bims-medebr 2022-12-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–12–04
thirty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Emerging mitochondrial-mediated mechanisms involved in oligodendrocyte development.
Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome.
Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.
Effect of fasting on short-term visual plasticity in adult humans.
Central Adiponectin Signaling - A Metabolic Regulator in Support of Brain Plasticity.
A dual tracer [11C]PBR28 and [18F]FDG microPET evaluation of neuroinflammation and brain energy metabolism in murine endotoxemia.
Cholesterol-24-hydroxylase (CYP46) in the old brain: Analysis of positive populations and factors triggering its expression in astrocytes.
Exercise modulates APOE expression in brain cortex of female APOE3 and APOE4 targeted replacement mice.
APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.
Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia.
Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration.
mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system.
Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
Choline supplementation for preterm infants: metabolism of four Deuterium-labeled choline compounds.
Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice.
Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles.
Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury.
Muscle-to-Brain Signaling Via Myokines and Myometabolites.
Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.
Neonatal Isoflurane Exposure in Rats Impairs Short-Term Memory, Cell Viability, and Glutamate Uptake in Slices of the Frontal Cerebral Cortex, But Not the Hippocampus, in Adulthood.
Focal non-motor seizures and subsequent focal motor seizures as the main clinical expression of GLUT-1 deficiency.
Mitochondrial respiration and dynamics of in vivo neural stem cells.
The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus.
Targeting the Central Nervous System in Lysosomal Storage Diseases: Strategies to Deliver Therapeutics Across the Blood-Brain Barrier.
Establishment and application of a novel in vitro model of microglial activation in traumatic brain injury.
The contribution of an imbalanced redox signalling to neurological and neurodegenerative conditions.
Neonatal motor functional connectivity and motor outcomes at age two years in very preterm children with and without high-grade brain injury.
Plasma leptin is associated with amyloid CSF biomarkers and Alzheimer's disease diagnosis in cognitively impaired patients.
PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.
Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia.
Repeated sevoflurane exposures inhibit neurogenesis by inducing the upregulation of glutamate transporter 1 in astrocytes.
Upregulation of glutamate transporter 1 by mTOR/Akt pathway in astrocyte culture during oxygen-glucose deprivation and reoxygenation.

J Neurosci Res. 2022 Dec 03.

Emerging mitochondrial-mediated mechanisms involved in oligodendrocyte development.

Melanie Gil, Vivian Gama.

  Oligodendrocytes are the myelinating glia of the central nervous system and are generated after oligodendrocyte progenitor cells (OPCs) transition into pre-oligodendrocytes and then into myelinating oligodendrocytes. Myelin is essential for proper signal transmission within the nervous system and axonal metabolic support. Although the intrinsic and extrinsic factors that support the differentiation, survival, integration, and subsequent myelination of appropriate axons have been well investigated, little is known about how mitochondria-related pathways such as mitochondrial dynamics, bioenergetics, and apoptosis finely tune these developmental events. Previous findings suggest that changes to mitochondrial morphology act as an upstream regulatory mechanism of neural stem cell (NSC) fate decisions. Whether a similar mechanism is engaged during OPC differentiation has yet to be elucidated. Maintenance of mitochondrial dynamics is vital for regulating cellular bioenergetics, functional mitochondrial networks, and the ability of cells to distribute mitochondria to subcellular locations, such as the growing processes of oligodendrocytes. Myelination is an energy-consuming event, thus, understanding the interplay between mitochondrial dynamics, metabolism, and apoptosis will provide further insight into mechanisms that mediate oligodendrocyte development in healthy and disease states. Here we will provide a concise overview of oligodendrocyte development and discuss the potential contribution of mitochondrial mitochondrial-mediated mechanisms to oligodendrocyte bioenergetics and development.

Keywords:  astrocytes; glia; glycolysis; mitochondria; neural precursor cells; neurons; oligodendrocytes; oxidative phosphorylation

DOI:  https://doi.org/10.1002/jnr.25151
Neuropharmacology. 2022 Nov 25. pii: S0028-3908(22)00409-9. [Epub ahead of print] 109350

Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome.

Chiara Urbinati, Chiara Lanzillotta, Livia Cosentino, Daniela Valenti, Maria Cristina Quattrini, Livia Di Crescenzo, Francesca Prestia, Donatella Pietraforte, Marzia Perluigi, Fabio Di Domenico, Rosa Anna Vacca, Bianca De Filippis.

  Metformin is the most common anti-diabetic drug and a promising therapy for disorders beyond diabetes, including Rett syndrome (RTT), a rare neurologic disease characterized by severe intellectual disability. A 10-day-long treatment rescued aberrant mitochondrial activity and restrained oxidative stress in a female RTT mouse model. However, this treatment regimen did not improve the phenotype of RTT mice. In the present study, we demonstrate that a 4-month-long treatment with metformin (150 mg/Kg/day, delivered in drinking bottles) provides a selective normalization of cognitive flexibility defects in RTT female mice at an advanced stage of disease, but it does not affect their impaired general health status and abnormal motor skills. The 4-month-long treatment also rescues the reduced activity of mitochondrial respiratory chain complex activities, the defective brain ATP production and levels as well as the increased production of reactive oxidizing species in the whole blood of RTT mice. A significant boost of PGC-1α-dependent pathways related to mitochondrial biogenesis and antioxidant defense occurs in the brain of RTT mice that received the metformin treatment. Further studies will have to verify whether these effects may underlie its long-lasting beneficial effects on brain energy metabolism.

Keywords:  Cognition; Metformin; Mitochondria; Oxidative stress status; Rett syndrome

DOI:  https://doi.org/10.1016/j.neuropharm.2022.109350
Front Nutr. 2022 ;9 947567

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.

Christiaan G J Saris, Silvie Timmers.

  Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.

Keywords:  ketogenic diet; ketone bodies; ketone supplementation; nutritional ketosis; precision nutrition

DOI:  https://doi.org/10.3389/fnut.2022.947567
Eur J Neurosci. 2022 Nov 28.

Effect of fasting on short-term visual plasticity in adult humans.

Silvia Animali, Cecilia Steinwurzel, Angela Dardano, Veronica Sancho-Bornez, Stefano Del Prato, Maria Concetta Morrone, Giuseppe Daniele, Paola Binda.

  Brain plasticity and function is impaired in conditions of metabolic dysregulation, such as obesity. Less is known on whether brain function is also affected by transient and physiological metabolic changes, such as the alternation between fasting and fed state. Here we asked whether these changes affect the transient shift of ocular dominance that follows short-term monocular deprivation, a form of homeostatic plasticity. We further asked whether variations in three of the main metabolic and hormonal pathways affected in obesity (glucose metabolism, leptin signaling and fatty acid metabolism) correlate with plasticity changes. We measured the effects of 2h monocular deprivation in three conditions: post-absorptive state (fasting), after ingestion of a standardized meal, and during infusion of glucagon-like peptide-1 (GLP-1), an incretin physiologically released upon meal ingestion that plays a key role in glucose metabolism. We found that short-term plasticity was less manifest in fasting than in fed state, while GLP-1 infusion did not elicit reliable changes compared to fasting. While we confirmed a positive association between plasticity and supraphysiological GLP-1 levels, achieved by GLP-1 infusion, we found that none of the parameters linked to glucose metabolism could predict the plasticity reduction in the fasting versus fed state. Instead, this was selectively associated with the increase in plasma Beta-Hydroxybutyrate (B-OH) levels during fasting, which suggests a link between neural function and energy substrates alternative to glucose. These results reveal a previously unexplored link between homeostatic brain plasticity and the physiological changes associated with the daily cycle of fasting and fed state.

Keywords:  binocular rivalry; glucose metabolism; ketone metabolism; ocular-dominance plasticity; psychophysics

DOI:  https://doi.org/10.1111/ejn.15873
Brain Plast. 2022 ;8(1): 79-96

Central Adiponectin Signaling - A Metabolic Regulator in Support of Brain Plasticity.

Douglas A Formolo, Tong Cheng, Jiasui Yu, Georg S Kranz, Suk-Yu Yau.

  Brain plasticity and metabolism are tightly connected by a constant influx of peripheral glucose to the central nervous system in order to meet the high metabolic demands imposed by neuronal activity. Metabolic disturbances highly affect neuronal plasticity, which underlies the prevalent comorbidity between metabolic disorders, cognitive impairment, and mood dysfunction. Effective pro-cognitive and neuropsychiatric interventions, therefore, should consider the metabolic aspect of brain plasticity to achieve high effectiveness. The adipocyte-secreted hormone, adiponectin, is a metabolic regulator that crosses the blood-brain barrier and modulates neuronal activity in several brain regions, where it exerts neurotrophic and neuroprotective properties. Moreover, adiponectin has been shown to improve neuronal metabolism in different animal models, including obesity, diabetes, and Alzheimer's disease. Here, we aim at linking the adiponectin's neurotrophic and neuroprotective properties with its main role as a metabolic regulator and to summarize the possible mechanisms of action on improving brain plasticity via its role in regulating the intracellular energetic activity. Such properties suggest adiponectin signaling as a potential target to counteract the central metabolic disturbances and impaired neuronal plasticity underlying many neuropsychiatric disorders.

Keywords:  Adiponectin; brain plasticity; cognition; depression; metabolism; stress

DOI:  https://doi.org/10.3233/BPL-220138
Bioelectron Med. 2022 Nov 30. 8(1): 18

A dual tracer [11C]PBR28 and [18F]FDG microPET evaluation of neuroinflammation and brain energy metabolism in murine endotoxemia.

Santhoshi P Palandira, Joseph Carrion, Lauren Turecki, Aidan Falvey, Qiong Zeng, Hui Liu, Tea Tsaava, Dov Herschberg, Michael Brines, Sangeeta S Chavan, Eric H Chang, An Vo, Yilong Ma, Christine N Metz, Yousef Al-Abed, Kevin J Tracey, Valentin A Pavlov.

   BACKGROUND: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge.
METHODS: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([11C]PBR28 - for microglial activation and [18F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis.
RESULTS: There were significant increases in [11C]PBR28 and [18F]FDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels.
CONCLUSIONS: Together, these findings demonstrate the applicability of [11C]PBR28 - [18F]FDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions "classically" characterized by peripheral inflammatory and metabolic pathogenesis.

Keywords:  Brain; Brain metabolism; Conjunction analysis; Microglia; Micropet imaging; Murine endotoxemia; Neuroinflammation; [11C]PBR28; [18F]FDG

DOI:  https://doi.org/10.1186/s42234-022-00101-2
J Comp Neurol. 2022 Dec 01.

Cholesterol-24-hydroxylase (CYP46) in the old brain: Analysis of positive populations and factors triggering its expression in astrocytes.

Gabriel G Cataldi, Setiembre D Elorza, Ana Toledano-Zaragoza, Soledad de Olmos, Andrea B Cragnolini, Mauricio G Martín.

  Cholesterol-24-hydroxylase (CYP46), a member of the cytochrome P450 superfamily of enzymes, is selectively expressed in the brain and is mainly responsible for cholesterol turnover in the central nervous system. Although increased cyp46A1 gene expression has been linked to cognitive alterations in aging and observed in neurodegenerative diseases and after traumatic brain injury, a detailed characterization of the brain regions and cell types in which CYP46 is expressed in old individuals has not been performed. Using immunohistochemistry and immunofluorescence, we investigated the specific regions and cell populations in the brain, in which cyp46A1 is expressed in 24-month-old mice. We found that CYP46 is localized in the same neuronal populations in young and old brains, mainly in the hippocampus, in cortical layers, and in Purkinje neurons of the cerebellum. No increase in CYP46 levels was found in astrocytes in old mice brains, in primary astrocyte-neuron cocultures aged in vitro, or in primary cultures of senescent astrocytes. However, interleukin-6 treatment strongly induced cyp46A1 expression in reactive astrocytes characterized by high GFAP levels but had no effect in nonactivated astrocytes. Our data suggest that cholesterol-24-hydroxylase expression is triggered in reactive astrocytes in response to proinflammatory signals, probably as part of a response mechanism to injury.

Keywords:  CYP46; aging; astrocytes; brain

DOI:  https://doi.org/10.1002/cne.25436
Neuropeptides. 2022 Nov 17. pii: S0143-4179(22)00082-8. [Epub ahead of print]97 102307

Exercise modulates APOE expression in brain cortex of female APOE3 and APOE4 targeted replacement mice.

Verona E Mulgrave, Abdulrahman A Alsayegh, Aida Jaldi, DianneMarie T Omire-Mayor, Niaya James, Oyonumo Ntekim, Eric Walters, Emanuel O Akala, Joanne S Allard.

  Apolipoprotein E (ApoE) is the main cholesterol carrier of the brain and the ε4 gene variant (APOE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold. Several studies indicate that APOE4 modulates critical factors for neuronal function, including brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Both proteins show exercise-induced upregulation, which is presumed to mediate many of the beneficial effects of physical activity including improved cognition; however, there is variability in results between individuals potentially in-part due to genetic variations including APOE isoform. This study aimed to determine if the two most prevalent human APOE isoforms influence adaptive responses to exercise-training. Targeted replacement mice, homozygous for either APOE3 or APOE4 were randomized into exercised and sedentary groups. Baseline locomotor function and voluntary wheel-running behavior was reduced in APOE4 mice. Exercised groups were subjected to daily treadmill running for 8 weeks. ApoE protein in brain cortex was significantly increased by exercise in both genotypes. PGC-1α mRNA levels in brain cortex were significantly lower in APOE4 mice, and only tended to increase with exercise in both genotypes. Hippocampal BDNF protein were similar between genotypes and was not significantly modulated by treadmill running. Behavioral and biochemical variations between APOE3 and APOE4 mice likely contribute to the differential risk for neurological and vascular diseases and the exercise-induced increase in ApoE levels suggests an added feature of the potential efficacy of physical activity as a preventative and therapeutic strategy for neurogenerative processes in both genotypes.

Keywords:  Apolipoprotein E (APOE); BDNF; Brain cortex; Exercise; PGC-1α

DOI:  https://doi.org/10.1016/j.npep.2022.102307
Curr Res Transl Med. 2022 Aug 11. pii: S2452-3186(22)00030-7. [Epub ahead of print]71(1): 103362

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.

Claire J C Huguenard, Adam Cseresznye, James E Evans, Teresa Darcey, Aurore Nkiliza, Andrew P Keegan, Cheryl Luis, David A Bennett, Zoe Arvanitakis, Hussein N Yassine, Michael Mullan, Fiona Crawford, Laila Abdullah.

   BACKGROUND: The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD.
METHODS: L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS).
FINDINGS: Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies.
INTERPRETATION: Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Keywords:  APOE; Acylcarnitines; Alzheimer's disease; L-carnitine; Lipidomics; TMAO, GBB

DOI:  https://doi.org/10.1016/j.retram.2022.103362
Brain. 2022 Nov 29. pii: awac439. [Epub ahead of print]

Metabolic patterns in brain 18F-fluorodeoxyglucose PET relate to aetiology in paediatric dystonia.

Stavros Tsagkaris, Eric K C Yau, Verity McClelland, Apostolos Papandreou, Ata Siddiqui, Daniel E Lumsden, Margaret Kaminska, Eric Guedj, Alexander Hammers, Jean-Pierre Lin.

  There is a lack of imaging markers revealing the functional characteristics of different brain regions in paediatric dystonia. In this observational study, we assessed the utility of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in understanding dystonia pathophysiology by revealing specific resting awake brain glucose metabolism patterns in different childhood dystonia subgroups. PET scans from 267 children with dystonia being evaluated for possible Deep Brain Stimulation (DBS) surgery between September 2007 and February 2018 at Evelina London Children's Hospital (ELCH) United Kingdom were examined. Scans without gross anatomical abnormality (e.g. large cysts, significant ventriculomegaly; n = 240) were analysed with Statistical Parametric Mapping (SPM12). Glucose metabolism patterns were examined in the 144/240 (60%) cases with the ten commonest childhood-onset dystonias, focusing on nine anatomical regions. A group of thirty-nine adult controls was used for comparisons. The genetic dystonias were associated with the following genes: TOR1A, THAP1, SGCE, KMT2B, HPRT1 (Lesch Nyhan disease), PANK2 and GCDH (Glutaric Aciduria type 1). The acquired Cerebral Palsy (CP) cases were divided into those related to prematurity (CP-Preterm), neonatal jaundice/kernicterus (CP-Kernicterus) and hypoxic-ischaemic encephalopathy (CP-Term). Each dystonia subgroup had distinct patterns of altered FDG-PET uptake. Focal glucose hypometabolism of the pallidi, putamina, or both, was the commonest finding, except in PANK2, where basal ganglia metabolism appeared normal. HPRT1 uniquely showed glucose hypometabolism across all nine cerebral regions. Temporal lobe glucose hypometabolism was found in KMT2B, HPRT1 and CP-Kernicterus. Frontal lobe hypometabolism was found in SGCE, HPRT1, and PANK2. Thalamic and brainstem hypometabolism were seen only in HPRT1, CP-Preterm and CP-term dystonia cases. The combination of frontal and parietal lobe hypermetabolism was uniquely found in CP-term cases. PANK2 cases showed a distinct combination of parietal hypermetabolism with cerebellar hypometabolism but intact putaminal-pallidal glucose metabolism. HPRT1, PANK2, CP-kernicterus and CP-preterm cases had cerebellar and insula glucose hypometabolism as well as parietal glucose hypermetabolism. The study findings offer insights into the pathophysiology of dystonia and support the network theory for dystonia pathogenesis. "Signature" patterns for each dystonia subgroup could be a useful biomarker to guide differential diagnosis and inform personalised management strategies.

Keywords:  PET functional imaging; dystonic cerebral palsy; inherited childhood dystonia

DOI:  https://doi.org/10.1093/brain/awac439
Neural Regen Res. 2023 Jun;18(6): 1196-1202

Vicious cycle of lipid peroxidation and iron accumulation in neurodegeneration.

Irene Villalón-García, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Marta Talaverón-Rey, Juan M Suárez-Rivero, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez, José A Sánchez-Alcázar.

  Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial dysfunction, lipofuscin accumulation, autophagy disruption, and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders. Currently, the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear. In this review, we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation, and the effect of iron overload on lipid peroxidation and cellular function. The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration. Therefore, the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration. In addition, we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration, particularly in PLA2G6-associated neurodegeneration, a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the group of neurodegeneration with brain iron accumulation disorders.

Keywords:  4-hidroxynonenal; PLA2G6-associated neurodegeneration; ferroptosis; iron; lipid peroxidation; lipofuscin; neurodegeneration; neurodegeneration with brain iron accumulation; oxidative stress

DOI:  https://doi.org/10.4103/1673-5374.358614
J Neurosci. 2022 Dec 01. pii: JN-RM-0010-22. [Epub ahead of print]

mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system.

Kristin D Dahl, Adam R Almeida, Hannah A Hathaway, Jennifer Bourne, Tanya L Brown, Lisbet T Finseth, Teresa L Wood, Wendy B Macklin.

In the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, an essential component for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR, which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both regions, Rictor loss in OPCs resulted in early reduction in myelin RNAs and proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin was noted at P21 and P45. By contrast, the losses in corpus callosum resulted in severe hypomyelination and increased unmyelinated axons. The hypomyelination may result from decreased oligodendrocytes in the corpus callosum, which persisted in animals as old as post-natal day 350. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.SIGNIFICANCE STATEMENT:mTORC1 and mTORC2 signaling have differential impact on myelination in the central nervous system. Numerous studies identify a role for mTORC1, but deletion of Rictor (mTORC2 signaling) in late-stage oligodendrocytes had little impact on myelination in the CNS. However, the current studies establish that deletion of mTORC2 signaling from oligodendrocyte progenitor cells results in reduced myelination of brain axons. These studies also establish a regional impact of mTORC2, with little change in spinal cord in these conditional Rictor deletion mice. Importantly, in both brain and spinal cord, mTORC2 downstream signaling targets were impacted by Rictor deletion. Yet, these signaling changes had little impact on myelination in spinal cord, while they resulted in long term alterations in myelination in brain.

DOI: https://doi.org/10.1523/JNEUROSCI.0010-22.2022
J Biol Chem. 2022 Oct 28. pii: S0021-9258(22)01091-2. [Epub ahead of print]298(12): 102648

Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.

Ebru S Selen, Susana Rodriguez, Kyle S Cavagnini, Han-Byeol Kim, Chan Hyun Na, Michael J Wolfgang.

  Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.

Keywords:  Pyruvate Carboxylase; acetylation; fasting; gluconeogenesis; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2022.102648
Eur J Nutr. 2022 Dec 03.

Choline supplementation for preterm infants: metabolism of four Deuterium-labeled choline compounds.

Katrin A Böckmann, Wolfgang Bernhard, Michaela Minarski, Anna Shunova, Cornelia Wiechers, Christian F Poets, Axel R Franz.

   BACKGROUND: Supply of choline is not guaranteed in current preterm infant nutrition. Choline serves in parenchyma formation by membrane phosphatidylcholine (PC), plasma transport of poly-unsaturated fatty acids (PUFA) via PC, and methylation processes via betaine. PUFA-PC concentrations are high in brain, liver and lung, and deficiency may result in developmental disorders. We compared different deuterated (D9-) choline components for kinetics of D9-choline, D9-betaine and D9-PC.
METHODS: Prospective study (1/2021-12/2021) in 32 enterally fed preterm infants (28 0/7-32 0/7 weeks gestation). Patients were randomized to receive enterally a single dose of 2.7 mg/kg D9-choline-equivalent as D9-choline chloride, D9-phosphoryl-choline, D9-glycerophosphorylcholine (D9-GPC) or D9-1-palmitoyl-2-oleoyl-PC(D9-POPC), followed by blood sampling at 1 + 24 h or 12 + 60 h after administration. Plasma concentrations were analyzed by tandem mass spectrometry. Results are expressed as median (25th/75th percentile).
RESULTS: At 1 h, plasma D9-choline was 1.8 (0.9/2.2) µmol/L, 1.3 (0.9/1.5) µmol/L and 1.2 (0.7/1.4) µmol/L for D9-choline chloride, D9-GPC and D9-phosphoryl-choline, respectively. D9-POPC did not result in plasma D9-choline. Plasma D9-betaine was maximal at 12 h, with lowest concentrations after D9-POPC. Maximum plasma D9-PC values at 12 h were the highest after D9-POPC (14.4 (9.1/18.9) µmol/L), compared to the other components (D9-choline chloride: 8.1 [5.6/9.9] µmol/L; D9-GPC: 8.4 (6.2/10.3) µmol/L; D9-phosphoryl-choline: 9.8 (8.6/14.5) µmol/L). Predominance of D9-PC comprising linoleic, rather than oleic acid, indicated fatty-acyl remodeling of administered D9-POPC prior to systemic delivery.
CONCLUSION: D9-Choline chloride, D9-GPC and D9-phosphoryl-choline equally increased plasma D9-choline and D9-betaine. D9-POPC shifted metabolism from D9-betaine to D9-PC. Combined supplementation of GPC and (PO) PC may be best suited to optimize choline supply in preterm infants. Due to fatty acid remodeling of (PO) PC during its assimilation, PUFA co-supplementation with (PO) PC may increase PUFA-delivery to critical organs. This study was registered (22.01.2020) at the Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020502.
STUDY REGISTRATION: This study was registered at the Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020502.

Keywords:  Choline; Deuterium; Preterm infant; Stable isotope labeling; Supplementation

DOI:  https://doi.org/10.1007/s00394-022-03059-8
Neurobiol Dis. 2022 Nov 25. pii: S0969-9961(22)00325-4. [Epub ahead of print]176 105933

Longitudinal spatial mapping of lipid metabolites reveals pre-symptomatic changes in the hippocampi of Huntington's disease transgenic mice.

Farheen Farzana, Malcolm J McConville, Thibault Renoir, Shanshan Li, Shuai Nie, Harvey Tran, Anthony J Hannan, Danny M Hatters, Berin A Boughton.

  In Huntington's disease (HD), a key pathological feature includes the development of inclusion-bodies of fragments of the mutant huntingtin protein in the neurons of the striatum and hippocampus. To examine the molecular changes associated with inclusion-body formation, we applied MALDI-mass spectrometry imaging and deuterium pulse labelling to determine lipid levels and synthesis rates in the hippocampus of a transgenic mouse model of HD (R6/1 line). The R6/1 HD mice lacked inclusions in the hippocampus at 6 weeks of age (pre-symptomatic), whereas inclusions were pervasive by 16 weeks of age (symptomatic). Hippocampal subfields (CA1, CA3 and DG), which formed the highest density of inclusion formation in the mouse brain showed a reduction in the relative abundance of neuron-enriched lipids that have roles in neurotransmission, synaptic plasticity, neurogenesis, and ER-stress protection. Lipids involved in the adaptive response to ER stress (phosphatidylinositol, phosphatidic acid, and ganglioside classes) displayed increased rates of synthesis in HD mice relative to WT mice at all the ages examined, including prior to the formation of the inclusion bodies. Our findings, therefore, support a role for ER stress occurring pre-symptomatically and potentially contributing to pathological mechanisms underlying HD.

Keywords:  Deuterium labelling; Huntingtin inclusions; In vivo metabolic activity; Kinetic mass spectrometry imaging (kMSI); Neurodegeneration; Neuronal membrane lipids

DOI:  https://doi.org/10.1016/j.nbd.2022.105933
Metab Brain Dis. 2022 Nov 30.

Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles.

Tatiane Grazieli Hammerschmidt, Bruna Donida, Marco Raabe, Jéssica Lamberty Faverzani, Franciele de Fátima Lopes, Andryele Z Machado, Rejane G Kessler, Luiza S Reinhardt, Fernanda Poletto, Dinara J Moura, Carmen R Vargas.

  Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.

Keywords:  Antioxidants; Mitochondrial disfunction; Nanoparticles; Niemann-Pick type C; Oxidative stress; β-cyclodextrin

DOI:  https://doi.org/10.1007/s11011-022-01128-9
Neural Regen Res. 2023 Jun;18(6): 1339-1346

Thrombin increases the expression of cholesterol 25-hydroxylase in rat astrocytes after spinal cord injury.

Chen Chen, Huiyuan Ji, Nan Jiang, Yingjie Wang, Yue Zhou, Zhenjie Zhu, Yuming Hu, Yongjun Wang, Aihong Li, Aisong Guo.

  Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level. Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols, which have profound effects on neuropathology. 25-Hydroxycholesterol (25-HC), the main product of the membrane-associated enzyme cholesterol-25-hydroxylase (CH25H), plays important roles in mediating neuroinflammation. However, whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC, as well as the resulting pathological effects, remain unclear. In the present study, spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression. A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo. In cultured primary astrocytes, thrombin interacted with protease-activated receptor 1, mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway. Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration. Finally, injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function. Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.

Keywords:  25-hydroxycholesterol; PAR1; astrocyte; chemotaxis; cholesterol metabolism; cholesterol-25-hydroxylase; lipid homeostasis; macrophage; spinal cord injury; thrombin

DOI:  https://doi.org/10.4103/1673-5374.357905
Brain Plast. 2022 ;8(1): 43-63

Muscle-to-Brain Signaling Via Myokines and Myometabolites.

Mamta Rai, Fabio Demontis.

  Skeletal muscle health and function are important determinants of systemic metabolic homeostasis and organism-wide responses, including disease outcome. While it is well known that exercise protects the central nervous system (CNS) from aging and disease, only recently this has been found to depend on the endocrine capacity of skeletal muscle. Here, we review muscle-secreted growth factors and cytokines (myokines), metabolites (myometabolites), and other unconventional signals (e.g. bioactive lipid species, enzymes, and exosomes) that mediate muscle-brain and muscle-retina communication and neuroprotection in response to exercise and associated processes, such as the muscle unfolded protein response and metabolic stress. In addition to impacting proteostasis, neurogenesis, and cognitive functions, muscle-brain signaling influences complex brain-dependent behaviors, such as depression, sleeping patterns, and biosynthesis of neurotransmitters. Moreover, myokine signaling adapts feeding behavior to meet the energy demands of skeletal muscle. Contrary to protective myokines induced by exercise and associated signaling pathways, inactivity and muscle wasting may derange myokine expression and secretion and in turn compromise CNS function. We propose that tailoring muscle-to-CNS signaling by modulating myokines and myometabolites may combat age-related neurodegeneration and brain diseases that are influenced by systemic signals.

Keywords:  Skeletal muscle; aging; brain; central nervous system; feeding behavior; myokine; myometabolite; neurodegeneration; retina; stress signaling

DOI:  https://doi.org/10.3233/BPL-210133
Cell Discov. 2022 Nov 29. 8(1): 128

Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.

Miao Zhao, Hui-Zhen Su, Yi-Heng Zeng, Yuan Sun, Xin-Xin Guo, Yun-Lu Li, Chong Wang, Zhi-Yuan Zhao, Xue-Jing Huang, Kai-Jun Lin, Zi-Ling Ye, Bi-Wei Lin, Shunyan Hong, Jitan Zheng, Yao-Bin Liu, Xiang-Ping Yao, Dehao Yang, Ying-Qian Lu, Hai-Zhu Chen, Erwei Zuo, Guang Yang, Hong-Tao Wang, Chen-Wei Huang, Xiao-Hong Lin, Zhidong Cen, Lu-Lu Lai, Yan-Ke Zhang, Xi Li, Tianmin Lai, Jingjing Lin, Dan-Dan Zuo, Min-Ting Lin, Chia-Wei Liou, Qing-Xia Kong, Chuan-Zhu Yan, Zhi-Qi Xiong, Ning Wang, Wei Luo, Cui-Ping Zhao, Xuewen Cheng, Wan-Jin Chen.

Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

DOI: https://doi.org/10.1038/s41421-022-00475-2
Neurotox Res. 2022 Nov 28.

Neonatal Isoflurane Exposure in Rats Impairs Short-Term Memory, Cell Viability, and Glutamate Uptake in Slices of the Frontal Cerebral Cortex, But Not the Hippocampus, in Adulthood.

Laíse Figueiredo de Oliveira, Gabriela Godoy Poluceno, Tuane Bazanella Sampaio, Leandra Celso Constantino, Ana Paula Costa, Wagner Carbolin Martins, Tharine Dal-Cim, Karen Andrinéia de Oliveira, Fabiana Kalyne Ludka, Rui Daniel Prediger, Frederico C Pereira, Carla Inês Tasca.

  Neonatal exposure to general anesthetics has been associated with neurotoxicity and morphologic changes in the developing brain. Isoflurane is a volatile anesthetic widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated the effects of a single neonatal isoflurane (3% in oxygen, 2 h) exposure in rats at postnatal day (PND) 7, in short-term (24 h - PND8) and long-term (adulthood) protocols. In PND8, ex vivo analysis of hippocampal and frontal cortex slices evaluated cell viability and susceptibility to in vitro glutamate challenge. In adult rats, behavioral parameters related to anxiety-like behavior, short-term memory, and locomotor activity (PND60-62) and ex vivo analysis of cell viability, membrane permeability, glutamate uptake, and susceptibility to in vitro glutamate challenge in hippocampal and cortical slices from PND65. A single isoflurane (3%, 2 h) exposure at PND7 did not acutely alter cell viability in cortical and hippocampal slices of infant rats (PND8) per se and did not alter slice susceptibility to in vitro glutamate challenge. In rat's adulthood, behavioral analysis revealed that the neonatal isoflurane exposure did not alter anxiety-like behavior and locomotor activity (open field and rotarod tests). However, isoflurane exposure impaired short-term memory evaluated in the novel object recognition task. Ex vivo analysis of brain slices showed isoflurane neonatal exposure selectively decreased cell viability and glutamate uptake in cortical slices, but it did not alter hippocampal slice viability or glutamate uptake (PND65). Isoflurane exposure did not alter in vitro glutamate-induced neurotoxicity to slices, and isoflurane exposure caused no significant long-term damage to cell membranes in hippocampal or cortical slices. These findings indicate that a single neonatal isoflurane exposure did not promote acute damage; however, it reduced cortical, but not hippocampal, slice viability and glutamate uptake in the adulthood. Additionally, behavioral analysis showed neonatal isoflurane exposure induces short-term recognition memory impairment, consolidating that neonatal exposure to volatile anesthetics may lead to behavioral impairment in the adulthood, although it may damage brain regions differentially.

Keywords:  Frontal cortex; Glutamatergic transmission; Isoflurane; Memory; Neonatal

DOI:  https://doi.org/10.1007/s12640-022-00607-2
Epilepsy Behav Rep. 2022 ;20 100571

Focal non-motor seizures and subsequent focal motor seizures as the main clinical expression of GLUT-1 deficiency.

M E Santarone, L M Piscitello, C Volponi, F Vigevano, L Fusco.

  The seizure type most frequently described in GLUT1 deficiency is generalized (mainly absence). We report the case of a young boy who, as the main clinical manifestation presented with focal non-motor, and then focal motor seizures. At the age of 3 months episodes of face pallor/cyanosis and hypotonus lasting about 1 min, occurred. They were initially misdiagnosed as gastroesophageal reflux. These episodes disappeared spontaneously at 6 months of age. At 12 months, episodes similar to the previous ones reappeared. A few months later, a cluster of several episodes manifest as impaired responsiveness and vomiting occurred. The patient initially performed long-term video-EEG monitoring (LTVEM) however, no seizures were captured. During a second hospitalization for LTVEM, a focal to bilateral clonic seizure was recorded. Brain MRI was normal. Next Generation Sequencing (NGS) panel for genes associated with epilepsy showed a de novo mutation of SCL2A1 gene. The CSF showed glucose of 41 mg/dL, and the CSF/serum glucose ratio was equal to 0.46. The ketogenic diet was started with optimal efficacy in seizure control. Meal-sensitivity in childhood onset focal seizures may be associated with GLUT-1 deficiency syndrome that can be confirmed by biochemical analysis on blood and CSF following diagnostic genetic study.

Keywords:  Brain energy failure syndrome; Childhood epilepsy; Glut1 deficiency; SCL2A1; Treatable epilepsy

DOI:  https://doi.org/10.1016/j.ebr.2022.100571
Development. 2022 Dec 01. pii: dev200870. [Epub ahead of print]149(23):

Mitochondrial respiration and dynamics of in vivo neural stem cells.

Stavroula Petridi, Dnyanesh Dubal, Richa Rikhy, Jelle van den Ameele.

  Neural stem cells (NSCs) in the developing and adult brain undergo many different transitions, tightly regulated by extrinsic and intrinsic factors. While the role of signalling pathways and transcription factors is well established, recent evidence has also highlighted mitochondria as central players in NSC behaviour and fate decisions. Many aspects of cellular metabolism and mitochondrial biology change during NSC transitions, interact with signalling pathways and affect the activity of chromatin-modifying enzymes. In this Spotlight, we explore recent in vivo findings, primarily from Drosophila and mammalian model systems, about the role that mitochondrial respiration and morphology play in NSC development and function.

Keywords:  Mitochondria; Mitochondrial morphology; Neural stem cell; Notch; Oxidative phosphorylation; Reactive oxygen species

DOI:  https://doi.org/10.1242/dev.200870
Mol Neurobiol. 2022 Nov 28.

The Depletion of NAMPT Disturbs Mitochondrial Homeostasis and Causes Neuronal Degeneration in Mouse Hippocampus.

Chen Shen, Cong Chen, Tong Wang, Tong-Yao Gao, Min Zeng, Yun-Bi Lu, Wei-Ping Zhang.

  Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the salvaging synthesis pathway of the nicotinamide adenine dinucleotide (NAD). Both NAMPT and NAD progressively decline upon aging and neurodegenerative diseases. The depletion of NAMPT induces mitochondrial dysfunction in motor neurons and causes bioenergetic stress in neurons. However, the roles of NAMPT in hippocampus neurons need to be further studied. Using floxed Nampt (Namptflox/flox) mice, we knocked out Nampt specifically in the hippocampus CA1 neurons by injecting rAAV-hSyn-Cre-APRE-pA. The depletion of NAMPT in hippocampus neurons induced cognitive deficiency in mice. Nevertheless, no morphological change of hippocampus neurons was observed with immunofluorescent imaging. Under the transmission electron microscope, we observed mitochondrial swollen and mitochondrial number decreasing in the cell body and the neurites of hippocampus neurons. In addition, we found the intracellular Aβ (6E10) increased in the hippocampus CA1 region. The intensity of Aβ42 remained unchanged, but it tended to aggregate. The GFAP level, an astrocyte marker, and the Iba1 level, a microglia marker, significantly increased in the mouse hippocampus. In the primary cultured rat neurons, NAMPT inhibition by FK866 decreased the NAD level of neurons at > 10-9 M. FK866 dropped the mitochondrial membrane potential in the cell body of neurons at > 10-9 M and in the dendrite of neurons at > 10-8 M. FK866 decreased the number and shortened the length of branches of neurons at > 10-7 M. Together, likely due to the injury of mitochondria, the decline of NAMPT level can be a critical risk factor for neurodegeneration.

Keywords:  Mitochondria homeostasis; NAD (nicotinamide adenine dinucleotide); NAMPT (nicotinamide phosphoribosyltransferase); Neurodegeneration

DOI:  https://doi.org/10.1007/s12035-022-03142-5
Mol Ther. 2022 Nov 30. pii: S1525-0016(22)00673-6. [Epub ahead of print]

Targeting the Central Nervous System in Lysosomal Storage Diseases: Strategies to Deliver Therapeutics Across the Blood-Brain Barrier.

Bethan J Critchley, H Bobby Gaspar, Sara Benedetti.

  Lysosomal storage diseases (LSDs) are multisystem inherited metabolic disorders caused by dysfunctional lysosomal enzymes, resulting in the accumulation of undegraded macromolecules in a variety of organs/tissues, including the central nervous system (CNS). Treatments include enzyme replacement therapy, stem/progenitor cell transplantation and in vivo gene therapy. However, these treatments are not fully effective in treating the CNS as neither enzymes, stem cells nor viral vectors efficiently cross the blood-brain barrier (BBB). Here we will review the latest advancements in improving delivery of different therapeutic agents to the CNS and comment upon outstanding questions in the field of neurological LSDs.

Keywords:  Lysosomal storage diseases (LSDs); blood-brain barrier (BBB); central nervous system (CNS); enzyme replacement therapy (ERT); gene therapy (GT); haematopoietic stem/progenitor cell (HSPC) transplantation

DOI:  https://doi.org/10.1016/j.ymthe.2022.11.015
J Neurosci. 2022 Nov 28. pii: JN-RM-1539-22. [Epub ahead of print]

Establishment and application of a novel in vitro model of microglial activation in traumatic brain injury.

Ning Liu, Yadan Li, Yinghua Jiang, Samuel Shi, Aim Niamnud, Sammy J Vodovoz, Prasad Vg Katakam, Charles Vidoudez, Aaron S Dumont, Xiaoying Wang.

  Mechanical impact-induced primary injury after traumatic brain injury (TBI) leads to acute microglial pro-inflammatory activation and consequently mediates neurodegeneration, which is a major secondary brain injury mechanism. However, the detailed pathological cascades have not been fully elucidated, partially due to the pathological complexity in animal TBI models. Although there are several in vitro TBI models, none of them closely mimic post-TBI microglial activation. In the present study, we aimed to establish an in vitro TBI model, specifically reconstituting the pro-inflammatory activation and associated neurodegeneration following TBI. We proposed three sets of experiments. Firstly, we established a needle scratch injured neuron (NSN)-induced microglial activation and neurodegeneration in vitro model of TBI. Secondly, we compared microglial pro-inflammatory cytokines profiles between the in vitro TBI model and TBI in male mice. Additionally, we validated the role of injured neurons-derived damage-associated molecular patterns (DAMPs) in amplifying microglial pro-inflammatory pathways using the in vitro TBI model. Thirdly, we applied the in vitro model for the first time to characterize the cellular metabolic profile of needle scratch injured-neuron-activated microglia (NCAM), and define the role of metabolic reprogramming in mediating pro-inflammatory microglial activation and mediated neurodegeneration. Our results showed we successfully established a novel in vitro TBI model, which closely mimics primary neuronal injury-triggered microglial pro-inflammatory activation and mediated neurodegeneration after TBI. This in vitro model provides an advanced and highly translational platform for dissecting interactions in the pathological processes of neuronal injury-microglial activation-neuronal degeneration cascade, and elucidating the detailed underlying cellular and molecular insights after TBI.SIGNIFICANCE STATEMENT:Microglial activation is a key component of acute neuroinflammation that leads to neurodegeneration and long-term neurological outcome deficits after TBI. However, it is not feasible to truly dissect primary neuronal injury-induced microglia activation, and consequently mediated neurodegeneration in vivo Furthermore, there is currently lacking of in vitro TBI models closely mimic the TBI primary injury-mediated microglial activation. In this study, we successfully established and validated a novel in vitro TBI model of microglial activation, and for the first time, characterized the cellular metabolic profile of microglia in this model. This novel microglial activation in vitro TBI model will help in elucidating microglial inflammatory activation and consequently associated neurodegeneration after TBI.

Keywords:  Traumatic brain injury; in vitro model; metabolic reprogramming; microglia and neuron co-culture; microglial pro-inflammatory activation; neuronal injury

DOI:  https://doi.org/10.1523/JNEUROSCI.1539-22.2022
Free Radic Biol Med. 2022 Nov 24. pii: S0891-5849(22)00998-4. [Epub ahead of print]194 71-83

The contribution of an imbalanced redox signalling to neurological and neurodegenerative conditions.

Joern R Steinert, Haitham Amal.

  Nitric oxide and other redox active molecules such as oxygen free radicals provide essential signalling in diverse neuronal functions, but their excess production and insufficient scavenging induces cytotoxic redox stress which is associated with numerous neurodegenerative and neurological conditions. A further component of redox signalling is mediated by a homeostatic regulation of divalent metal ions, the imbalance of which contributes to neuronal dysfunction. Additional antioxidant molecules such as glutathione and enzymes such as super oxide dismutase are involved in maintaining a physiological redox status within neurons. When cellular processes are perturbed and generation of free radicals overwhelms the antioxidants capacity of the neurons, a resulting redox damage leads to neuronal dysfunction and cell death. Cellular sources for production of redox-active molecules may include NADPH oxidases, mitochondria, cytochrome P450 and nitric oxide (NO)-generating enzymes, such as endothelial, neuronal and inducible NO synthases. Several neurodegenerative and developmental neurological conditions are associated with an imbalanced redox state as a result of neuroinflammatory processes leading to nitrosative and oxidative stress. Ongoing research aims at understanding the causes and consequences of such imbalanced redox homeostasis and its role in neuronal dysfunction.

Keywords:  Alzheimer's disease; Autism spectrum disorder; Neurodegeneration; Neurological disorders; Nitric oxide; Nitrosative stress; Oxidative stress; Redox signalling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.11.035
Neuroimage Clin. 2022 Nov 09. pii: S2213-1582(22)00325-4. [Epub ahead of print]36 103260

Neonatal motor functional connectivity and motor outcomes at age two years in very preterm children with and without high-grade brain injury.

Peppar E P Cyr, Rachel E Lean, Jeanette K Kenley, Sydney Kaplan, Dominique E Meyer, Jeffery J Neil, Dimitrios Alexopoulos, Rebecca G Brady, Joshua S Shimony, Thomas L Rodebaugh, Cynthia E Rogers, Christopher D Smyser.

  Preterm-born children have high rates of motor impairments, but mechanisms for early identification remain limited. We hypothesized that neonatal motor system functional connectivity (FC) would relate to motor outcomes at age two years; currently, this relationship is not yet well-described in very preterm (VPT; born <32 weeks' gestation) infants with and without brain injury. We recruited 107 VPT infants - including 55 with brain injury (grade III-IV intraventricular hemorrhage, cystic periventricular leukomalacia, post-hemorrhagic hydrocephalus) - and collected FC data at/near term-equivalent age (35-45 weeks postmenstrual age). Correlation coefficients were used to calculate the FC between bilateral motor and visual cortices and thalami. At two years corrected-age, motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, 3rd edition. Multiple imputation was used to estimate missing data, and regression models related FC measures to motor outcomes. Within the brain-injured group only, interhemispheric motor cortex FC was positively related to gross motor outcomes. Thalamocortical and visual FC were not related to motor scores. This suggests neonatal alterations in motor system FC may provide prognostic information about impairments in children with brain injury.

Keywords:  Brain injury; Cerebral palsy; Functional connectivity; Motor cortex; Preterm birth

DOI:  https://doi.org/10.1016/j.nicl.2022.103260
J Gerontol A Biol Sci Med Sci. 2022 Nov 28. pii: glac234. [Epub ahead of print]

Plasma leptin is associated with amyloid CSF biomarkers and Alzheimer's disease diagnosis in cognitively impaired patients.

Matthieu Lilamand, Elodie Bouaziz-Amar, Julien Dumurgier, Emmanuel Cognat, Claire Hourregue, François Mouton-Liger, Manuel Sanchez, Anne-Cécile Troussière, Matthieu Martinet, Jacques Hugon, Claire Paquet.

   BACKGROUND: Metabolic dysfunction and dysregulation of leptin signaling have been linked to Alzheimer's Disease (AD)'s pathophysiology. The objectives of this study were to examine the associations between plasma leptin, cerebrospinal fluid (CSF) beta-amyloid (Aβ) and tau biomarkers (AT(N) status) and with the stage of cognitive impairment.
METHODS: Cross-sectional analysis of data from cognitively impaired patients from a tertiary memory clinic. Plasma leptin levels were compared according to the stage of cognitive impairment and biomarker profiles, using the AT(N) classification. Linear regression models were performed to examine the relationship between leptin and CSF biomarkers. Results were adjusted for age, gender, body mass index (BMI) and APOE ε4. In a subgroup of A+T+ individuals, we compared the 2-year evolution of Mini Mental Status scores, according to the participants' tertile of plasma leptin levels.
RESULTS: We included 1036 participants (age 68.7±9.1, females=54.1%). A+T+ and A+T- patients had significantly lower plasma leptin levels than amyloid negative subjects (p<0.01). CSF Aβ concentration was significantly associated with lower plasma leptin β= -4.3 (1.5), p=0.005 unadjusted; and β= -3.4 (1.6), p=0.03 after adjustment for age, female gender, BMI and APOE ε4. Patients with major neurocognitive disorder due to AD had a difference of leptin of -7.3 ng/ml 95%CI[-11.8;-2.8],p=0.0002, compared to individuals with other causes of cognitive impairment. Leptin was not associated with the slope of cognitive decline.
CONCLUSION: Plasma leptin levels were associated with CSF Aβ and with the diagnosis of AD confirmed by CSF biomarkers, suggesting a molecular interplay between leptin metabolism and brain amyloid deposition.

Keywords:  Alzheimer’s disease; biomarkers; leptin; metabolic dysfunction

DOI:  https://doi.org/10.1093/gerona/glac234
Neurochem Res. 2022 Dec 01.

PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.

Dongxu Li, Linhai Zhang, Jinmei Tuo, Fan Zhang, Zhenzhen Tai, Xiping Liu, Xiaowei Qiu, Haiqing Zhang, Juan Yang, Jing Wang, Zhong Luo, Zucai Xu.

   BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulated by AMPK, is an important regulator of mitochondrial fusion. At present, whether the AMPK/PGC-1α signaling pathway regulates mitochondrial dynamics in epileptic rats is still unknown.
METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into fourgroups: the control group (0.9% saline, n = 5), the EP groups (lithium-pilocarpine was used to induce epilepsy, and tissues were harvested at 6 and 24 h, every time point, n = 5), the EP + Compound C group (the specific inhibitor of PGC-1α, 15 mg/kg in 2% DMSO, n = 5), and the EP + DMSO group (0.9% saline + 2% DMSO, n = 5). To investigate whether PGC-1α participates in seizures by regulating the expression of mitofusin1/2(MFN1/2)in rats.
RESULTS: In this study, the behavioral results indicate that the seizure susceptibility of the rats to epilepsy was increased when the expression of PGC-1α was inhibited. Subsequently, Western blot results suggested that the expression level of both MFN1 and MFN2 in the hippocampus was higher at 6 and 24 h after an epileptic seizure. Besides, the expression of PGC-1α and MFN2 was significantly decreased in the hippocampus when the epileptic rats were treated with Compound C. Furthermore, the immunofluorescence analysis of the localization of MFN1/2 and PGC-1α showed that MFN1/2 was mainly expressed in neurons but not astrocytes in the hippocampus and cerebral cortex of rats. Meanwhile, PGC-1α colocalized with the excitatory post-synaptic marker PSD95, suggesting that PGC-1α may regulate the seizure susceptibility of the rats by mediating excitatory post-synaptic signaling.
CONCLUSION: The AMPK/PGC-1α signaling pathway may play an important role in the lithium-pilocarpine-induced epileptic rat model by mediating the expression of fusion proteins.

Keywords:  AMPK; Compound C; Epilepsy; MFN1/2; PGC-1α

DOI:  https://doi.org/10.1007/s11064-022-03834-3
Endocrine. 2022 Dec 02.

Effects of gastric bypass surgery on brain connectivity responses to hypoglycemia.

Giovanni Fanni, Christakis Kagios, Erika Roman, Magnus Sundbom, Johan Wikström, Sven Haller, Jan W Eriksson.

   INTRODUCTION: Roux-en-Y gastric bypass (RYGB) leads to beneficial effects on glucose homeostasis, and attenuated hormonal counterregulatory responses to hypoglycemia are likely to contribute. RYGB also induces alterations in neural activity of cortical and subcortical brain regions. We aimed to characterize RYGB-induced changes in resting-state connectivity of specific brain regions of interest for energy homeostasis and behavioral control during hypoglycemia.
METHOD: Ten patients with BMI > 35 kg/m2 were investigated with brain PET/MR imaging during a hyperinsulinemic normo- and hypoglycemic clamp, before and 4 months after RYGB. Hormonal levels were assessed throughout the clamp. Resting-state (RS) fMRI scans were acquired in the glucose-lowering phase of the clamp, and they were analyzed with a seed-to-voxel approach.
RESULTS: RS connectivity during initiation of hypoglycemia was significantly altered after RYGB between nucleus accumbens, thalamus, caudate, hypothalamus and their crosstalk with cortical and subcortical regions. Connectivity between the nucleus accumbens and the frontal pole was increased after RYGB, and this was associated with a reduction of ACTH (r = -0.639, p = 0.047) and cortisol (r = -0.635, p = 0.048) responses. Instead, connectivity between the caudate and the frontal pole after RYGB was reduced and this was associated with less attenuation of glucagon response during the hypoglycemic clamp (r = -0.728, p = 0.017), smaller reduction in fasting glucose (r = -0.798, p = 0.007) and less excess weight loss (r = 0.753, p = 0.012). No other significant associations were found between post-RYGB changes in ROI-to-voxel regional connectivity hormonal responses and metabolic or anthropometric outcomes.
CONCLUSION: RYGB alters brain connectivity during hypoglycemia of several neural pathways involved in reward, inhibitory control, and energy homeostasis. These changes are associated with altered hormonal responses to hypoglycemia and may be involved in the glucometabolic outcome of RYGB.

Keywords:  Counterregulatory response; Feeding behavior; RYGB; fMRI

DOI:  https://doi.org/10.1007/s12020-022-03253-y
Eur J Neurosci. 2022 Nov 28.

Repeated sevoflurane exposures inhibit neurogenesis by inducing the upregulation of glutamate transporter 1 in astrocytes.

Fanli Kong, Yao Zhang, Tingting Wang, Liang Zhong, Chun Feng, Yuanyuan Wu.

  Sevoflurane is a widely used general anesthetic in pediatric patients. Although repeated sevoflurane exposure is known to cause neurodevelopmental disorders in children, the mechanism of this neurotoxicity remains largely unknown. Herein, we investigated the role of glutamate transporter 1(GLT1) in sevoflurane-induced decreased neurogenesis. Neonatal rat pups (postnatal day 7, PN7) were exposed to 3% sevoflurane for two hours for three consecutive days. Neuron loss and decreased neurogenesis have been observed in the neonatal rat brain, along with decreased number of astrocytes. Apoptotic astrocytes were observed after repeated sevoflurane exposure in vitro, resulting in decreased levels of brain-derived neurotrophic factor (BDNF). Calcium overload was observed in astrocytes after repeated sevoflurane exposure, in addition to upregulation of GLT1. Inhibition of GLT1 activity ameliorates repeated sevoflurane exposure-induced cognitive deficits in adult rats. Mechanically, the upregulation of GLT1 was caused by the activation of mRNA translation. RNA-sequencing analysis further confirmed that translation-related genes were activated by repeated sevoflurane exposure. These results indicate that cognitive deficits caused by repeated sevoflurane exposure during PN7-9 are triggered decreased neurogenesis. The proposed underlying mechanism involves upregulation of apoptosis in astrocytes induced by GLT1, therefore, we propose GLT1 as a potential pharmacological target for brain injury in pediatric practice.

Keywords:  apoptosis; astrocytes; glutamate transporter 1; neurogenesis; sevoflurane

DOI:  https://doi.org/10.1111/ejn.15874
Exp Brain Res. 2022 Nov 27.

Upregulation of glutamate transporter 1 by mTOR/Akt pathway in astrocyte culture during oxygen-glucose deprivation and reoxygenation.

Mi Li, Jingmei Yu, Huan Deng, Shansha Xie, Qiuling Li, Yuping Zhao, Shubin Yin, Yi-Fei Ji.

  Astrocyte-specific glutamate transporter subtype 1 (GLT-1) plays an important role in influencing glutamate excitatory toxicity and preventing the death of excitatory toxic neurons. Although the mammalian target of rapamycin (mTOR)/protein kinase B(Akt)/nuclear factor kappa B signaling cascade is involved in the upregulation of astrocytic GLT-1 in oxygen-glucose deprivation (OGD), it is unclear whether the mTOR/Akt pathway is involved in astrocytic GLT-1 upregulation in OGD and reoxygenation (OGD/R). In this study, we found that the treatment of cultured astrocytes with rapamycin and triciribine led to the decreased astrocytes' protrusions, smaller nuclei, and an increased apoptotic rate. The inhibitors of mTOR complex 1 significantly increased the expression levels of phosphorylated Akt-Ser473 (p-Akt), phosphorylated Akt-Thr308(p-Akt), and GLT-1, while Akt-specific inhibitors blocked GLT-1 expression, suggesting that the mTOR/Akt pathway is involved in GLT-1 upregulation. We further demonstrated that astrocytes under OGD/R adapted to environmental changes through the mTOR/Akt pathway, mainly by altering cell morphology and apoptosis and upregulating the expression levels of p-Akt and GLT-1. Our results suggested that astrocytes may adapt to short-term ischemic-reperfusion injury by regulating cell morphology, apoptosis and GLT-1 upregulation.

Keywords:  Astrocytes; GLT-1; OGD/R; Rapamycin; p-Akt

DOI:  https://doi.org/10.1007/s00221-022-06514-4