. This channel has been linked to mitochondrial Ca2+ overload and cell death under neurotoxic conditions, but its physiologic roles for normal brain function remain poorly understood. Despite high expression of MCU in excitatory hippocampal neurons, it is unknown whether this channel is required for learning and memory. Here, we genetically down-regulated the Mcu gene in dentate granule cells (DGCs) of the hippocampus and found that this manipulation increases the overall respiratory activity of mitochondrial complexes I and II, augmenting the generation of reactive oxygen species in the context of impaired electron transport chain. The metabolic remodeling of MCU-deficient neurons also involved changes in the expression of enzymes that participate in glycolysis and the regulation of the tricarboxylic acid cycle, as well as the cellular antioxidant defenses. We found that MCU deficiency in DGCs does not change circadian rhythms, spontaneous exploratory behavior, or cognitive function in middle-aged mice (11-13 months old), when assessed with a food-motivated working memory test with three choices. DGC-targeted down-regulation of MCU significantly impairs reversal learning assessed with an 8-arm radial arm water maze but does not affect their ability to learn the task for the first time. Our results indicate that neuronal MCU plays an important physiologic role in memory formation and may be a potential therapeutic target to develop interventions aimed at improving cognitive function in aging, neurodegenerative diseases, and brain injury.

Keywords:  calcium; hippocampus; learning; memory; mitochondria; mitochondrial calcium uniporter

DOI:  https://doi.org/10.1111/jnc.15901
Neuroscience. 2023 Jul 03. pii: S0306-4522(23)00294-4. [Epub ahead of print]

Mechanism of cAMP response element-binding protein 1/death-associated protein kinase 1 axis-mediated hippocampal neuron apoptosis in rat brain injury after cardiopulmonary resuscitation.

Yadong Zhou, Xianjing Zhang, Hui Yang, Bo Chu, Maochuan Zhen, Junli Zhang, Lin Yang.

  Brain injury represents a leading cause of deaths following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). This study explores the role of CREB1 (cAMP responsive element binding protein 1)/DAPK1 (death associated protein kinase 1) axis in brain injury after CPR. CA was induced by asphyxia in rats, followed by CPR. After CREB1 over-expression, the survival rate and neurological function score of rats were measured. Nissl and TUNEL staining evaluated the pathological condition of hippocampus and apoptosis of hippocampal neurons respectively. H19-7 cells were subjected to OGD/R and infected with oe-CREB1. CCK-8 assay and flow cytometry measured the cell viability and apoptosis. CREB1, DAPK1, and cleaved Caspase-3 expressions were examined using Western blot. The binding between CREB1 and DAPK1 was determined using ChIP and dual-luciferase reporter assays. CREB1 was poorly expressed while DAPK1 was highly expressed in rat hippocampus after CPR. CREB1 overexpression improved rat neurological function, repressed neuron apoptosis, and reduced cleaved Caspase-3 expression. CREB1 was enriched on the DAPK1 promoter and suppressed DAPK1 expression. DAPK1 overexpression reversed the inhibition of OGD/R-insulted apoptosis by CREB1 overexpression. To conclude, CREB1 suppresses hippocampal neuron apoptosis and mitigates brain injury after CPR by inhibiting DAPK1 expression.

Keywords:  CREB1; DAPK1; apoptosis; cardiac arrest; cardiopulmonary resuscitation; hippocampal neurons

DOI:  https://doi.org/10.1016/j.neuroscience.2023.06.024
Front Pediatr. 2023 ;11 1162226

Case report: Tackling the complexities of an extremely premature newborn with intrauterine growth restriction and congenital metabolic disorders through a multidisciplinary approach.

Ioana Roșca, Andrei Gheorghe Preda, Andreea Teodora Constantin, Ciprian Coroleucă, Emilia Severin, Raluca Ioana Teleanu, Alina Turenschi.

  Background and objectives: The premature birth of a newborn can present a complex challenge for healthcare providers, particularly in cases of extreme prematurity combined with intrauterine growth restriction and multiple metabolic deficiencies. In this report, we aim to shed light on the difficulties and considerations involved in the management of such a case. In addition, our study is aimed to raise awareness of the importance of a multidisciplinary team in managing an extreme premature case with multiple comorbidities.Case presentation and main findings: We present the case of a 28-week premature female newborn with very low birth weight (660 g, percentile <10%) and intrauterine growth restriction. She was born through emergency cesarean delivery due to maternal Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome and had a high-risk pregnancy (spontaneous twin pregnancy, with one fetus stopping development at 16 weeks and maternal hypertension). In the first hours of life, she presented with persistent hypoglycemia requiring progressive glucose supplementation up to 16 g/kg/day to maintain normal blood glucose levels. The baby then showed favorable progress. However, from days 24 to 25, hypoglycemia recurred and did not respond to glucose boluses or supplementation in both intravenous and oral feeds, leading to the suspicion of a congenital metabolic disorder. Endocrine and metabolic screenings led to suspicion of primary carnitine deficiency and a deficiency in hepatic form of carnitine-palmitoyltransferase type I (CPT1) on the second screening.
Conclusion and clinical implications: The study highlights rare metabolic anomalies that can be due to both organ and system immaturity and delayed enteral feeding and excessive use of antibiotics. The clinical implications of this study emphasize the need for careful monitoring and comprehensive care of premature infants to prevent and manage potential metabolic abnormalities by neonatal metabolic screening.

Keywords:  L-carnitine deficiency; VLBW; extreme premature newborn; hypoglycemia; multidisciplinary approach

DOI:  https://doi.org/10.3389/fped.2023.1162226