bims-medebr 2023-04-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒04‒23
thirty-two papers selected by
Regina F. Fernández
Johns Hopkins University

The Ketogenic Diet but not Hydroxycitric Acid Keeps Brain Mitochondria Quality Control and mtDNA Integrity Under Focal Stroke.
Homeostasis of carbohydrates and reactive oxygen species is critically changed in the brain of middle-aged mice: Molecular mechanisms and functional reasons.
α-D-Glucose as a non-radioactive MRS tracer for metabolic studies of the brain.
Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo.
Metabolic switch in the aging astrocyte supported via integrative approach comprising network and transcriptome analyses.
Differential Effects of Chronic Ethanol Use on Mouse Neuronal and Astroglial Metabolic Activity.
Astrocytic aerobic glycolysis provides lactate to support neuronal oxidative metabolism in the hippocampus.
Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.
Alzheimer's disease-specific cytokine secretion suppresses neuronal mitochondrial metabolism.
Role of EEG as a Monitoring Tool in Patients with Glucose Transporter Type I Deficiency Syndrome (GLUT1 -DS) on Ketogenic Diet.
Changes in brain metabolite levels across childhood.
Multi-regional alterations in glucose and purine metabolic pathways in the Parkinson's disease dementia brain.
Role of Lipids in Regulation of Neuroglial Interactions.
Cortical metabolic characteristics of anti-leucine-rich glioma-inactivated 1 antibody encephalitis based on 18F-FDG PET.
Characterization of mitochondria degeneration in spinal motor neurons triggered by chronic over-activation of AMPA receptors in the rat spinal cord in vivo.
The potential of CYP46A1 as a novel therapeutic target for neurological disorders: An updated review of mechanisms.
Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein.
Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model.
A rapid microglial metabolic response controls metabolism and improves memory.
Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation.
Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.
Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype.
Pathology and Astrocytes in Autism.
Systemic Metabolic and Mitochondrial Defects in Rett Syndrome Models.
Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation.
Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.
Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer's Disease.
Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency.
Early-life metabolic dysfunction impairs cognition and mitochondrial function in mice.
mTOR/α-ketoglutarate-mediated signaling pathways in the context of brain neurodegeneration and neuroprotection.
The Promise of Niacin in Neurology.
Megf10-related engulfment of excitatory postsynapses by astrocytes following severe brain injury.

Mol Neurobiol. 2023 Apr 19.

The Ketogenic Diet but not Hydroxycitric Acid Keeps Brain Mitochondria Quality Control and mtDNA Integrity Under Focal Stroke.

Artem P Gureev, Denis N Silachev, Irina S Sadovnikova, Ekaterina P Krutskikh, Ekaterina V Chernyshova, Daria E Volodina, Natalia A Samoylova, Daria V Potanina, Inna Yu Burakova, Yuliya D Smirnova, Vasily N Popov, Egor Y Plotnikov.

  Mitochondrial dysfunction in the ischemic brain is one of the hallmarks of stroke. Dietary interventions such as the ketogenic diet and hydroxycitric acid supplementation (a caloric restriction mimetic) may potentially protect neurons from mitochondrial damage induced by focal stroke in mice. We showed that in control mice, the ketogenic diet and the hydroxycitric acid did not impact significantly on the mtDNA integrity and expression of genes involved in the maintenance of mitochondrial quality control in the brain, liver, and kidney. The ketogenic diet changed the bacterial composition of the gut microbiome, which via the gut-brain axis may affect the increase in anxiety behavior and reduce mice mobility. The hydroxycitric acid causes mortality and suppresses mitochondrial biogenesis in the liver. Focal stroke modelling caused a significant decrease in the mtDNA copy number in both ipsilateral and contralateral brain cortex and increased the levels of mtDNA damage in the ipsilateral hemisphere. These alterations were accompanied by a decrease in the expression of some of the genes involved in maintaining mitochondrial quality control. The ketogenic diet consumption before stroke protects mtDNA in the ipsilateral cortex, probably via activation of the Nrf2 signaling. The hydroxycitric acid, on the contrary, increased stroke-induced injury. Thus, the ketogenic diet is the most preferred variant of dietetic intervention for stroke protection compared with the hydroxycitric acid supplementation. Our data confirm some reports about hydroxycitric acid toxicity, not only for the liver but also for the brain under stroke condition.

Keywords:  Focal stroke; Gut microbiome; Hydroxycitric acid; Ketogenic diet; Mitochondrial DNA; Nrf2/ARE signal pathway

DOI:  https://doi.org/10.1007/s12035-023-03325-8
BBA Adv. 2023 ;3 100077

Homeostasis of carbohydrates and reactive oxygen species is critically changed in the brain of middle-aged mice: Molecular mechanisms and functional reasons.

Maria M Bayliak, Dmytro V Gospodaryov, Volodymyr I Lushchak.

  The brain is an organ that consumes a lot of energy. In the brain, energy is required for synaptic transmission, numerous biosynthetic processes and axonal transport in neurons, and for many supportive functions of glial cells. The main source of energy in the brain is glucose and to a lesser extent lactate and ketone bodies. ATP is formed at glucose catabolism via glycolysis and oxidative phosphorylation in mitochondrial electron transport chain (ETC) within mitochondria being the main source of ATP. With age, brain's energy metabolism is disturbed, involving a decrease in glycolysis and mitochondrial dysfunction. The latter is accompanied by intensified generation of reactive oxygen species (ROS) in ETC leading to oxidative stress. Recently, we have found that crucial changes in energy metabolism and intensity of oxidative stress in the mouse brain occur in middle age with minor progression in old age. In this review, we analyze the metabolic changes and functional causes that lead to these changes in the aging brain.

Keywords:  Aging; Brain; Electron transport chain; Glycolysis; Oxidative stress; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.bbadva.2023.100077
Sci Rep. 2023 Apr 15. 13(1): 6159

α-D-Glucose as a non-radioactive MRS tracer for metabolic studies of the brain.

Guodong Weng, Piotr Radojewski, Johannes Slotboom.

Changes in brain glucose metabolism occur in many neurological disorders as well as during aging. Most studies on the uptake of glucose in the brain use positron emission tomography, which requires injection of a radioactive tracer. Our study shows that ultra-high-field 1H-MRS can be used to measure α-D-glucose at 5.22 ppm in vivo, and the α-D-glucose can be used as a radiation-free tracer in the human brain.

DOI: https://doi.org/10.1038/s41598-023-33161-8
Biochemistry (Mosc). 2023 Jan;88(1): 105-118

Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo.

Vasily A Aleshin, Daria A Sibiryakina, Alexey V Kazantsev, Anastasia V Graf, Victoria I Bunik.

  Organism adaptation to metabolic challenges requires coupling of metabolism to gene expression. In this regard, acylations of histones and metabolic proteins acquire significant interest. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, is mediated by changes in the protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetyl(methyl)phosphinate (AcMeP) or acetylphosphonate methyl ester (AcPMe), followed by the assessment of physiological parameters, brain protein acylation, and expression/phosphorylation of PDHA subunit. At the same dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins with apparent molecular masses of 15-20 kDa. Regarding the proteins of 30-50 kDa, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. The unchanged succinylation of the 30-50 kDa proteins after the administration of AcMeP coincides with the upregulation of desuccinylase SIRT5. No significant differences between the levels of brain PDHA expression, PDHA phosphorylation, parameters of behavior or ECG are observed in the studied animal groups. The data indicate that the short-term inhibition of brain PDH affects acetylation and/or succinylation of the brain proteins, that depends on the inhibitor potency, protein molecular mass, and acylation type. The homeostatic nature of these changes is implied by the stability of physiological parameters after the PDH inhibition.

Keywords:  brain protein acetylation; brain protein succinylation; phosphonate/phosphinate analog of pyruvate; pyruvate dehydrogenase; sirtuin

DOI:  https://doi.org/10.1134/S0006297923010091
Aging (Albany NY). 2023 Apr 18. 15

Metabolic switch in the aging astrocyte supported via integrative approach comprising network and transcriptome analyses.

Alejandro Acevedo, Felipe Torres, Miguel Kiwi, Felipe Baeza-Lehnert, L Felipe Barros, Dasfne Lee-Liu, Christian González-Billault.

  Dysregulated central-energy metabolism is a hallmark of brain aging. Supplying enough energy for neurotransmission relies on the neuron-astrocyte metabolic network. To identify genes contributing to age-associated brain functional decline, we formulated an approach to analyze the metabolic network by integrating flux, network structure and transcriptomic databases of neurotransmission and aging. Our findings support that during brain aging: (1) The astrocyte undergoes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, decreasing lactate supply to the neuron, while the neuron suffers intrinsic energetic deficit by downregulation of Krebs cycle genes, including mdh1 and mdh2 (Malate-Aspartate Shuttle); (2) Branched-chain amino acid degradation genes were downregulated, identifying dld as a central regulator; (3) Ketone body synthesis increases in the neuron, while the astrocyte increases their utilization, in line with neuronal energy deficit in favor of astrocytes. We identified candidates for preclinical studies targeting energy metabolism to prevent age-associated cognitive decline.

Keywords:  astrocyte; brain aging; flux balance analysis; network centrality; neuron

DOI:  https://doi.org/10.18632/aging.204663
Neurochem Res. 2023 Apr 17.

Differential Effects of Chronic Ethanol Use on Mouse Neuronal and Astroglial Metabolic Activity.

Unis Ahmad Bhat, Sreemantula Arun Kumar, Sumana Chakravarty, Anant Bahadur Patel, Arvind Kumar.

  Chronic alcohol use disorder, a major risk factor for the development of neuropsychiatric disorders including addiction to other substances, is associated with several neuropathology including perturbed neuronal and glial activities in the brain. It affects carbon metabolism in specific brain regions, and perturbs neuro-metabolite homeostasis in neuronal and glial cells. Alcohol induced changes in the brain neurochemical profile accompany the negative emotional state associated with dysregulated reward and sensitized stress response to withdrawal. However, the underlying alterations in neuro-astroglial activities and neurochemical dysregulations in brain regions after chronic alcohol use are poorly understood. This study evaluates the impact of chronic ethanol use on the regional neuro-astroglial metabolic activity using 1H-[13C]-NMR spectroscopy in conjunction with infusion of [1,6-13C2]glucose and sodium [2-13C]acetate, respectively, after 48 h of abstinence. Besides establishing detailed 13C labeling of neuro-metabolites in a brain region-specific manner, our results show chronic ethanol induced-cognitive deficits along with a reduction in total glucose oxidation rates in the hippocampus and striatum. Furthermore, using [2-13C]acetate infusion, we showed an alcohol-induced increase in astroglial metabolic activity in the hippocampus and prefrontal cortex. Interestingly, increased astroglia activity in the hippocampus and prefrontal cortex was associated with a differential expression of monocarboxylic acid transporters that are regulating acetate uptake and metabolism in the brain.

Keywords:  13C NMR spectroscopy; Alcohol abuse; Astrocytes; Brain metabolism; GABA; Glutamate; Monocarboxylic acid transporters; Neurons

DOI:  https://doi.org/10.1007/s11064-023-03922-y
Biofactors. 2023 Apr 17.

Astrocytic aerobic glycolysis provides lactate to support neuronal oxidative metabolism in the hippocampus.

Cândida Dias, Eliana Fernandes, Rui M Barbosa, João Laranjinha, Ana Ledo.

  Under physiological conditions, the energetic demand of the brain is met by glucose oxidation. However, ample evidence suggests that lactate produced by astrocytes through aerobic glycolysis may also be an oxidative fuel, highlighting the metabolic compartmentalization between neural cells. Herein, we investigate the roles of glucose and lactate in oxidative metabolism in hippocampal slices, a model that preserves neuron-glia interactions. To this purpose, we used high-resolution respirometry to measure oxygen consumption (O2 flux) at the whole tissue level and amperometric lactate microbiosensors to evaluate the concentration dynamics of extracellular lactate. We found that lactate is produced from glucose and transported to the extracellular space by neural cells in hippocampal tissue. Under resting conditions, endogenous lactate was used by neurons to support oxidative metabolism, which was boosted by exogenously added lactate even in the presence of excess glucose. Depolarization of hippocampal tissue with high K+ significantly increased the rate of oxidative phosphorylation, which was accompanied by a transient decrease in extracellular lactate concentration. Both effects were reverted by inhibition of the neuronal lactate transporter, monocarboxylate transporters 2 (MCT2), supporting the concept of an inward flux of lactate to neurons to fuel oxidative metabolism. We conclude that astrocytes are the main source of extracellular lactate which is used by neurons to fuel oxidative metabolism, both under resting and stimulated conditions.

Keywords:  MCT; astrocytes; lactate; neurometabolism; neurons

DOI:  https://doi.org/10.1002/biof.1951
Biochemistry (Mosc). 2023 Apr;88(4): 466-480

Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.

Andrey G Moiseenok, Nina P Kanunnikova.

  The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington's and Alzheimer's diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson's disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4'-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

Keywords:  Alzheimer’s disease; CoA biosynthesis; CoA-synthetase; acetyl-CoA; acyl-CoA; glutathione; neurodegeneration; oxidative stress; panothenate kinase; pantothenic acid deficiency in the CNS

DOI:  https://doi.org/10.1134/S000629792304003X
bioRxiv. 2023 Apr 07. pii: 2023.04.07.536014. [Epub ahead of print]

Alzheimer's disease-specific cytokine secretion suppresses neuronal mitochondrial metabolism.

Madison K Kuhn, Rebecca M Fleeman, Lynne M Beidler, Amanda M Snyder, Dennis C Chan, Elizabeth A Proctor.

Introduction: Neuroinflammation and metabolic dysfunction are early alterations in Alzheimer's disease brain that are thought to contribute to disease onset and progression. Glial activation due to protein deposition results in cytokine secretion and shifts in brain metabolism, which have been observed in Alzheimer's disease patients. However, the mechanism by which this immunometabolic feedback loop can injure neurons and cause neurodegeneration remains unclear.Methods: We used Luminex XMAP technology to quantify hippocampal cytokine concentrations in the 5xFAD mouse model of Alzheimer's disease at milestone timepoints in disease development. We used partial least squares regression to build cytokine signatures predictive of disease progression, as compared to healthy aging in wild-type littermates. We applied the disease-defining cytokine signature to wild-type primary neuron cultures and measured downstream changes in gene expression using the NanoString nCounter system and mitochondrial function using the Seahorse Extracellular Flux live-cell analyzer.
Results: We identified a pattern of up-regulated IFNγ, IP-10, and IL-9 as predictive of advanced disease. When healthy neurons were exposed to these cytokines in proportions found in diseased brain, gene expression of mitochondrial electron transport chain complexes, including ATP synthase, was suppressed. In live cells, basal and maximal mitochondrial respiration were impaired following cytokine stimulation.
Conclusions: An Alzheimer's disease-specific pattern of cytokine secretion reduces expression of mitochondrial electron transport complexes and impairs mitochondrial respiration in healthy neurons. We establish a mechanistic link between disease-specific immune cues and impaired neuronal metabolism, potentially causing neuronal vulnerability and susceptibility to degeneration in Alzheimer's disease.

DOI: https://doi.org/10.1101/2023.04.07.536014
Epileptic Disord. 2023 Apr 18.

Role of EEG as a Monitoring Tool in Patients with Glucose Transporter Type I Deficiency Syndrome (GLUT1 -DS) on Ketogenic Diet.

Juan Toro-Perez, Sarah Healy, Erick Sell, Srinivas Bulusu, Sharon Whiting.

  RATIONALE: Glucose transporter type I deficiency syndrome (GLUT1-DS) is the fourth most frequent single-gene epilepsy refractory to standard antiepileptic drugs. Multiple seizures types and variable electrographic findings are reported. Ketogenic diet is expected to result in the complete resolution of the epileptiform activity.METHODS: A retrospective chart review of patients with GLUT1-DS on ketogenic diet between December 2012 and February 2022 was done. Analysis of the EEGs prior to and during the ketogenic diet was done.
RESULTS: 34 patients on ketogenic diet were reviewed. Ten had clinical diagnosis of GLUT1-DS, seven of them had genetic confirmation. 71% were female. Average age at seizure onset was 13.85 m.o. (range: 3-60, SD±20.52), at diagnosis was 44.57 m.o (range: 19-79), and at the onset of Ketogenic Diet was 46.43 m.o. (range: 20-83). 29 months (range: 13-38) delay between symptoms onset until diagnosis was noticed. At the diagnosis 100% reported seizures: 71% myoclonic, 57% generalized motor, 57% absence, 28% atonic, and 14% focal motor. Also, 71% abnormal eyes movements, 57% ataxia and 28% intolerance to fasting. 86% had normal brain MRI. 71% had abnormal EEG. All were on ketogenic diet, four on classical (1.75:1 - 2.25:1 ratio). Six were clinically seizure-free after ketogenic diet. EEG features included notch delta, focal spike and wave, and generalized spike/polyspike and wave. One patient had bilateral independent centrotemporal spikes. Spikes showed high and very high amplitude in all of them (>200 μV). The variation of the spike index decreased in three patients but increased in two.
CONCLUSION: Ketogenic diet is the choice treatment for patients with GLUT1-DS. Electrographic features could show worsening after initiation of the ketogenic diet even with seizure control. EEG did not prove to be reliable tool for adjusting KD in our cohort. Centrotemporal spikes have not been reported in patients with GLUT-1 DS.

Keywords:  EEG; GLUT1-DS; epilepsy; ketogenic diet; seizure

DOI:  https://doi.org/10.1002/epd2.20063
Neuroimage. 2023 Apr 18. pii: S1053-8119(23)00233-1. [Epub ahead of print] 120087

Changes in brain metabolite levels across childhood.

Meaghan V Perdue, Marilena M DeMayo, Tiffany K Bell, Elodie Boudes, Mercedes Bagshawe, Ashley D Harris, Catherine Lebel.

  Metabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N=101 children, 112 observations; LTP: N=95 children, 318 observations). We found age-related effects for all metabolites. tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only, and mI decreased with age in the ACC only. Glx did not show linear age effects in either region, but a follow-up analysis in only participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.

Keywords:  development; magnetic resonance spectroscopy; metabolites; neurochemistry

DOI:  https://doi.org/10.1016/j.neuroimage.2023.120087
NPJ Parkinsons Dis. 2023 Apr 20. 9(1): 66

Multi-regional alterations in glucose and purine metabolic pathways in the Parkinson's disease dementia brain.

Melissa Scholefield, Stephanie J Church, George Taylor, David Knight, Richard D Unwin, Garth J S Cooper.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, most commonly characterised by motor dysfunction, but also with a high prevalence of cognitive decline in the decades following diagnosis-a condition known as Parkinson's disease dementia (PDD). Although several metabolic disruptions have been identified in PD, there has yet to be a multi-regional analysis of multiple metabolites conducted in PDD brains. This discovery study attempts to address this gap in knowledge. A semi-targeted liquid chromatography-mass spectrometry analysis of nine neuropathologically-confirmed PDD cases vs nine controls was performed, looking at nine different brain regions, including the cingulate gyrus, cerebellum, hippocampus, motor cortex, medulla, middle temporal gyrus, pons, substantia nigra and primary visual cortex. Case-control differences were determined by multiple t-tests followed by 10% FDR correction. Of 64 identified analytes, 49 were found to be altered in at least one region of the PDD brain. These included metabolites from several pathways, including glucose and purine metabolism and the TCA cycle, with widespread increases in fructose, inosine and ribose-5-phosphate, as well as decreases in proline, serine and deoxyguanosine. Higher numbers of alterations were observed in PDD brain regions that are affected during earlier α-synuclein Braak stages-with the exception of the cerebellum, which showed an unexpectedly high number of metabolic changes. PDD brains show multi-regional alterations in glucose and purine metabolic pathways that reflect the progression of α-synuclein Braak staging. Unexpectedly, the cerebellum also shows a high number of metabolic changes.

DOI: https://doi.org/10.1038/s41531-023-00488-y
Biochemistry (Mosc). 2023 Mar;88(3): 337-352

Role of Lipids in Regulation of Neuroglial Interactions.

Olga V Galkina, Oleg V Vetrovoy, Irina E Krasovskaya, Nataliya D Eschenko.

  Lipids comprise an extremely heterogeneous group of compounds that perform a wide variety of biological functions. Traditional view of lipids as important structural components of the cell and compounds playing a trophic role is currently being supplemented by information on the possible participation of lipids in signaling, not only intracellular, but also intercellular. The review article discusses current data on the role of lipids and their metabolites formed in glial cells (astrocytes, oligodendrocytes, microglia) in communication of these cells with neurons. In addition to metabolic transformations of lipids in each type of glial cells, special attention is paid to the lipid signal molecules (phosphatidic acid, arachidonic acid and its metabolites, cholesterol, etc.) and the possibility of their participation in realization of synaptic plasticity, as well as in other possible mechanisms associated with neuroplasticity. All these new data can significantly expand our knowledge about the regulatory functions of lipids in neuroglial relationships.

Keywords:  astrocytes; brain; central nervous system; lipid metabolism; lipids; microglia; neuronal-glial interactions; neurons; oligodendrocytes; synaptic plasticity

DOI:  https://doi.org/10.1134/S0006297923030045
Front Neurol. 2023 ;14 1100760

Cortical metabolic characteristics of anti-leucine-rich glioma-inactivated 1 antibody encephalitis based on 18F-FDG PET.

Kai Wang, Xiaobin Zhao, Leilei Yuan, Qian Chen, Qun Wang, Lin Ai.

  Purpose: A general glucose metabolism pattern is observed in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis; however, it is unclear whether further subregional metabolic differences exist. Therefore, the present study aimed to conduct an in-depth exploration of the features of glucose metabolism within specific brain areas using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET).Materials and methods: This retrospective study enrolled thirteen patients confirmed with LGI1 antibody encephalitis who were admitted to Beijing Tiantan Hospital from June 2021 to September 2022. All patients underwent 18F-FDG PET before initiating clinical treatment. Changes in glucose metabolism in specific brain areas were analyzed using Cortex ID software. The laterality of 18F-FDG uptake was assessed, and differences in specific brain areas were compared using paired t-tests.
Results: Significant metabolic changes in at least one brain region in 11 out of 13 patients (84.6%) were revealed by semi-quantitative analysis (z-score > 2). A bilateral decrease in the 18F-FDG metabolic pattern was revealed in almost all brain regions of interest; in contrast, a hypermetabolic pattern was observed in the medial temporal region, with mean z-scores of 1.75 ± 3.27 and 2.36 ± 5.90 on the left and right sides, respectively (p = 0.497). In the prefrontal and temporal lobes, 18F-FDG metabolism was significantly lower in the lateral region than in the medial region on both sides. For the cingulate cortex, significant hypometabolism was also observed in the posterior part compared to the anterior counterpart on both the left (z-score: -1.20 ± 1.93 vs. -0.42 ± 1.18, respectively; p = 0.047) and right (z-score: -1.56 ± 1.96 vs. -0.33 ± 1.63, respectively; p = 0.001) sides. However, a significant difference in regional metabolism was observed only on the left side (p = 0.041).
Conclusion: An asymmetric 18F-FDG metabolic pattern exists in patients with anti-LGI1 encephalitis. Meanwhile, varied regional metabolic differences were revealed bilaterally in specific cerebral areas, which could be associated with the clinical manifestations.

Keywords:  LGI1; cortical metabolism; encephalitis; fluorodeoxyglucose; positron emission tomography

DOI:  https://doi.org/10.3389/fneur.2023.1100760
Neuroscience. 2023 Apr 19. pii: S0306-4522(23)00164-1. [Epub ahead of print]

Characterization of mitochondria degeneration in spinal motor neurons triggered by chronic over-activation of AMPA receptors in the rat spinal cord in vivo.

Ramirez-Jarquin Uri Nimrod, Lopez-Huerta Violeta Gisselle, Tapia Ricardo.

  Mitochondrial damage is a central mechanism involved in neurological disorders as Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Energy production is the most studied mitochondrial function; however, mitochondria are also involved in processes like calcium buffering homeostasis, and cell death control during apoptosis and necrosis. Using transmission electron microscopy, in this in vivo study in males rats we describe ultrastructural mitochondrial alterations of spinal motor neurons along chronic AMPA-induced excitotoxicity, which has been described as one of the most relevant mechanisms in ALS disease. Mitochondrial alterations begin with a crest swelling, which progresses to a full mitochondrial swelling and crest disruption. Changes on the mitochondrial morphology from elongated to a circular shape also occur along the AMPA-excitotoxicity process. In addition, by combining the TUNEL assay and immunohistochemistry for mitochondrial enzymes, we show evidence of mitochondrial DNA damage. Evidence of mitochondrial alterations during an AMPA-excitotoxic event is relevant because resembles the mitochondrial alterations previously reported in ALS patients and in transgenic familial ALS models, suggesting that a chronic excitotoxic model can be related to sporadic ALS (as has been shown in recent papers), which represent more than the 90% of the ALS cases. Understanding the mechanisms involved in motor neuron degenerative process, such as the ultrastructural mitochondrial changes permits to design strategies for MN-degeneration treatments in ALS.

Keywords:  Excitotoxicity; Mitochondria; Motor neurons; Spinal cord; Ultrastructure

DOI:  https://doi.org/10.1016/j.neuroscience.2023.04.005
Eur J Pharmacol. 2023 Apr 14. pii: S0014-2999(23)00237-6. [Epub ahead of print]949 175726

The potential of CYP46A1 as a novel therapeutic target for neurological disorders: An updated review of mechanisms.

Mohaddeseh Sadat Alavi, Gholamreza Karimi, Hussein A Ghanimi, Ali Roohbakhsh.

  Cholesterol is a key component of the cell membrane that impacts the permeability, fluidity, and functions of membrane-bound proteins. It also participates in synaptogenesis, synaptic function, axonal growth, dendrite outgrowth, and microtubule stability. Cholesterol biosynthesis and metabolism are in balance in the brain. Its metabolism in the brain is mediated mainly by CYP46A1 or cholesterol 24-hydroxylase. It is responsible for eliminating about 80% of the cholesterol excess from the human brain. CYP46A1 converts cholesterol to 24S-hydroxycholesterol (24HC) that readily crosses the blood-brain barrier and reaches the liver for the final elimination process. Studies show that cholesterol and 24HC levels change during neurological diseases and conditions. So, it was hypothesized that inhibition or activation of CYP46A1 would be an effective therapeutic strategy. Accordingly, preclinical studies, using genetic and pharmacological interventions, assessed the role of CYP46A1 in main neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, spinocerebellar ataxias, and amyotrophic lateral sclerosis. In addition, its role in seizures and brain injury was evaluated. The recent development of soticlestat, as a selective and potent CYP46A1 inhibitor, with significant anti-seizure effects in preclinical and clinical studies, suggests the importance of this target for future drug developments. Previous studies have shown that both activation and inhibition of CYP46A1 are of therapeutic value. This article, using recent studies, highlights the role of CYP46A1 in various brain diseases and insults.

Keywords:  CYP46A1; Cholesterol; Cholesterol 24-hydroxylase; Neurodegenerative disorders; Soticlestat

DOI:  https://doi.org/10.1016/j.ejphar.2023.175726
Proc Natl Acad Sci U S A. 2023 Apr 25. 120(17): e2217396120

Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein.

Andrew Shum, Sofia Zaichick, Gregory S McElroy, Karis D'Alessandro, Milad J Alasady, Michaela Novakovic, Wesley Peng, Ekaterina A Grebenik, Daayun Chung, Margaret E Flanagan, Roger Smith, Alejandro Morales, Laetitia Stumpf, Kaitlyn McGrath, Dimitri Krainc, Marc L Mendillo, Murali Prakriya, Navdeep S Chandel, Gabriela Caraveo.

  Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.

Keywords:  astrocytes; calcineurin; lactate; octopamine; synuclein

DOI:  https://doi.org/10.1073/pnas.2217396120
Front Cell Neurosci. 2023 ;17 1154772

Creatine in the fetal brain: A regional investigation of acute global hypoxia and creatine supplementation in a translational fetal sheep model.

Nhi T Tran, Anna M Muccini, Nadia Hale, Mary Tolcos, Rod J Snow, David W Walker, Stacey J Ellery.

  Background: Creatine supplementation during pregnancy is a promising prophylactic treatment for perinatal hypoxic brain injury. Previously, in near-term sheep we have shown that fetal creatine supplementation reduces cerebral metabolic and oxidative stress induced by acute global hypoxia. This study investigated the effects of acute hypoxia with or without fetal creatine supplementation on neuropathology in multiple brain regions.Methods: Near-term fetal sheep were administered continuous intravenous infusion of either creatine (6 mg kg-1 h-1) or isovolumetric saline from 122 to 134 days gestational age (dGA; term is approx. 145 dGA). At 131 dGA, global hypoxia was induced by a 10 min umbilical cord occlusion (UCO). Fetuses were then recovered for 72 h at which time (134 dGA) cerebral tissue was collected for either RT-qPCR or immunohistochemistry analyses.
Results: UCO resulted in mild injury to the cortical gray matter, thalamus and hippocampus, with increased cell death and astrogliosis and downregulation of genes involved in regulating injury responses, vasculature development and mitochondrial integrity. Creatine supplementation reduced astrogliosis within the corpus callosum but did not ameliorate any other gene expression or histopathological changes induced by hypoxia. Of importance, effects of creatine supplementation on gene expression irrespective of hypoxia, including increased expression of anti-apoptotic (BCL-2) and pro-inflammatory (e.g., MPO, TNFa, IL-6, IL-1β) genes, particularly in the gray matter, hippocampus, and striatum were identified. Creatine treatment also effected oligodendrocyte maturation and myelination in white matter regions.
Conclusion: While supplementation did not rescue mild neuropathology caused by UCO, creatine did result in gene expression changes that may influence in utero cerebral development.

Keywords:  creatine metabolism; hypoxia-ischemia encephalopathy; neuroprotection; perinatal asphyxia (PNA); perinatal brain injury

DOI:  https://doi.org/10.3389/fncel.2023.1154772
bioRxiv. 2023 Apr 04. pii: 2023.04.03.535373. [Epub ahead of print]

A rapid microglial metabolic response controls metabolism and improves memory.

Anne Drougard, Eric H Ma, Vanessa Wegert, Ryan Sheldon, Ilaria Panzeri, Naman Vatsa, Stefanos Apostle, Luca Fagnocchi, Judith Schaf, Klaus Gossens, Josephine Völker, Shengru Pang, Anna Bremser, Erez Dror, Francesca Giacona, Sagar, Michael X Henderson, Marco Prinz, Russell G Jones, J Andrew Pospisilik.

Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1-3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. 13 C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

DOI: https://doi.org/10.1101/2023.04.03.535373
Cell Metab. 2023 Apr 14. pii: S1550-4131(23)00127-4. [Epub ahead of print]

Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation.

Hyung-Lok Chung, Qi Ye, Ye-Jin Park, Zhongyuan Zuo, Jung-Wan Mok, Oguz Kanca, Sudhir Gopal Tattikota, Shenzhao Lu, Nobert Perrimon, Hyun Kyoung Lee, Hugo J Bellen.

  VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also toxic in vertebrates based on a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Indeed, reducing VLCFA with bezafibrate ameliorates the phenotypes. Moreover, simultaneous use of bezafibrate and fingolimod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a treatment avenue for MS.

Keywords:  NF-κB activation; VLCFA β-oxidation; fingolimod; lipid metabolism; multiple sclerosis; myelin lipid; neurodegeneration; neuroinflammation; sphingolipid; sphingosine 1-phosphate

DOI:  https://doi.org/10.1016/j.cmet.2023.03.022
Brain. 2023 Apr 17. pii: awad037. [Epub ahead of print]

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Min-Ho Nam, Hae Young Ko, Dongwoo Kim, Sangwon Lee, Yongmin Mason Park, Seung Jae Hyeon, Woojin Won, Jee-In Chung, Seon Yoo Kim, Han Hee Jo, Kyeong Taek Oh, Young-Eun Han, Gwan-Ho Lee, Yeon Ha Ju, Hyowon Lee, Hyunjin Kim, Jaejun Heo, Mridula Bhalla, Ki Jung Kim, Jea Kwon, Thor D Stein, Mingyu Kong, Hyunbeom Lee, Seung Eun Lee, Soo-Jin Oh, Joong-Hyun Chun, Mi-Ae Park, Ki Duk Park, Hoon Ryu, Mijin Yun, C Justin Lee.

  Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Keywords:   11C-Acetate; 18F-Fluorodeoxyglucose; Alzheimer’s disease; PET imaging; monocarboxylate transporter 1 (MCT1); reactive astrocyte

DOI:  https://doi.org/10.1093/brain/awad037
Anal Biochem. 2023 Apr 16. pii: S0003-2697(23)00121-5. [Epub ahead of print] 115156

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype.

Paige E Lawler, James G Bollinger, Suzanne E Schindler, Cynthia R Hodge, Nicolas J Iglesias, Vishal Krishnan, John B Coulton, Yan Li, David M Holtzman, Randall J Bateman.

  Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.

Keywords:  Alzheimer's disease; Apolipoprotein E; Glycosylation; Mass spectrometry; Proteomics

DOI:  https://doi.org/10.1016/j.ab.2023.115156
Neuropsychiatr Dis Treat. 2023 ;19 841-850

Pathology and Astrocytes in Autism.

Gelareh Vakilzadeh, Veronica Martinez-Cerdeño.

  A distinct pathology for autism spectrum disorder (ASD) remains elusive. Human and animal studies have focused on investigating the role of neurons in ASD. However, recent studies have hinted that glial cell pathology could be a characteristic of ASD. Astrocytes are the most abundant glial cell in the brain and play an important role in neuronal function, both during development and in adult. They regulate neuronal migration, dendritic and spine development, and control the concentration of neurotransmitters at the synaptic cleft. They are also responsible for synaptogenesis, synaptic development, and synaptic function. Therefore, any change in astrocyte number and/or function could contribute to the impairment of connectivity that has been reported in ASD. Data available to date is scarce but indicates that while the number of astrocytes is reduced, their state of activation and their GFAP expression is increased in ASD. Disruption of astrocyte function in ASD may affect proper neurotransmitter metabolism, synaptogenesis, and the state of brain inflammation. Astrocytes alterations are common to ASD and other neurodevelopmental disorders. Future studies about the role of astrocytes in ASD are required to better understand this disorder.

Keywords:  GFAP; astrocyte; autism; postmortem

DOI:  https://doi.org/10.2147/NDT.S390053
bioRxiv. 2023 Apr 04. pii: 2023.04.03.535431. [Epub ahead of print]

Systemic Metabolic and Mitochondrial Defects in Rett Syndrome Models.

Stephanie A Zlatic, Erica Werner, Veda Surapaneni, Chelsea E Lee, Avanti Gokhale, Kaela Singleton, Duc Duong, Amanda Crocker, Karen Gentile, Frank Middleton, Anupam Patgiri, Daniel Tarquinio, Randall Carpenter, Victor Faundez.

Neurodevelopmental disorder genes are broadly expressed supporting the concept that these disorders are systemic diseases that impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2 . Transcriptomes and proteomes of organs and brain regions from Mecp2 -null mice and MECP2 -null human cells were assessed. Widespread changes in the transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2 -null male mice and mutant cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2 - and MECP2 -sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2 / MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

DOI: https://doi.org/10.1101/2023.04.03.535431
Brain. 2023 Apr 21. pii: awad137. [Epub ahead of print]

Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation.

An Cheng, Ichiro Kawahata, Yifei Wang, Wenbin Jia, Wang Haoyang, Tomoki Sekimori, Yi Chen, Hiroyoshi Suzuki, Atsushi Takeda, Nadia Stefanova, David I Finkelstein, Wenbo Ma, Min Chen, Takuya Sasaki, Kohji Fukunaga.

  Multiple system atrophy (MSA) is a neurodegenerative disease characterised by the accumulation of misfolded α-synuclein (αSyn) and myelin disruption. However, the mechanism underlying αSyn accumulation in MSA brains remains unclear. Here, we aimed to identify epsin-2 as a potential regulator of αSyn propagation in MSA brains. In the MSA mouse model, PLP-hαSyn mice, and FABP7/αSyn hetero-aggregate-injected mice, we initially discovered that fatty acid-binding protein 7 (FABP7) is related to MSA development and forms hetero-aggregates with αSyn, which exhibit stronger toxicity than αSyn aggregates. Moreover, the injected FABP7/αSyn hetero-aggregates in mice selectively accumulated only in oligodendrocytes and Purkinje neurons, causing cerebellar dysfunction. Furthermore, bioinformatic analyses of whole blood from MSA patients and FABP7 knock-down mice revealed that epsin-2, a protein expressed in both oligodendrocytes and Purkinje cells, could potentially regulate FABP7/αSyn hetero-aggregate propagation via clathrin-dependent endocytosis. Lastly, AAV5-dependent epsin-2 knock-down mice exhibited decreased levels of αSyn aggregate accumulation in Purkinje neurons and oligodendrocytes, as well as improved myelin levels and Purkinje neuron function in the cerebellum and motor performance. These findings suggest that epsin-2 plays a significant role in αSyn accumulation in MSA, and we propose epsin-2 as a novel therapeutic target for MSA.

Keywords:  FABP7; Multiple system atrophy; epsin-2; α-synuclein aggregates

DOI:  https://doi.org/10.1093/brain/awad137
Nat Commun. 2023 04 17. 14(1): 2194

Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

Ziheng Chen, I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L Rose, Sanjana Srinivasan, Shan Jiang, Q Edward Chang, Ningping Feng, Jason P Gay, Qi Wang, Jing Wang, Philip L Lorenzi, Lucas J Veillon, Bo Wei, John N Weinstein, Angela K Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A Lyssiotis, Joseph R Marszalek, Giulio F Draetta, Haoqiang Ying.

Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial supercomplex assembly and ROS production; accordingly, blocking de novo ether phospholipid biosynthesis sensitized PDAC cells to complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. These data identify ether phospholipids as a regulator of mitochondrial redox control that contributes to the sensitivity of PDAC cells to complex I inhibition.

DOI: https://doi.org/10.1038/s41467-023-37924-9
J Alzheimers Dis. 2023 Apr 10.

Mitochondrial Dysfunction Links to Impaired Hippocampal Serotonin Release in a Mouse Model of Alzheimer's Disease.

Jing Tian, Chase Stucky, Tienju Wang, Nancy A Muma, Michael Johnson, Heng Du.

  BACKGROUND: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer's disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown.OBJECTIVE: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice.
METHODS: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency.
RESULTS: 5xFAD mice exhibited serotonin release decrease and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings.
CONCLUSION: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions.

Keywords:  Alzheimer’s disease; amyloid-β; hippocampus; mitochondria; serotonin

DOI:  https://doi.org/10.3233/JAD-230072
Front Mol Neurosci. 2023 ;16 1118707

Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency.

Aloïse Mabondzo, Rania Harati, Léa Broca-Brisson, Anne-Cécile Guyot, Narciso Costa, Francesco Cacciante, Elena Putignano, Laura Baroncelli, Matthew R Skelton, Cathy Saab, Emmanuelle Martini, Henri Benech, Thomas Joudinaud, Jean-Charles Gaillard, Jean Armengaud, Rifat Hamoudi.

  Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8-/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8-/y mice and wild type and DCE-treated Slc6a8-/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD.

Keywords:  CTD-pathophysiology; cognitive function; creatine transporter deficiency; dodecyl creatine ester; target identification

DOI:  https://doi.org/10.3389/fnmol.2023.1118707
J Nutr Biochem. 2023 Apr 13. pii: S0955-2863(23)00085-2. [Epub ahead of print] 109352

Early-life metabolic dysfunction impairs cognition and mitochondrial function in mice.

Wembley Rodrigues Vilela, Paula Maria Quaglio Bellozi, Victor Luna Picolo, Bruna Neves Cavadas, Keila Valentina Silva Marques, Louise Tavares Garcia Pereira, Ainhoa Rodriguez de Yurre Guirao, Angélica Amorim Amato, Kelly Grace Magalhães, Márcia Renata Mortari, Emiliano Horacio Medei, Jair Trapé Goulart, Andreza Fabro de Bem.

  The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by a two-hit protocol and their impact on cognitive function in juvenile mice. Three-week-old male C57BL/6 mice received a high-fat diet (HFD) or control diet for 7 weeks, associated with 2 low doses of streptozotocin (STZ) or vehicle. Despite the absence of obesity, HFD+STZ impaired glucose metabolism and induced a trend towards cholesterol increase. The two-hit protocol impaired recognition and spatial memories in juvenile mice, without inducing a depressive-like behavior. HFD+STZ mice presented increased immunoreactivity for GFAP and a trend towards a decrease in NeuN in the hippocampus. The treatment caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by the two-hit protocol, here verified through the absence of a decrease in O2 consumption after uncoupled protein-1 inhibition and an increase in the reserve respiratory capacity. Impaired mitochondrial function was also observed in the liver of HFD+STZ juvenile mice, but not in their heart. These results indicate that exposure to HFD+STZ early in life has a detrimental impact on the bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment.

Keywords:  High-fat diet; brown adipose tissue; cognition; hippocampus; mitochondria; streptozotocin

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109352
BBA Adv. 2022 ;2 100066

mTOR/α-ketoglutarate-mediated signaling pathways in the context of brain neurodegeneration and neuroprotection.

Olha Kostiuchenko, Iryna Lushnikova, Magdalena Kowalczyk, Galyna Skibo.

  Cerebral disorders are largely associated with impaired cellular metabolism, despite the regulatory mechanisms designed to ensure cell viability and adequate brain function. Mechanistic target of rapamycin (mTOR) signaling is one of the most crucial factors in the regulation of energy homeostasis and its imbalance is linked with a variety of neurodegenerative diseases. Recent advances in the metabolic pathways' modulation indicate the role of α-ketoglutarate (AKG) as a major signaling hub, additionally highlighting its anti-aging and neuroprotective properties, but the mechanisms of its action are not entirely clear. In this review, we analyzed the physiological and pathophysiological aspects of mTOR in the brain. We also discussed AKG's multifunctional properties, as well as mTOR/AKG-mediated functional communications in cellular metabolism. Thus, this article provides a broad overview of the mTOR/AKG-mediated signaling pathways, in the context of neurodegeneration and endogenous neuroprotection, with the aim to find novel therapeutic strategies.

Keywords:  Aging; Autophagy; Metabolism; Neurodegeneration; Neuroprotection; mTOR; α-ketoglutarate (AKG)

DOI:  https://doi.org/10.1016/j.bbadva.2022.100066
Neurotherapeutics. 2023 Apr 21.

The Promise of Niacin in Neurology.

Emily Wuerch, Gloria Roldan Urgoiti, V Wee Yong.

  Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD+ supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.

Keywords:  Hydroxycarboxylic acid receptor (Hcar)2; Immunomodulation; NAD+/NADP; Neurological diseases; Niacin treatment; Phagocytosis

DOI:  https://doi.org/10.1007/s13311-023-01376-2
CNS Neurosci Ther. 2023 Apr 20.

Megf10-related engulfment of excitatory postsynapses by astrocytes following severe brain injury.

Yuan Zhuang, Xiaojian Xu, Hao Li, Fei Niu, Mengshi Yang, Qianqian Ge, Shenghua Lu, Yu Deng, Hongbin Wu, Bin Zhang, Baiyun Liu.

  AIMS: To investigate astrocyte-related phagocytosis of synapses in the ipsilateral hippocampus after traumatic brain injury (TBI).METHODS: We performed controlled cortical impact to simulate TBI in mice. Seven days postinjury, we performed cognitive tests, synapse quantification, and examination of astrocytic phagocytosis in association with Megf10 expression.
RESULTS: During the subacute stage post-TBI, we found a reduction in excitatory postsynaptic materials in the ipsilateral hippocampus, which was consistent with poor performance in the cognitive test. The transcriptome data suggested that robust phagocytosis was responsible for this process. Coincidently, we identified phagocytic astrocytes containing secondary lysosomes that were wrapped around the synapses in the ipsilateral hippocampus. Moreover, a significant increase in the co-location of GFAP and PSD-95 in the CA1 region suggested astrocytic engulfment of excitatory postsynaptic proteins. After examining the reported phagocytic pathways, we found that both the transcription level and protein expression of Megf10 were elevated. Co-immunofluorescence of GFAP and Megf10 demonstrated that the expression of Megf10 was spatially upregulated in astrocytes, exclusively in the CA1 region, and was related to the astrocytic engulfment of PSD-95.
CONCLUSION: Our study elaborated that the Megf10-related astrocytic engulfment of PSD-95 in the CA1 region of the ipsilateral hippocampus aggravated cognitive dysfunction following severe TBI.

Keywords:  Megf10; astrocytes; hippocampus; phagocytosis; traumatic brain injury

DOI:  https://doi.org/10.1111/cns.14223