bims-medebr 2023-11-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒11‒26
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Investigating the origin of the 13 C lactate signal in the anesthetized healthy rat brain in vivo after hyperpolarized [1-13 C]pyruvate injection.
Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.
Potential Use of the Cholesterol Transfer Inhibitor U18666A as a Potent Research Tool for the Study of Cholesterol Mechanisms in Neurodegenerative Disorders.
Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist.
Cholesterol alterations in fragile X syndrome, autism spectrum disorders and other neurodevelopmental disorders.
Comparative Hippocampal Proteome and Phosphoproteome in a Niemann-Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms.
Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.
Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.
Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.
Metabolic Regulation of Single Synaptic Vesicle Exo- and Endocytosis in Hippocampal Synapses.
Phospholipidomics in Clinical Trials for Brain Disorders: Advancing our Understanding and Therapeutic Potentials.
Mitochondrial Proteomes in Neural Cells: A Systematic Review.
The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk.
Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia.
Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction.
Sirtuins and Metabolism Biomarkers in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: a Correlation Study with Clinical Outcomes and Cognitive Impairments.
Astrocytes and microglia in the coordination of CNS development and homeostasis.
Quantitative Metabolomic Analysis of the Rat Hippocampus: Effects of Age and of the Development of Alzheimer's Disease-Like Pathology.
Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.
Co-fractionation-mass spectrometry to characterize native mitochondrial protein assemblies in mammalian neurons and brain.
Identification of a Novel Acid Sphingomyelinase Activity Associated with Recombinant Human Acid Ceramidase.
Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.
Differential Neuroprotective Effects of N-Acetylcysteine against Dithianon Toxicity in Glutamatergic, Dopaminergic, and GABAergic Neurons: Assessment Using Zebrafish.
Maternal exposure to polystyrene nanoplastics alters fetal brain metabolism in mice.
Involvement of brain metabolism in neurodevelopmental disorders.

NMR Biomed. 2023 Nov 22. e5073

Investigating the origin of the 13 C lactate signal in the anesthetized healthy rat brain in vivo after hyperpolarized [1-13 C]pyruvate injection.

Minjie Zhu, Aditya Jhajharia, Sonal Josan, Jae Mo Park, Yi-Fen Yen, Adolf Pfefferbaum, Ralph E Hurd, Daniel M Spielman, Dirk Mayer.

  The goal of this study was to investigate the origin of brain lactate (Lac) signal in the healthy anesthetized rat after injection of hyperpolarized (HP) [1-13 C]pyruvate (Pyr). Dynamic two-dimensional spiral chemical shift imaging with flow-sensitizing gradients revealed reduction in both vascular and brain Pyr, while no significant dependence on the level of flow suppression was detected for Lac. These results support the hypothesis that the HP metabolites predominantly reside in different compartments in the brain (i.e., Pyr in the blood and Lac in the parenchyma). Data from high-resolution metabolic imaging of [1-13 C]Pyr further demonstrated that Lac detected in the brain was not from contributions of vascular signal attributable to partial volume effects. Additionally, metabolite distributions and kinetics measured with dynamic imaging after injection of HP [1-13 C]Lac were similar to Pyr data when Pyr was used as the substrate. These data do not support the hypothesis that Lac observed in the brain after Pyr injection was generated in other organs and then transported across the blood-brain barrier (BBB). Together, the presented results provide further evidence that even in healthy anesthetized rats, the transport of HP Pyr across the BBB is sufficiently fast to permit detection of its metabolic conversion to Lac within the brain.

Keywords:  blood-brain barrier; brain metabolism; hyperpolarized 13C; lactate; pyruvate; rat

DOI:  https://doi.org/10.1002/nbm.5073
J Cell Biol. 2024 Jan 01. pii: e202305048. [Epub ahead of print]223(1):

Sirtuin3 ensures the metabolic plasticity of neurotransmission during glucose deprivation.

Anupama Tiwari, Arsalan Hashemiaghdam, Marissa A Laramie, Dario Maschi, Tristaan Haddad, Marion I Stunault, Carmen Bergom, Ali Javaheri, Vitaly Klyachko, Ghazaleh Ashrafi.

Neurotransmission is an energetically expensive process that underlies cognition. During intense electrical activity or dietary restrictions, the glucose level in the brain plummets, forcing neurons to utilize alternative fuels. However, the molecular mechanisms of neuronal metabolic plasticity remain poorly understood. Here, we demonstrate that glucose-deprived neurons activate the CREB and PGC1α transcriptional program, which induces expression of the mitochondrial deacetylase Sirtuin 3 (Sirt3) both in vitro and in vivo. We show that Sirt3 localizes to axonal mitochondria and stimulates mitochondrial oxidative capacity in hippocampal nerve terminals. Sirt3 plays an essential role in sustaining synaptic transmission in the absence of glucose by providing metabolic support for the retrieval of synaptic vesicles after release. These results demonstrate that the transcriptional induction of Sirt3 facilitates the metabolic plasticity of synaptic transmission.

DOI: https://doi.org/10.1083/jcb.202305048
Mol Neurobiol. 2023 Nov 23.

Potential Use of the Cholesterol Transfer Inhibitor U18666A as a Potent Research Tool for the Study of Cholesterol Mechanisms in Neurodegenerative Disorders.

Saman Yasamineh, Fatemeh Jabbari Mehrabani, Ehsan Derafsh, Renizo Danihiel Cosimi, Amir Mohammad Karimi Forood, Siamak Soltani, Meead Hadi, Omid Gholizadeh.

  Cholesterol is an essential component of mammalian cell membranes and a precursor for crucial signaling molecules. The brain contains the highest level of cholesterol in the body, and abnormal cholesterol metabolism links to many neurodegenerative disorders. The results indicate that faulty cholesterol metabolism is a common feature among people living with neurodegenerative conditions. The researchers suggest that restoring cholesterol levels may become a beneficial new strategy in treating certain neurodegenerative conditions. Several neurodegenerative disorders, such as Alzheimer's disease (AD), Niemann-Pick type C (NPC) disease, and Parkinson's disease (PD), have been connected to abnormalities in brain cholesterol metabolism. Consequently, using a lipid research tool is vital to study further and understand the effect of lipids in neurodegenerative disorders such as NPC, AD, PD, and Huntington's disease (HD). U18666A, also known as 3-(2-(diethylamino) ethoxy) androst-5-en-17-one, is a pharmaceutical drug that suppresses cholesterol trafficking and is a well-known class-2 amphiphile. U18666A has performed many functions, allowing for essential discoveries in lipid studies and shedding light on the pathophysiology of neurodegenerative disorders. Additionally, U18666A prevented the downregulation of low-density lipoprotein (LDL) receptors that are induced by LDL and led to the buildup of cholesterol in lysosomes. Numerous studies show that U18666A impacts the function of cholesterol trafficking to control the metabolism and transport of amyloid precursor proteins (APPs). Treating cortical neurons with U18666A may provide a new in vitro model system for studying the underlying molecular process of NPC, AD, HD, and PD. In this article, we review the mechanism and function of U18666A as a vital tool for studying cholesterol mechanisms in neurological diseases related to abnormal cholesterol metabolism, such as AD, NPC, HD, and PD.

Keywords:  Alzheimer’s disease (AD); Cholesterol; Neurodegenerative diseases; Niemann-Pick type C (NPC) disease; U18666A

DOI:  https://doi.org/10.1007/s12035-023-03798-7
Neuron. 2023 Nov 16. pii: S0896-6273(23)00804-8. [Epub ahead of print]

Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist.

Alexandra Litvinchuk, Jung H Suh, Jing L Guo, Karin Lin, Sonnet S Davis, Nga Bien-Ly, Eric Tycksen, G Travis Tabor, Javier Remolina Serrano, Melissa Manis, Xin Bao, Choonghee Lee, Megan Bosch, Enmanuel J Perez, Carla M Yuede, Anil G Cashikar, Jason D Ulrich, Gilbert Di Paolo, David M Holtzman.

  Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.

Keywords:  Abca1; ApoE4; LXR agonist; Tau; cholesterol metabolism; lipid; microglia

DOI:  https://doi.org/10.1016/j.neuron.2023.10.023
Int Rev Neurobiol. 2023 ;pii: S0074-7742(23)00088-0. [Epub ahead of print]173 115-139

Cholesterol alterations in fragile X syndrome, autism spectrum disorders and other neurodevelopmental disorders.

Sérine Benachenhou, Asma Laroui, Olivier Dionne, Daniela Rojas, Amanda Toupin, Artuela Çaku.

  Neurodevelopmental disorders (NDDs) are a group of etiologically diverse diseases primarily associated with abnormal brain development, impaired cognition, and various behavioral problems. The majority of NDDs present a wide range of clinical phenotypes while sharing distinct cellular and biochemical alterations. Low plasma cholesterol levels have been reported in a subset of NNDs including, autism spectrum disorder (ASD) and fragile X syndrome (FXS). The present review focuses on cholesterol metabolism and discusses the current evidence of lipid disruption in ASD, FXS, and other genetically related NDDs. The characterization of these common deficits might provide valuable insights into their underlying physiopathology and help identify potential therapeutic targets.

Keywords:  Autism spectrum disorders; Brain cholesterol; Cholesterol; Fragile X syndrome; Lipid rafts; Rett syndrome; Smith–Lemli–Opitz syndrome

DOI:  https://doi.org/10.1016/bs.irn.2023.08.011
J Proteome Res. 2023 Nov 24.

Comparative Hippocampal Proteome and Phosphoproteome in a Niemann-Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms.

Thu T A Nguyen, Varshasnata Mohanty, Ying Yan, Kevin R Francis, Stephanie M Cologna.

  Niemann-Pick disease, type C (NPC) is a neurodegenerative, lysosomal storage disorder in individuals carrying two mutated copies of either the NPC1 or NPC2 gene. Consequently, impaired cholesterol recycling and an array of downstream events occur. Interestingly, in NPC, the hippocampus displays lysosomal lipid storage but does not succumb to progressive neurodegeneration as significantly as other brain regions. Since defining the neurodegeneration mechanisms in this disease is still an active area of research, we use mass spectrometry to analyze the overall proteome and phosphorylation pattern changes in the hippocampal region of a murine model of NPC. Using 3 week old mice representing an early disease time point, we observed changes in the expression of 47 proteins, many of which are consistent with the previous literature. New to this study, changes in members of the SNARE complex, including STX7, VTI1B, and VAMP7, were identified. Furthermore, we identified that phosphorylation of T286 on CaMKIIα and S1303 on NR2B increased in mutant animals, even at the late stage of the disease. These phosphosites are crucial to learning and memory and can trigger neuronal death by altering protein-protein interactions.

Keywords:  Niemann–Pick disease; TMT10plex; cholesterol; phosphorylation; synaptic plasticity

DOI:  https://doi.org/10.1021/acs.jproteome.3c00375
Nat Metab. 2023 Nov 20.

Mitochondrial fission drives neuronal metabolic burden to promote stress susceptibility in male mice.

Wan-Ting Dong, Li-Hong Long, Qiao Deng, Duo Liu, Jia-Lin Wang, Fang Wang, Jian-Guo Chen.

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders.

DOI: https://doi.org/10.1038/s42255-023-00924-6
Nat Neurosci. 2023 Nov 23.

Aerobic glycolysis is the predominant means of glucose metabolism in neuronal somata, which protects against oxidative damage.

Yao Wei, QianQian Miao, Qian Zhang, Shiyu Mao, Mengke Li, Xing Xu, Xian Xia, Ke Wei, Yu Fan, Xinlei Zheng, Yinquan Fang, Meng Mei, Qingyu Zhang, Jianhua Ding, Yi Fan, Ming Lu, Gang Hu.

It is generally thought that under basal conditions, neurons produce ATP mainly through mitochondrial oxidative phosphorylation (OXPHOS), and glycolytic activity only predominates when neurons are activated and need to meet higher energy demands. However, it remains unknown whether there are differences in glucose metabolism between neuronal somata and axon terminals. Here, we demonstrated that neuronal somata perform higher levels of aerobic glycolysis and lower levels of OXPHOS than terminals, both during basal and activated states. We found that the glycolytic enzyme pyruvate kinase 2 (PKM2) is localized predominantly in the somata rather than in the terminals. Deletion of Pkm2 in mice results in a switch from aerobic glycolysis to OXPHOS in neuronal somata, leading to oxidative damage and progressive loss of dopaminergic neurons. Our findings update the conventional view that neurons uniformly use OXPHOS under basal conditions and highlight the important role of somatic aerobic glycolysis in maintaining antioxidant capacity.

DOI: https://doi.org/10.1038/s41593-023-01476-4
Genetics. 2023 Nov 23. pii: iyad202. [Epub ahead of print]

Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.

Jongkyun Kang, Chen Zhang, Yuhao Wang, Jian Feng, Bonnie Berger, Norbert Perrimon, Jie Shen.

  Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical systems, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing γ-secretase activity. Mouse genetic analysis highlighted the importance of Presenilin (PS) in learning and memory, synaptic plasticity and neurotransmitter release, and neuronal survival, and Drosophila studies further demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, molecular pathways that interact with PS in neuronal survival remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila Psn model that exhibits age-dependent neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, we tested top ranked candidate genes by selective knockdown (KD) of each gene in neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid transport and metabolism. Specifically, neuron-specific KD of lipophorin receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that LpRs modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.

Keywords:  Alzheimer’s disease; Presenilin; genetic modifier; lipid transport and metabolism; lipoproteins

DOI:  https://doi.org/10.1093/genetics/iyad202
bioRxiv. 2023 Nov 11. pii: 2023.11.08.566236. [Epub ahead of print]

Metabolic Regulation of Single Synaptic Vesicle Exo- and Endocytosis in Hippocampal Synapses.

Jongyun Myeong, Marion I Stunault, Vitaly A Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered a primary source of energy for synaptic function. However, it remains unclear under what conditions alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in cultured hippocampal synapses, we found that mitochondrial ATP production from oxidation of lactate/pyruvate regulates basal vesicle release probability and release location within the active zone (AZ) evoked by single action potentials (APs). Mitochondrial inhibition shifted vesicle release closer to the AZ center, suggesting that the energetic barrier for vesicle release is lower in the AZ center that the periphery. Mitochondrial inhibition also altered the efficiency of single AP evoked vesicle retrieval by increasing occurrence of ultrafast endocytosis, while inhibition of glycolysis had no effect. Mitochondria are sparsely distributed along hippocampal axons and we found that nerve terminals containing mitochondria displayed enhanced vesicle release and reuptake during high-frequency trains, irrespective of whether neurons were supplied with glucose or lactate. Thus, synaptic terminals can entirely bypass glycolysis to robustly maintain the vesicle cycle using oxidative fuels in the absence of glucose. These observations further suggest that mitochondrial metabolic function not only regulates several fundamental features of synaptic transmission but may also contribute to modulation of short-term synaptic plasticity.Highlights: Synapses can sustain neurotransmission across various activity levels by bypassing glycolysis and utilizing oxidative fuels.Mitochondria, but not glycolysis, regulate release probability and nanoscale organization of vesicle release within the active zone.Mitochondrial inhibition increases the occurrence of vesicle retrieval via ultra-fast endocytosis.Mitochondrial localization in nerve terminals enhances vesicle release and retrieval in the absence of glucose, representing a form of synaptic plasticity.

DOI: https://doi.org/10.1101/2023.11.08.566236
Mol Neurobiol. 2023 Nov 20.

Phospholipidomics in Clinical Trials for Brain Disorders: Advancing our Understanding and Therapeutic Potentials.

Mayssa Hachem, Mirja Kaizer Ahmmed, Houda Nacir-Delord.

  Phospholipidomics is a specialized branch of lipidomics that focuses on the characterization and quantification of phospholipids. By using sensitive analytical techniques, phospholipidomics enables researchers to better understand the metabolism and activities of phospholipids in brain disorders such as Alzheimer's and Parkinson's diseases. In the brain, identifying specific phospholipid biomarkers can offer valuable insights into the underlying molecular features and biochemistry of these diseases through a variety of sensitive analytical techniques. Phospholipidomics has emerged as a promising tool in clinical studies, with immense potential to advance our knowledge of neurological diseases and enhance diagnosis and treatment options for patients. In the present review paper, we discussed numerous applications of phospholipidomics tools in clinical studies, with a particular focus on the neurological field. By exploring phospholipids' functions in neurological diseases and the potential of phospholipidomics in clinical research, we provided valuable insights that could aid researchers and clinicians in harnessing the full prospective of this innovative practice and improve patient outcomes by providing more potent treatments for neurological diseases.

Keywords:  Analytical approaches; Brain lipid; Clinical trials; Lipid biomarkers; Lipid profiling; Lipidomics

DOI:  https://doi.org/10.1007/s12035-023-03793-y
Biomolecules. 2023 Nov 11. pii: 1638. [Epub ahead of print]13(11):

Mitochondrial Proteomes in Neural Cells: A Systematic Review.

Aya Nusir, Patricia Sinclair, Nadine Kabbani.

  Mitochondria are ancient endosymbiotic double membrane organelles that support a wide range of eukaryotic cell functions through energy, metabolism, and cellular control. There are over 1000 known proteins that either reside within the mitochondria or are transiently associated with it. These mitochondrial proteins represent a functional subcellular protein network (mtProteome) that is encoded by mitochondrial and nuclear genomes and significantly varies between cell types and conditions. In neurons, the high metabolic demand and differential energy requirements at the synapses are met by specific modifications to the mtProteome, resulting in alterations in the expression and functional properties of the proteins involved in energy production and quality control, including fission and fusion. The composition of mtProteomes also impacts the localization of mitochondria in axons and dendrites with a growing number of neurodegenerative diseases associated with changes in mitochondrial proteins. This review summarizes the findings on the composition and properties of mtProteomes important for mitochondrial energy production, calcium and lipid signaling, and quality control in neural cells. We highlight strategies in mass spectrometry (MS) proteomic analysis of mtProteomes from cultured cells and tissue. The research into mtProteome composition and function provides opportunities in biomarker discovery and drug development for the treatment of metabolic and neurodegenerative disease.

Keywords:  bioinformatics; energetics; evolution; mass spectrometry; neurodegeneration; protein quantification; synapses

DOI:  https://doi.org/10.3390/biom13111638
Mol Psychiatry. 2023 Nov 22.

The role of polyunsaturated fatty acids in the neurobiology of major depressive disorder and suicide risk.

M Elizabeth Sublette, Federico Manuel Daray, Licínia Ganança, Saame Raza Shaikh.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are obtained from diet or derived from essential shorter-chain fatty acids, and are crucial for brain development and functioning. Fundamentally, LC-PUFAs' neurobiological effects derive from their physicochemical characteristics, including length and double bond configuration, which differentiate LC-PUFA species and give rise to functional differences between n(omega)-3 and n-6 LC-PUFAs. LC-PUFA imbalances are implicated in psychiatric disorders, including major depression and suicide risk. Dietary intake and genetic variants in enzymes involved in biosynthesis of LC-PUFAs from shorter chain fatty acids influence LC-PUFA status. Domains impacted by LC-PUFAs include 1) cell signaling, 2) inflammation, and 3) bioenergetics. 1) As major constituents of lipid bilayers, LC-PUFAs are determinants of cell membrane properties of viscosity and order, affecting lipid rafts, which play a role in regulation of membrane-bound proteins involved in cell-cell signaling, including monoaminergic receptors and transporters. 2) The n-3:n-6 LC-PUFA balance profoundly influences inflammation. Generally, metabolic products of n-6 LC-PUFAs (eicosanoids) are pro-inflammatory, while those of n-3 LC-PUFAs (docosanoids) participate in the resolution of inflammation. Additionally, n-3 LC-PUFAs suppress microglial activation and the ensuing proinflammatory cascade. 3) N-3 LC-PUFAs in the inner mitochondrial membrane affect oxidative stress, suppressing production of and scavenging reactive oxygen species (ROS), with neuroprotective benefits. Until now, this wealth of knowledge about LC-PUFA biomechanisms has not been adequately tapped to develop translational studies of LC-PUFA clinical effects in humans. Future studies integrating neurobiological mechanisms with clinical outcomes may suggest ways to identify depressed individuals most likely to respond to n-3 LC-PUFA supplementation, and mechanistic research may generate new treatment strategies.

DOI: https://doi.org/10.1038/s41380-023-02322-6
Int J Mol Sci. 2023 Nov 18. pii: 16480. [Epub ahead of print]24(22):

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia.

Caio Yogi Yonamine, Maria Luiza Estimo Michalani, Rafael Junges Moreira, Ubiratan Fabres Machado.

  The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood-brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer's disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions.

Keywords:  Alzheimer’s disease; cognitive dysfunction; glucose transporters; insulin resistance; obesity

DOI:  https://doi.org/10.3390/ijms242216480
Res Sq. 2023 Nov 08. pii: rs.3.rs-3526342. [Epub ahead of print]

Neuronal Glycogen Breakdown Mitigates Tauopathy via Pentose Phosphate Pathway-Mediated Oxidative Stress Reduction.

Pankaj Kapahi, Sudipta Bar, Kenneth Wilson, Tyler Hilsabeck, Sydney Alderfer, Eric Dammer, Jordan Burton, Samah Shah, Anja Holtz, Enrique Carrera, Jennifer Beck, Jackson Chen, Grant Kauwe, Tara Tracy, Nicholas Seyfried, Birgit Schilling, Lisa Ellerby.

Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unfortunately, current treatment approaches for tauopathies have yielded limited success, underscoring the pressing need for novel therapeutic strategies. We observed distinct signatures of impaired glycogen metabolism in the Drosophila brain of the tauopathy model and the brain of AD patients, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen by activating glycogen phosphorylase (GlyP) ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC) derived neurons from FTD patients. We observed that glycogen breakdown redirects the glucose flux to the pentose phosphate pathway to alleviate oxidative stress. Our findings uncover a critical role for increased GlyP activity in mediating the neuroprotection benefit of dietary restriction (DR) through the cAMP-mediated protein kinase A (PKA) activation. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy treatment.

DOI: https://doi.org/10.21203/rs.3.rs-3526342/v1
Mol Neurobiol. 2023 Nov 23.

Sirtuins and Metabolism Biomarkers in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: a Correlation Study with Clinical Outcomes and Cognitive Impairments.

Forough Foolad, Zahra Samadi-Bahrami, Fariba Khodagholi, Seyed Massood Nabavi, G R Wayne Moore, Mohammad Javan.

  Multiple sclerosis (MS) is a primary inflammatory demyelinating disease with different clinical courses and subtypes. The present study aimed to determine whether mitochondrial dysfunction and sirtuins 1 and 3, as metabolism and epigenetic modifying factors, might contribute to MS disease progression measured by physical disability and cognitive impairment.The volunteers (n = 20 controls, n = 59 MS) were recruited and assessed for cognitive function and disability scores; then, patients were clinically classified as relapsing-remitting (RR) in remission phase, RR in relapse phase, and secondary progressive MS. We measured sirtuin (SIRT) 1 and 3 levels, mitochondrial complex I, IV, aconitase, and α-ketoglutarate dehydrogenase (α-KGD) activity in the peripheral blood mononuclear cells (PBMCs). Furthermore, SIRT1, pyruvate, lactate, and cytochrome c (Cyt c) were determined in plasma. Finally, we performed postmortem tissue immunohistochemistry to assess the level of SIRT1 and SIRT3 in the brain lesions of patients with MS.Increased disability and cognitive impairment in patients were correlated. Plasma level of lactate showed a correlation with the disability in MS patients; moreover, a trend toward increased Cyt c plasma level was observed. Investigation of PBMCs exhibited decreased SIRT1 during the relapse phase along with a reduced complex IV activity in all MS subgroups. α-KGD activity was significantly increased in the RR-remission, and SIRT3 was elevated in RR-relapse group. This elevation correlated with disability and cognitive impairment. Finally, immunohistochemistry demonstrated increased levels of SIRT1 and 3 in the brain active lesion of patients with MS.Our data suggest that mitochondrial dysfunction and alteration in some epigenetics and metabolism modifying factors in the CNS and peripheral blood cells may contribute or correlate with MS progression.

Keywords:  Cognitive impairment; Disability; Mitochondrial dysfunction; Multiple sclerosis; Sirtuins

DOI:  https://doi.org/10.1007/s12035-023-03778-x
J Neurochem. 2023 Nov 20.

Astrocytes and microglia in the coordination of CNS development and homeostasis.

Aída Oryza Lopez-Ortiz, Ukpong B Eyo.

  Glia have emerged as important architects of central nervous system (CNS) development and maintenance. While traditionally glial contributions to CNS development and maintenance have been studied independently, there is growing evidence that either suggests or documents that glia may act in coordinated manners to effect developmental patterning and homeostatic functions in the CNS. In this review, we focus on astrocytes, the most abundant glia in the CNS, and microglia, the earliest glia to colonize the CNS highlighting research that documents either suggestive or established coordinated actions by these glial cells in various CNS processes including cell and/or debris clearance, neuronal survival and morphogenesis, synaptic maturation, and circuit function, angio-/vasculogenesis, myelination, and neurotransmission. Some molecular mechanisms underlying these processes that have been identified are also described. Throughout, we categorize the available evidence as either suggestive or established interactions between microglia and astrocytes in the regulation of the respective process and raise possible avenues for further research. We conclude indicating that a better understanding of coordinated astrocyte-microglial interactions in the developing and mature brain holds promise for developing effective therapies for brain pathologies where these processes are perturbed.

Keywords:  astrocytes; brain; development; glia; homeostasis; microglia

DOI:  https://doi.org/10.1111/jnc.16006
J Alzheimers Dis. 2023 Nov 13.

Quantitative Metabolomic Analysis of the Rat Hippocampus: Effects of Age and of the Development of Alzheimer's Disease-Like Pathology.

Olga Snytnikova, Darya Telegina, Ekaterina Savina, Yuri Tsentalovich, Nataliya Kolosova.

  BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease.OBJECTIVE: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs.
METHODS: High resolution 1H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the "preclinical" period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control.
RESULTS: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups.
CONCLUSIONS: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans.

Keywords:  Aging; Alzheimer’s disease; OXYS rats; hippocampal metabolome; hypotaurine; nuclear magnetic resonance spectroscopy; scyllo-inositol

DOI:  https://doi.org/10.3233/JAD-230706
J Nutr Biochem. 2023 Nov 17. pii: S0955-2863(23)00269-3. [Epub ahead of print] 109536

Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.

Ela Mishra, Mahendra Kumar Thakur.

  Memory impairment during aging and amnesia is attributed to compromised mitochondrial dynamics and mitophagy and other mitochondrial quality control mechanisms. Mitochondrial dynamics involves the continuous process of fission and fusion of mitochondria within a cell and is a fundamental mechanism for regulating mitochondrial quality and function. An extensive range of potential nutritional supplements has been shown to improve mitochondrial health, synaptic plasticity, and cognitive functions. Previous findings revealed that supplementation of vitamin B12-folic acid reduces locomotor deficits and mitochondrial abnormalities but enhances mitochondrial and neuronal health. The present study aims to explore the impact of combined vitamin B12-folic acid supplementation on mitochondrial dynamics, neuronal health, and memory decline in old age and scopolamine-induced amnesia, which remains elusive. The results demonstrated that supplementation led to a noteworthy increase in recognition and spatial memory and expression of memory-related protein BDNF in old and amnesic mice. Moreover, the decrease in the fragmented mitochondrial number was validated by the downregulation of mitochondrial fission p-Drp1 (S616) protein and the increase in elongated mitochondria by the upregulation of mitochondrial fusion Mfn2 protein. The increased spine density and dendritic arborization in old and amnesic mice upon supplementation were confirmed by the enhanced expression level of PSD95 and synaptophysin. Furthermore, supplementation reduced ROS production, inhibited Caspase-3 activation, mitigated neurodegeneration, and enhanced mitochondrial membrane potential, ATP production, Vdac1 expression, myelination, in old and amnesic mice. Collectively, our findings imply that combined supplementation of vitamin B12-folic acid improves mitochondrial dynamics and neuronal health, and leads to recovery of memory during old age and amnesia.

Keywords:  Aging; Amnesia; Memory; Mitochondrial dynamics; Neurodegeneration; Nutritional supplement

DOI:  https://doi.org/10.1016/j.jnutbio.2023.109536
Nat Protoc. 2023 Nov 20.

Co-fractionation-mass spectrometry to characterize native mitochondrial protein assemblies in mammalian neurons and brain.

Mara Zilocchi, Matineh Rahmatbakhsh, Mohamed Taha Moutaoufik, Kirsten Broderick, Alla Gagarinova, Matthew Jessulat, Sadhna Phanse, Hiroyuki Aoki, Khaled A Aly, Mohan Babu.

Human mitochondrial (mt) protein assemblies are vital for neuronal and brain function, and their alteration contributes to many human disorders, e.g., neurodegenerative diseases resulting from abnormal protein-protein interactions (PPIs). Knowledge of the composition of mt protein complexes is, however, still limited. Affinity purification mass spectrometry (MS) and proximity-dependent biotinylation MS have defined protein partners of some mt proteins, but are too technically challenging and laborious to be practical for analyzing large numbers of samples at the proteome level, e.g., for the study of neuronal or brain-specific mt assemblies, as well as altered mtPPIs on a proteome-wide scale for a disease of interest in brain regions, disease tissues or neurons derived from patients. To address this challenge, we adapted a co-fractionation-MS platform to survey native mt assemblies in adult mouse brain and in human NTERA-2 embryonal carcinoma stem cells or differentiated neuronal-like cells. The workflow consists of orthogonal separations of mt extracts isolated from chemically cross-linked samples to stabilize PPIs, data-dependent acquisition MS to identify co-eluted mt protein profiles from collected fractions and a computational scoring pipeline to predict mtPPIs, followed by network partitioning to define complexes linked to mt functions as well as those essential for neuronal and brain physiological homeostasis. We developed an R/CRAN software package, Macromolecular Assemblies from Co-elution Profiles for automated scoring of co-fractionation-MS data to define complexes from mtPPI networks. Presently, the co-fractionation-MS procedure takes 1.5-3.5 d of proteomic sample preparation, 31 d of MS data acquisition and 8.5 d of data analyses to produce meaningful biological insights.

DOI: https://doi.org/10.1038/s41596-023-00901-z
Biomolecules. 2023 Nov 06. pii: 1623. [Epub ahead of print]13(11):

Identification of a Novel Acid Sphingomyelinase Activity Associated with Recombinant Human Acid Ceramidase.

Xingxuan He, Edward H Schuchman.

  Acid ceramidase (AC) is a lysosomal enzyme required to hydrolyze ceramide to sphingosine by the removal of the fatty acid moiety. An inherited deficiency in this activity results in two disorders, Farber Lipogranulomatosis and spinal muscular atrophy with myoclonic epilepsy, leading to the accumulation of ceramides and other sphingolipids in various cells and tissues. In addition to ceramide hydrolysis, several other activities have been attributed to AC, including a reverse reaction that synthesizes ceramide from free fatty acids and sphingosine, and a deacylase activity that removes fatty acids from complex lipids such as sphingomyelin and glycosphingolipids. A close association of AC with another important enzyme of sphingolipid metabolism, acid sphingomyelinase (ASM), has also been observed. Herein, we used a highly purified recombinant human AC (rhAC) and novel UPLC-based assay methods to investigate the recently described deacylase activity of rhAC against three sphingolipid substrates, sphingomyelin, galactosyl- and glucosylceramide. No deacylase activities were detected using this method, although we did unexpectedly identify a significant ASM activity using natural (C-18) and artificial (Bodipy-C12) sphingomyelin substrates as well as the ASM-specific fluorogenic substrate, hexadecanoylamino-4-methylumbelliferyl phosphorylcholine (HMU-PC). We showed that this ASM activity was not due to contaminating, hamster-derived ASM in the rhAC preparation, and that the treatment of ASM-knockout mice with rhAC significantly reduced sphingomyelin storage in the liver. However, unlike the treatment with rhASM, this did not lead to elevated ceramide or sphingosine levels.

Keywords:  Farber disease; ceramidase; deacylase; sphingomyelinase

DOI:  https://doi.org/10.3390/biom13111623
Cell Metab. 2023 Nov 16. pii: S1550-4131(23)00386-8. [Epub ahead of print]

Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration.

Venkat Krishnan Sundaram, Vlad Schütza, Nele H Schröter, Aline Backhaus, Annika Bilsing, Lisa Joneck, Anna Seelbach, Clara Mutschler, Jose A Gomez-Sanchez, Erik Schäffner, Eva Ernst Sánchez, Dagmar Akkermann, Christina Paul, Nancy Schwagarus, Silvana Müller, Angela Odle, Gwen Childs, David Ewers, Theresa Kungl, Maren Sitte, Gabriela Salinas, Michael W Sereda, Klaus-Armin Nave, Markus H Schwab, Mario Ost, Peter Arthur-Farraj, Ruth M Stassart, Robert Fledrich.

  The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

Keywords:  Schwann cell; adipocytes; energy metabolism; leptin; leptin receptor; metabolic adaptation; mitochondrial respiration; myelin autophagy; myelinophagy; nerve repair; oxidative phosphorylation; peripheral nerve injury; regeneration; remyelination

DOI:  https://doi.org/10.1016/j.cmet.2023.10.017
Antioxidants (Basel). 2023 Oct 27. pii: 1920. [Epub ahead of print]12(11):

Differential Neuroprotective Effects of N-Acetylcysteine against Dithianon Toxicity in Glutamatergic, Dopaminergic, and GABAergic Neurons: Assessment Using Zebrafish.

Amit Banik, Juneyong Eum, Byung Joon Hwang, Yun Kee.

  Despite the widespread agricultural use of dithianon as an antifungal agent, its neurotoxic implications for humans and wildlife have not been comprehensively explored. Using zebrafish embryonic development as our model, we found that dithianon treatment induced behavioral alterations in zebrafish larvae that appeared normal. Detailed quantitative analyses showed that dithianon at ≥0.0001 µgmL-1 induced cytoplasmic and mitochondrial antioxidant responses sequentially, followed by the disruption of mitochondrial and cellular homeostasis. Additionally, dithianon at 0.01 and 0.1 µgmL-1 downregulated the expressions of glutamatergic (slc17a6b), GABAergic (gad1b), and dopaminergic (th) neuronal markers. Contrarily, dithianon upregulated the expression of the oligodendrocyte marker (olig2) at concentrations of 0.001 and 0.01 µgmL-1, concurrently suppressing the gene expression of the glucose transporter slc2a1a/glut1. Particularly, dithianon-induced increase in reactive oxygen species (ROS) production was reduced by both N-acetylcysteine (NAC) and betaine; however, only NAC prevented dithianon-induced mortality of zebrafish embryos. Moreover, NAC specifically prevented dithianon-induced alterations in glutamatergic and dopaminergic neurons while leaving GABAergic neurons unaffected, demonstrating that the major neurotransmission systems in the central nervous system differentially respond to the protective effects. Our findings contribute to a better understanding of the neurotoxic potential of dithianon and to developing preventive strategies.

Keywords:  GABAergic neurons; N-acetylcysteine; antioxidants; betaine; developmental neurotoxicity; dithianon; neuroprotection; zebrafish

DOI:  https://doi.org/10.3390/antiox12111920
Metabolomics. 2023 Nov 21. 19(12): 96

Maternal exposure to polystyrene nanoplastics alters fetal brain metabolism in mice.

Grace V Mercer, Nikita E Harvey, Katherine L Steeves, Céline M Schneider, John G Sled, Christopher K Macgowan, Ahmet A Baschat, John C Kingdom, André J Simpson, Myrna J Simpson, Karl J Jobst, Lindsay S Cahill.

  INTRODUCTION: Plastics used in everyday materials accumulate as waste in the environment and degrade over time. The impacts of the resulting particulate micro- and nanoplastics on human health remain largely unknown. In pregnant mice, we recently demonstrated that exposure to nanoplastics throughout gestation and during lactation resulted in changes in brain structure detected on MRI. One possible explanation for this abnormal postnatal brain development is altered fetal brain metabolism.OBJECTIVES: To determine the effect of maternal exposure to nanoplastics on fetal brain metabolism.
METHODS: Healthy pregnant CD-1 mice were exposed to 50 nm polystyrene nanoplastics at a concentration of 106 ng/L through drinking water during gestation. Fetal brain samples were collected at embryonic day 17.5 (n = 18-21 per group per sex) and snap-frozen in liquid nitrogen. Magic angle spinning nuclear magnetic resonance was used to determine metabolite profiles and their relative concentrations in the fetal brain.
RESULTS: The relative concentrations of gamma-aminobutyric acid (GABA), creatine and glucose were found to decrease by 40%, 21% and 30% respectively following maternal nanoplastic exposure when compared to the controls (p < 0.05). The change in relative concentration of asparagine with nanoplastic exposure was dependent on fetal sex (p < 0.005).
CONCLUSION: Maternal exposure to polystyrene nanoplastics caused abnormal fetal brain metabolism in mice. The present study demonstrates the potential impacts of nanoplastic exposure during fetal development and motivates further studies to evaluate the risk to human pregnancies.

Keywords:  1H magic angle spinning nuclear magnetic resonance; Fetal brain; Metabolomics; Mouse; Nanoplastics; Pregnancy

DOI:  https://doi.org/10.1007/s11306-023-02061-3
Int Rev Neurobiol. 2023 ;pii: S0074-7742(23)00081-8. [Epub ahead of print]173 67-113

Involvement of brain metabolism in neurodevelopmental disorders.

Pavel Kotchetkov, Nicole Blakeley, Baptiste Lacoste.

  Neurodevelopmental disorders (NDDs) affect a significant portion of the global population and have a substantial social and economic impact worldwide. Most NDDs manifest in early childhood and are characterized by deficits in cognition, communication, social interaction and motor control. Due to a limited understanding of the etiology of NDDs, current treatment options primarily focus on symptom management rather than on curative solutions. Moreover, research on NDDs is problematic due to its reliance on a neurocentric approach. However, recent studies are broadening the scope of research on NDDs, to include dysregulations within a diverse network of brain cell types, including vascular and glial cells. This review aims to summarize studies from the past few decades on potential new contributions to the etiology of NDDs, with a special focus on metabolic signatures of various brain cells. In particular, we aim to convey how the metabolic functions are intimately linked to the onset and/or progression of common NDDs such as autism spectrum disorders, fragile X syndrome, Rett syndrome and Down syndrome.

Keywords:  Autism; Brain; Endothelium; Glia; Metabolism; Neurons; Neurovascular unit

DOI:  https://doi.org/10.1016/bs.irn.2023.08.004