bims-medebr 2023-02-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒02‒05
35 papers selected by
Regina F. Fernández
Johns Hopkins University

In vivo calibration of genetically-encoded metabolite biosensors must account for metabolite metabolism during calibration and cellular volume.
The role of ApoE-mediated microglial lipid metabolism in brain aging and disease.
PCSK9 deficiency alters brain lipid composition without affecting brain development and function.
In Vivo Investigation of Glucose Metabolism in Idiopathic and PRKN-Related Parkinson's Disease.
EPA stronger than DHA increases the mitochondrial membrane potential and cardiolipin levels but does not change the ATP level in astrocytes.
The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.
Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle.
Cerebral creatine deficiency affects the timing of oligodendrocyte myelination.
Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders.
VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis.
Targeting carnitine palmitoyltransferase 1 isoforms in the hypothalamus: A promising strategy to regulate energy balance.
D-2-hydroxyglutarate dehydrogenase governs adult neural stem cell activation and promotes histone acetylation via ATP-citrate lyase.
Noninvasive 3-Dimensional 1H-Magnetic Resonance Spectroscopic Imaging of Human Brain Glucose and Neurotransmitter Metabolism Using Deuterium Labeling at 3T: Feasibility and Interscanner Reproducibility.
Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson's Disease: What We Know so Far.
The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus.
Alpha lipoic acid treatment in late middle age improves cognitive function: Proteomic analysis of the protective mechanisms in the hippocampus.
HIGH-CARBOHYDRATE AND FAT DIET CONSUMPTION CAUSES METABOLIC DETERIORATION, NEURONAL DAMAGE, AND LOSS OF RECOGNITION MEMORY IN RATS.
Mitochondrial genes in the 22q11.2 deleted region regulate neural stem and progenitor cell proliferation.
Prenatal exposure to valproic acid induces alterations in the expression and activity of purinergic receptors in the embryonic rat brain.
Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.
Research progress of PPARγ regulation of cholesterol and inflammation in Alzheimer's disease.
Regulation of plasmalogen biosynthesis in mammalian cells and tissues.
A prospective 18F-FDG PET/CT study of the neurometabolic effects in cocaine use and HIV infection.
Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis.
Cholesterol metabolism pathway in autism spectrum disorder: From animal models to clinical observations.
TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.
Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis.
De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome.
Oral lipid-based formulations alter delivery of cannabidiol to different anatomical regions in the brain.
Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.
Nicotinamide Mononucleotide Prevents Cisplatin-Induced Mitochondrial Defects in Cortical Neurons Derived from Human Induced Pluripotent Stem Cells.
Neuroimaging findings of inborn errors of metabolism: urea cycle disorders, aminoacidopathies, and organic acidopathies.
Butyrate ameliorates chronic alcoholic central nervous damage by suppressing microglia-mediated neuroinflammation and modulating the microbiome-gut-brain axis.
Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson's Disease.
Mitochondrial Oxidative Stress in Brain Microvascular Endothelial Cells: Triggering Blood-Brain Barrier Disruption.

J Neurochem. 2023 Feb 01.

In vivo calibration of genetically-encoded metabolite biosensors must account for metabolite metabolism during calibration and cellular volume.

Gerald A Dienel, Douglas L Rothman.

  Isotopic assays of brain glucose utilization rates have been used for more than four decades to establish relationships between energetics, functional activity, and neurotransmitter cycling. Limitations of these methods include the relatively long time (1-60 min) for determination of labeled metabolite levels and the lack of cellular resolution. Identification and quantification of fuels for neurons and astrocytes that support activation and higher brain functions are a major, unresolved issues. Glycolysis is preferentially upregulated during activation even though oxygen level and supply are adequate, causing lactate concentrations to quickly rise during alerting, sensory processing, cognitive tasks, and memory consolidation. However, the fate of lactate (rapid release from brain or cell-cell shuttling coupled with local oxidation) is long-disputed. Genetically-encoded biosensors can determine intracellular metabolite concentrations and report real-time lactate level responses to sensory, behavioral, and biochemical challenges at the cellular level. Kinetics and time courses of cellular lactate concentration changes are informative, but accurate biosensor calibration is required for quantitative comparisons of lactate levels in astrocytes and neurons. An in vivo calibration procedure for the Laconic lactate biosensor involves intracellular lactate depletion by intravenous pyruvate-mediated trans-acceleration of lactate efflux followed by sensor saturation by intravenous infusion of high doses of lactate plus ammonium chloride. In the present paper, the validity of this procedure is questioned because rapid lactate-pyruvate interconversion in blood, preferential neuronal oxidation of both monocarboxylates, on-going glycolytic metabolism, and cellular volumes were not taken into account. Calibration pitfalls for the Laconic lactate biosensor also apply to other metabolite biosensors that are standardized in vivo by infusion of substrates that can be metabolized in peripheral tissues. We discuss how technical shortcomings negate the conclusion that Laconic sensor calibrations support the existence of an in vivo astrocyte-neuron lactate concentration gradient linked to lactate shuttling from astrocytes to neurons to fuel neuronal activity.

Keywords:  Laconic; calibration; genetically-encoded biosensor; pyruvate/lactate metabolism; sensor saturation; trans-acceleration

DOI:  https://doi.org/10.1111/jnc.15775
Immunometabolism (Cobham). 2023 Jan;5(1): e00018

The role of ApoE-mediated microglial lipid metabolism in brain aging and disease.

Jui-Hung Jimmy Yen, I-Chen Ivorine Yu.

  Microglia are a unique population of immune cells resident in the brain that integrate complex signals and dynamically change phenotypes in response to the brain microenvironment. In recent years, single-cell sequencing analyses have revealed profound cellular heterogeneity and context-specific transcriptional plasticity of microglia during brain development, aging, and disease. Emerging evidence suggests that microglia adapt phenotypic plasticity by flexibly reprogramming cellular metabolism to fulfill distinct immune functions. The control of lipid metabolism is central to the appropriate function and homeostasis of the brain. Microglial lipid metabolism regulated by apolipoprotein E (ApoE), a crucial lipid transporter in the brain, has emerged as a critical player in regulating neuroinflammation. The ApoE gene allelic variant, ε4, is associated with a greater risk for neurodegenerative diseases. In this review, we explore novel discoveries in microglial lipid metabolism mediated by ApoE. We elaborate on the functional impact of perturbed microglial lipid metabolism on the underlying pathogenesis of brain aging and disease.

Keywords:  apolipoprotein E; lipid metabolism; microglia

DOI:  https://doi.org/10.1097/IN9.0000000000000018
Front Mol Neurosci. 2022 ;15 1084633

PCSK9 deficiency alters brain lipid composition without affecting brain development and function.

Angela Pärn, Ditte Olsen, Jürgen Tuvikene, Mathias Kaas, Ekaterina Borisova, Mesut Bilgin, Mie Elhauge, Joachim Vilstrup, Peder Madsen, Mateusz C Ambrozkiewicz, Roman U Goz, Tõnis Timmusk, Victor Tarabykin, Camilla Gustafsen, Simon Glerup.

  PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor (LDLR) in the liver, hereby preventing removal of LDL cholesterol from the circulation. Accordingly, PCSK9 inhibitory antibodies and siRNA potently reduce LDL cholesterol to unprecedented low levels and are approved for treatment of hypercholesterolemia. In addition, PCSK9 inactivation alters the levels of several other circulating lipid classes and species. Brain function is critically influenced by cholesterol and lipid composition. However, it remains unclear how the brain is affected long-term by the reduction in circulating lipids as achieved with potent lipid lowering therapeutics such as PCSK9 inhibitors. Furthermore, it is unknown if locally expressed PCSK9 affects neuronal circuits through regulation of receptor levels. We have studied the effect of lifelong low peripheral cholesterol levels on brain lipid composition and behavior in adult PCSK9 KO mice. In addition, we studied the effect of PCSK9 on neurons in culture and in vivo in the developing cerebral cortex. We found that PCSK9 reduced LDLR and neurite complexity in cultured neurons, but neither PCSK9 KO nor overexpression affected cortical development in vivo. Interestingly, PCSK9 deficiency resulted in changes of several lipid classes in the adult cortex and cerebellum. Despite the observed changes, PCSK9 KO mice had unchanged behavior compared to WT controls. In conclusion, our findings demonstrate that altered PCSK9 levels do not compromise brain development or function in mice, and are in line with clinical trials showing that PCSK9 inhibitors have no adverse effects on cognitive function.

Keywords:  LDLR; brain development; brain functioning; brain lipids; cholesterol; lipidomics; mouse behavior; proprotein convertase subtilisin/kexin type 9

DOI:  https://doi.org/10.3389/fnmol.2022.1084633
Mov Disord. 2023 Jan 30.

In Vivo Investigation of Glucose Metabolism in Idiopathic and PRKN-Related Parkinson's Disease.

Max Borsche, Andre Märtens, Philipp Hörmann, Theresa Brückmann, Katja Lohmann, Sinem Tunc, Christine Klein, Karsten Hiller, Alexander Balck.

  BACKGROUND: Alterations in mitochondrial dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). Mitochondrial energy production is linked to glucose metabolism, and diabetes is associated with PD. However, studies investigating glucose metabolism in vivo in genetically stratified PD patients and controls have yet to be performed.OBJECTIVES: The objectives of this study were to explore glucose production, gluconeogenesis, and the contribution of gluconeogenesis to glucose production in idiopathic and PRKN PD compared with healthy controls with state-of-the-art biochemical methods.
METHODS: We applied a dried-blood sampling/gas chromatography/mass spectrometry approach to monitor fluxes in the Cori cycle in vivo.
RESULTS: The contribution of gluconeogenesis to total glucose production is increased in idiopathic PD patients (n = 33), but not in biallelic PRKN mutation carriers (n = 5) compared with healthy controls (n = 13).
CONCLUSIONS: We provide first-time in vivo evidence for alterations in glucose metabolism in idiopathic PD, in keeping with the epidemiological evidence for an association between PD and diabetes. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  PRKN; Parkinson's disease; diabetes; glucose metabolism; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/mds.29333
Exp Cell Res. 2023 Jan 26. pii: S0014-4827(23)00038-1. [Epub ahead of print]424(1): 113491

EPA stronger than DHA increases the mitochondrial membrane potential and cardiolipin levels but does not change the ATP level in astrocytes.

Dawid Stulczewski, Emilia Zgorzynska, Barbara Dziedzic, Katarzyna Wieczorek-Szukala, Kacper Szafraniec, Anna Walczewska.

  Astrocytes are highly energy-consuming glial cells critical for metabolic support to neurons. A growing body of evidence suggests that mitochondrial dysfunction in astrocytes is involved in age-related neurodegenerative disorders and that fish oil, rich in docosahexaenoic (DHA) and eicosapentaenoic (EPA) fatty acids, may alleviate cognition impairment in Parkinson's and Alzheimer's diseases. The present study examines the effect of DHA and EPA on mitochondrial membrane potential (MMP), apoptosis activation and ATP levels in astrocytes cultured in medium containing glucose or galactose, which limits oxidative phosphorylation (OXPHOS). MMP, expressed as the ratio of red to green JC-10 and MitoTracker fluorescence, increased in EPA-incubated cells in a dose dependent manner and was higher than in DHA-incubated astrocytes, also after uncoupling of OXPHOS by carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In cells cultured in glucose and galactose medium mitochondrial hyperpolarization had no impact on intracellular ATP level. Furthermore, both EPA and DHA elevated mitochondrial cardiolipin content, however only EPA did so in a dose-dependent manner and reduced apoptosis which was analyzed by flow cytometry.

Keywords:  ATP; Astrocytes; Cardiolipin; Docosahexaenoic acid; Eicosapentaenoic acid; Mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.yexcr.2023.113491
J Sleep Res. 2023 Feb 03. e13832

The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.

Lydia Rose Henderson, Margo van den Berg, David M Shaw.

  Extended wakefulness, or sleep deprivation, impairs cognitive performance and brain glucose metabolism. A ketogenic diet (KD) provides an alternative fuel source, ketone bodies, that could elicit a metabolic benefit during sleep deprivation. A randomised, cross-over trial was conducted with seven male military personnel. Participants ingested an iso-energetic ketogenic diet or carbohydrate-based diet for 14 days, immediately followed by 36 h of extended wakefulness and separated by a 12 day washout. Cognitive performance, mood, subjective sleepiness, capillary blood glucose, and D-β-hydroxybutyrate concentrations were measured every 2 h during extended wakefulness. Linear mixed models were used to analyse data. D-β-hydroxybutyrate was higher (p < 0.001) and glucose was lower (p < 0.01) on the KD compared with the carbohydrate-based diet. The KD improved psychomotor vigilance task performance (number of lapses, mean reciprocal response time, mean fastest 10% response time (RT), and mean slowest 10% RT; all p < 0.05), running memory continuous performance test performance (RT and number of correct responses per minute; both p < 0.01), and vigour, fatigue, and sleepiness (all, p ≤ 0.001) compared with the carbohydrate-based diet. In conclusion, a KD demonstrated beneficial effects on cognitive performance, mood, and sleepiness during 36 h of extended wakefulness compared with a carbohydrate-based diet.

Keywords:  fatigue management; keto-adaptation; ketosis; psychomotor vigilance task; randomised controlled trial; sleep deprivation

DOI:  https://doi.org/10.1111/jsr.13832
iScience. 2023 Jan 20. 26(1): 105830

Serotonergic neurons control cortical neuronal intracellular energy dynamics by modulating astrocyte-neuron lactate shuttle.

Akiyo Natsubori, Shinobu Hirai, Soojin Kwon, Daisuke Ono, Fei Deng, Jinxia Wan, Momoka Miyazawa, Takashi Kojima, Haruo Okado, Akihiro Karashima, Yulong Li, Kenji F Tanaka, Makoto Honda.

  The central serotonergic system has multiple roles in animal physiology and behavior, including sleep-wake control. However, its function in controlling brain energy metabolism according to the state of animals remains undetermined. Through in vivo monitoring of energy metabolites and signaling, we demonstrated that optogenetic activation of raphe serotonergic neurons increased cortical neuronal intracellular concentration of ATP, an indispensable cellular energy molecule, which was suppressed by inhibiting neuronal uptake of lactate derived from astrocytes. Raphe serotonergic neuronal activation induced cortical astrocytic Ca2+ and cAMP surges and increased extracellular lactate concentrations, suggesting the facilitation of lactate release from astrocytes. Furthermore, chemogenetic inhibition of raphe serotonergic neurons partly attenuated the increase in cortical neuronal intracellular ATP levels as arousal increased in mice. Serotonergic neuronal activation promoted an increase in cortical neuronal intracellular ATP levels, partly mediated by the facilitation of the astrocyte-neuron lactate shuttle, contributing to state-dependent optimization of neuronal intracellular energy levels.

Keywords:  Biological sciences; Neuroscience; molecular neuroscience

DOI:  https://doi.org/10.1016/j.isci.2022.105830
J Neurosci. 2023 Jan 27. pii: JN-RM-2120-21. [Epub ahead of print]

Cerebral creatine deficiency affects the timing of oligodendrocyte myelination.

Lauren M Rosko, Tyler Gentile, Victoria N Smith, Zeeba Manavi, George S Melchor, Jingwen Hu, Nataliia V Shults, Chris Albanese, Yichien Lee, Olga Rodriguez, Jeffrey K Huang.

Cerebral creatine deficiency syndrome (CCDS) is an inborn error of metabolism characterized by intellectual delays, seizures, and autistic-like behavior. However, the role of endogenously synthesized creatine on central nervous system (CNS) development and function remains poorly understood. Here, magnetic resonance spectroscopy (MRS) of adult mouse brains from both sexes revealed creatine synthesis is dependent on the expression of the enzyme, guanidinoacetate methyltransferase (GAMT). To identify Gamt-expressed cells, and how Gamt affects postnatal CNS development, we generated a mouse line by knocking-in a green fluorescent protein (GFP) which is expressed upon excision of Gamt We found that Gamt is expressed in mature oligodendrocytes during active myelination in the developing postnatal CNS. Homozygous deletion of Gamt resulted in significantly reduced mature oligodendrocytes and delayed myelination in the corpus callosum. Moreover, the absence of endogenous creatine resulted in altered AMPK signaling in the brain, reduced brain creatine kinase expression in cortical neurons, and signs of axonal damage. Experimental demyelination in mice after tamoxifen induced conditional deletion of Gamt in oligodendrocyte lineage cells resulted in delayed maturation of oligodendrocytes and myelin coverage in lesions. Moreover, creatine and cyclocreatine supplementation can enhance remyelination after demyelination. Our results suggest endogenously synthesized creatine controls the bioenergetic demand required for the timely maturation of oligodendrocytes during postnatal CNS development, and that delayed myelination and altered CNS energetics through the disruption of creatine synthesis might contribute to conditions such as CCDS.SIGNIFICANCE STATEMENT:Cerebral creatine deficiency syndrome (CCDS) is a rare disease of inborn errors in metabolism, which is characterized by intellectual delays, seizures, and autism-like behavior. We found that oligodendrocytes are the main source of endogenously synthesized creatine in the adult CNS, and the loss of endogenous creatine synthesis led to delayed myelination. Our study suggests impaired cerebral creatine synthesis affects the timing of myelination and may impact brain bioenergetics.

DOI: https://doi.org/10.1523/JNEUROSCI.2120-21.2022
Biochem Pharmacol. 2023 Jan 26. pii: S0006-2952(23)00024-2. [Epub ahead of print] 115433

Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders.

Bianca Seminotti, Mateus Grings, Nícolas Manzke Glänzel, Jerry Vockley, Guilhian Leipnitz.

  Inherited metabolic disorders (IMDs) are genetic disorders that cause a disruption of a specific metabolic pathway leading to biochemical, clinical and pathophysiological sequelae. While the metabolite abnormalities in body fluids and tissues can usually be defined by directed or broad-spectrum metabolomic analysis, the pathophysiology of these changes is often not obvious. Mounting evidence has revealed that secondary mitochondrial dysfunction, mainly oxidative phosphorylation impairment and elevated reactive oxygen species, plays a pivotal role in many disorders. Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.

Keywords:  Inherited metabolic disorders; bezafibrate; mitochondrial dysfunction; peroxisome proliferator-activated receptors-PPAR

DOI:  https://doi.org/10.1016/j.bcp.2023.115433
Neurosci Res. 2023 Jan 27. pii: S0168-0102(23)00022-6. [Epub ahead of print]

VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis.

Shaked Segev, Assif Yitzhaky, Dorit Ben Shachar, Libi Hertzberg.

  Mitochondrial dysfunction was shown to be involved in schizophrenia pathophysiology. Abnormal energy states can lead to alterations in neural function and thereby to the cognitive and behavioral aberrations characteristics of schizophrenia. Voltage-dependent anion-selective channels (VDAC) are located in the outer mitochondrial membrane and are involved in mitochondrial energy production. Only few studies explored VDAC genes' expression in schizophrenia, and their results weren't consistent. We conducted a systematic meta-analysis of ten brain samples gene expression datasets (overall 368 samples, 179 schizophrenia, 189 controls). In addition, we conducted a meta-analysis of three blood samples datasets (overall 300 samples, 167 schizophrenia, 133 controls). Pairwise correlation analysis was conducted between the VDAC and proteasome subunit genes' expression patterns. VDAC1, VDAC2 and VDAC3 showed significant down-regulation in brain samples of patients with schizophrenia. They also showed significant positive correlations with the proteasome subunit genes' expression levels. Our findings suggest that VDAC genes might play a role in mitochondrial dysfunction in schizophrenia. VDAC1 was down-regulated also in blood samples, which suggests its potential role as a biomarker for schizophrenia. The correlation with proteasome subunits, which were previously shown to be down-regulated in a subgroup of the patients, suggests that our findings might characterize a subgroup of the patients. This direction has the potential to lead to patients' stratification and more precisely-targeted therapy and necessitates further study.

Keywords:  Gene expression; Meta-analysis, brain samples; Mitochondrial dysfunction; Schizophrenia; VDAC

DOI:  https://doi.org/10.1016/j.neures.2023.01.012
J Neuroendocrinol. 2023 Jan 02. e13234

Targeting carnitine palmitoyltransferase 1 isoforms in the hypothalamus: A promising strategy to regulate energy balance.

Rosalía Rodríguez-Rodríguez, Anna Fosch, Jesús Garcia-Chica, Sebastián Zagmutt, Nuria Casals.

  Tackling the growing incidence and prevalence of obesity urgently requires uncovering new molecular pathways with therapeutic potential. The brain, and in particular the hypothalamus, is a major integrator of metabolic signals from peripheral tissues that regulate functions such as feeding behavior and energy expenditure. In obesity, hypothalamic capacity to sense nutritional status and regulate these functions is altered. An emerging line of research is that hypothalamic lipid metabolism plays a critical role in regulating energy balance. Here, we focus on the carnitine palmitoyltransferase 1 (CPT1) enzyme family responsible for long-chain fatty acid metabolism. The evidence suggests that two of its isoforms expressed in the brain, CPT1A and CPT1C, play a crucial role in hypothalamic lipid metabolism, and their promise as targets in food intake and bodyweight management is currently being intensively investigated. In this review we describe and discuss the metabolic actions and potential up- and downstream effectors of hypothalamic CPT1 isoforms, and posit the need to develop innovative nanomedicine platforms for selective targeting of CPT1 and related nutrient sensors in specific brain areas as potential next-generation therapy to treat obesity.

Keywords:  CPT1A; CPT1C; hypothalamus; lipid metabolism; obesity

DOI:  https://doi.org/10.1111/jne.13234
Cell Rep. 2023 Jan 31. pii: S2211-1247(23)00078-5. [Epub ahead of print]42(2): 112067

D-2-hydroxyglutarate dehydrogenase governs adult neural stem cell activation and promotes histone acetylation via ATP-citrate lyase.

Yinghao Liu, Min Wang, Ye Guo, Lei Wang, Weixiang Guo.

  The generation of neurons from quiescent radial-glia-like neural stem cells (RGLs) in adult brain goes hand in hand with the modulation of cellular metabolism. However, it is still unclear how the exact metabolic program governs the balance between quiescent and activated RGLs. Here, we find that loss of mitochondrial D-2-hydroxyglutarate dehydrogenase (D2HGDH) leads to aberrant accumulation of D-2-hydroxyglutarate (D-2-HG) and impaired RGL activation. Mechanistically, accumulated D-2-HG bonds directly to ATP-citrate lyase and competitively inhibits its enzymatic activity, thereby reducing acetyl-CoA production and diminishing histone acetylation. However, administration of acetate restores the acetyl-CoA levels via acetyl-CoA synthetase-mediated catabolism and rescues the deficiencies in histone acetylation and RGL activation caused by loss of D2HGDH. Therefore, our findings define the role of cross talk between mitochondria and the nucleus via a mitochondrial metabolite, D-2-HG, the aberrant accumulation of which hinders the regulation of histone acetylation in RGL activation and attenuates continuous neurogenesis in adult mammalian brain.

Keywords:  ATP-citrate lyase; CP: Neuroscience; CP: Stem cell research; D-2-hydroxyglutarate; D-2-hydroxyglutarate dehydrogenase; adult neurogenesis; histone acetylation; neural stem cells

DOI:  https://doi.org/10.1016/j.celrep.2023.112067
Invest Radiol. 2023 Feb 03.

Noninvasive 3-Dimensional 1H-Magnetic Resonance Spectroscopic Imaging of Human Brain Glucose and Neurotransmitter Metabolism Using Deuterium Labeling at 3T: Feasibility and Interscanner Reproducibility.

Fabian Niess, Lukas Hingerl, Bernhard Strasser, Petr Bednarik, Dario Goranovic, Eva Niess, Gilbert Hangel, Martin Krššák, Benjamin Spurny-Dworak, Thomas Scherer, Rupert Lanzenberger, Wolfgang Bogner.

OBJECTIVES: Noninvasive, affordable, and reliable mapping of brain glucose metabolism is of critical interest for clinical research and routine application as metabolic impairment is linked to numerous pathologies, for example, cancer, dementia, and depression. A novel approach to map glucose metabolism noninvasively in the human brain has been presented recently on ultrahigh-field magnetic resonance (MR) scanners (≥7T) using indirect detection of deuterium-labeled glucose and downstream metabolites such as glutamate, glutamine, and lactate. The aim of this study was to demonstrate the feasibility to noninvasively detect deuterium-labeled downstream glucose metabolites indirectly in the human brain via 3-dimensional (3D) proton (1H) MR spectroscopic imaging on a clinical 3T MR scanner without additional hardware.MATERIALS AND METHODS: This prospective, institutional review board-approved study was performed in 7 healthy volunteers (mean age, 31 ± 4 years, 5 men/2 women) after obtaining written informed consent. After overnight fasting and oral deuterium-labeled glucose administration, 3D metabolic maps were acquired every ∼4 minutes with ∼0.24 mL isotropic spatial resolution using real-time motion-, shim-, and frequency-corrected echo-less 3D 1H-MR spectroscopic Imaging on a clinical routine 3T MR system. To test the interscanner reproducibility of the method, subjects were remeasured on a similar 3T MR system. Time courses were analyzed using linear regression and nonparametric statistical tests. Deuterium-labeled glucose and downstream metabolites were detected indirectly via their respective signal decrease in dynamic 1H MR spectra due to exchange of labeled and unlabeled molecules.
RESULTS: Sixty-five minutes after deuterium-labeled glucose administration, glutamate + glutamine (Glx) signal intensities decreased in gray/white matter (GM/WM) by -1.63 ± 0.3/-1.0 ± 0.3 mM (-13% ± 3%, P = 0.02/-11% ± 3%, P = 0.02), respectively. A moderate to strong negative correlation between Glx and time was observed in GM/WM (r = -0.64, P < 0.001/r = -0.54, P < 0.001), with 60% ± 18% (P = 0.02) steeper slopes in GM versus WM, indicating faster metabolic activity. Other nonlabeled metabolites showed no significant changes. Excellent intrasubject repeatability was observed across scanners for static results at the beginning of the measurement (coefficient of variation 4% ± 4%), whereas differences were observed in individual Glx dynamics, presumably owing to physiological variation of glucose metabolism.
CONCLUSION: Our approach translates deuterium metabolic imaging to widely available clinical routine MR scanners without specialized hardware, offering a safe, affordable, and versatile (other substances than glucose can be labeled) approach for noninvasive imaging of glucose and neurotransmitter metabolism in the human brain.

DOI: https://doi.org/10.1097/RLI.0000000000000953
Degener Neurol Neuromuscul Dis. 2023 ;13 1-13

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson's Disease: What We Know so Far.

Narmadhaa Sivagurunathan, Priyadharshini Gnanasekaran, Latchoumycandane Calivarathan.

  Parkinson's disease (PD) is one of the most common progressive neurodegenerative diseases caused by the loss of dopamine-producing neuronal cells in the region of substantia nigra pars compacta of the brain. During biological aging, neuronal cells slowly undergo degeneration, but the rate of cell death increases tremendously under some pathological conditions, leading to irreversible neurodegenerative diseases. By the time symptoms of PD usually appear, more than 50 to 60% of neuronal cells have already been destroyed. PD symptoms often start with tremors, followed by slow movement, stiffness, and postural imbalance. The etiology of PD is still unknown; however, besides genetics, several factors contribute to neurodegenerative disease, including exposure to pesticides, environmental chemicals, solvents, and heavy metals. Postmortem brain tissues of patients with PD show mitochondrial abnormalities, including dysfunction of the electron transport chain. Most chemicals present in our environment have been shown to target the mitochondria; remarkably, patients with PD show a mild deficiency in NADH dehydrogenase activity, signifying a possible link between PD and mitochondrial dysfunction. Inhibition of electron transport complexes generates free radicals that further attack the macromolecules leading to neuropathological conditions. Apart from that, oxidative stress also causes neuroinflammation-mediated neurodegeneration due to the activation of microglial cells. However, the mechanism that causes mitochondrial dysfunction, especially the electron transport chain, in the pathogenesis of PD remains unclear. This review discusses the recent updates and explains the possible mechanisms of mitochondrial toxicant-induced neuroinflammation and neurodegeneration in PD.

Keywords:  Parkinson’s disease; apoptosis; mitochondrial dysfunction; mitochondrial toxicant; neurodegenerative disorder

DOI:  https://doi.org/10.2147/DNND.S361526
Res Sq. 2023 Jan 17. pii: rs.3.rs-2392941. [Epub ahead of print]

The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus.

Jun Yup Lee, Dylan Harney, John Kwok, Mark Larance, Anthony Simon Don.

Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. Methods Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66-104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Results Forty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. Transmembrane protein 106B (TMEM106B), a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with age was specific to carriers of the rs1990622-A allele in the TMEM106B gene that is associated with increased risk for frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and hippocampal sclerosis with ageing. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. Conclusions Our study provides the first evidence that TMEM106B protein abundance is increased with brain ageing in humans, and the first evidence that the major TMEM106B dementia risk allele affects brain lipid homeostasis, with a clear effect on myelin lipid content. Our data implies that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.

DOI: https://doi.org/10.21203/rs.3.rs-2392941/v1
Neurosci Lett. 2023 Jan 25. pii: S0304-3940(23)00052-6. [Epub ahead of print]798 137098

Alpha lipoic acid treatment in late middle age improves cognitive function: Proteomic analysis of the protective mechanisms in the hippocampus.

Jian Zhang, Yuan Zhao, Yidan Zhang, Ya Gao, Shuyue Li, Cui Chang, Xuan Gao, Jingru Zhao, Guofeng Yang.

  Alpha lipoic acid (ALA), a powerful antioxidant, has the potential to relieve age-related cognitive impairment and neurodegenerative disease. Clinical randomized controlled studies have demonstrated the cognitive improvement effects of lipoic acid in Alzheimer's disease (AD). In the present study, we examined the effects of ALA on cognitive function in ageing mice and its protective mechanisms. Eighteen-month-old male C57BL6/J mice received ALA or normal saline for 2 months. The Morris water maze test revealed improved cognitive function in animals that received ALA. Furthermore, tandem Mass Tags (TMT) based liquid chromotography with mass spectrometry/mass spectrometry (LC-MS/MS) was established to identify the target proteins. The results showed that 10 proteins were changed significantly. Gene Ontology (GO) analysis indicated that the upregulated proteins were enriched in terminal bouton, synaptic transmission and lipid transporter activity while the down-regulated proteins were involved in nuclear transcription factor-κB binding, apoptosis and mitogen-activated protein kinase binding. Based on the GO results, two upregulated proteins oxysterol-binding protein-related protein 10 (OSBPL10) and oligophrenin 1 (OPHN1), and one downregulated protein, CDK5 regulatory subunit-associated protein 3 (CDK5rap3), were validated through Western blotting. The results were consistent with the proteomic results. Modulation of synaptic transmission, lipid transporter activity and neuroinflammation appears to be the mechanisms of ALA in the aged brain.

Keywords:  Alpha lipoic acid; Brain ageing; Proteomics; Tandem mass tags

DOI:  https://doi.org/10.1016/j.neulet.2023.137098
J Chem Neuroanat. 2023 Jan 31. pii: S0891-0618(23)00007-8. [Epub ahead of print] 102237

HIGH-CARBOHYDRATE AND FAT DIET CONSUMPTION CAUSES METABOLIC DETERIORATION, NEURONAL DAMAGE, AND LOSS OF RECOGNITION MEMORY IN RATS.

Estefania Fuentes, Berenice Venegas, Guadalupe Muñoz-Arenas, Carolina Moran, Rubén A Vazquez-Roque, Gonzalo Flores, Samuel Treviño, Alfonso Diaz, Jorge Guevara.

  The number of people diagnosed with metabolic syndrome (MetS) has increased dramatically to reach alarming proportions worldwide. The origin of MetS derives from bad eating habits and sedentary lifestyle. Most people consume foods high in carbohydrates and saturated fat. In recent years, it has been reported that alterations in insulin at the brain level could have an impact on the appearance of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia, depression, and other types of disorders that compromise brain function. These alterations have been associated with damage to the structure and function of neurons located in the reptilian and limbic systems, a decrease in dendritic arborization and an exacerbated inflammatory state that impaired learning and memory and increased in the state of stress and anxiety. Although the molecular mechanisms induced by MetS to cause neurodegeneration are not fully understood. The aim of this study is to know the effect of the intake of hypercaloric diets on the structure and function of neurons located in the frontal cortex, hypothalamus and hippocampus and its impact on behavior in rats with metabolic syndrome. In conclusion, the present study illustrated that chronic exposure to hypercaloric diets, with a high content of sugars and saturated fatty acids, induces a proinflammatory state and exacerbates oxidative stress in brain regions such as the hypothalamus, hippocampus, and frontal cortex, leading to dysfunction. metabolism, neuronal damage, and recognition memory loss.

Keywords:  Hypercaloric diets; disfunction metabolism; inflammaging; neural damage; neurodegeneration; oxidative stress

DOI:  https://doi.org/10.1016/j.jchemneu.2023.102237
bioRxiv. 2023 Jan 03. pii: 2023.01.03.522615. [Epub ahead of print]

Mitochondrial genes in the 22q11.2 deleted region regulate neural stem and progenitor cell proliferation.

Philip D Campbell, Isaiah Lee, Summer Thyme, Michael Granato.

Microdeletion of a 3Mbp region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes, mrpl40 and prodha , encode for mitochondrial proteins and, similar to what we observed in mrpl40 and prodha mutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Finally, we show that both mrpl40 and prodha mutants display neural stem and progenitor cell phenotypes, with each gene regulating different neural stem cell populations. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.

DOI: https://doi.org/10.1101/2023.01.03.522615
Folia Neuropathol. 2022 ;pii: 49860. [Epub ahead of print]60(4): 390-402

Prenatal exposure to valproic acid induces alterations in the expression and activity of purinergic receptors in the embryonic rat brain.

Lidia Babiec, Anna Wilkaniec, Agata Adamczyk.

  Purinergic signalling is involved in the control of several processes related to brain development, such as neurogenesis and gliogenesis, migration and differentiation of neuronal precursors, synaptogenesis and synaptic elimination to achieve a fully wired and efficient mature brain. Therefore, any deregulation of purine-dependent signalling mediated by stimulation of specific adenosine and purinergic receptor subtypes: P1, P2X, or P2Y, can lead to functional deficits and the development of neuropsychiatric disorders, including autism spectrum disorders (ASD). In this study, we investigated the changes in expression and activity of selected purinergic receptors during rat brain development in an animal model of ASD. Pregnant dams received an intraperitoneal injection of valproic acid (VPA; 450 mg/kg body weight) at embryonic day (ED) 12.5, around the time of neural tube closure. Subsequently, changes in the expression and activity of specific purinergic receptor subtypes were analysed at ED19, an important prenatal stage of brain development. Our results suggest that prenatal VPA exposure leads to a significant increase in the level and activity of adenosinergic receptors A1, A2b and A3, which are involved in the regulation of progenitor cell proliferation and nerve growth, and upregulation of purinergic P2X2/P2X3 receptors, which in turn may contribute to the postnatal neuroanatomical abnormalities and synaptic dysfunction. Conversely, the significant downregulation of P2Y1 and P2X7 receptors, together with their reduced activity in the embryonic VPA brain, may indicate disturbances in the processes of neuronal precursor migration and differentiation, dendritic and axonal formation, and glutamate/GABA imbalance, thereby altering neuronal excitability. In conclusion, defects in purinergic signalling induced by prenatal VPA exposure could have a profound impact on brain development during embryogenesis and on intellectual and behavioural functions after birth. These observations could provide clues for future implementation of potential therapeutic strategies for ASD.

Keywords:   ATP; P1 receptors; P2 receptors; adenosine; brain development; intracellular calcium; autism spectrum disorders

DOI:  https://doi.org/10.5114/fn.2022.123999
bioRxiv. 2023 Jan 10. pii: 2023.01.05.522933. [Epub ahead of print]

Dihydroxy-Metabolites of Dihomo-gamma-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Morteza Sarparast, Elham Pourmand, Jennifer Hinman, Derek Vonarx, Tommy Reason, Fan Zhang, Shreya Paithankar, Bin Chen, Babak Borhan, Jennifer L Watts, Jamie Alan, Kin Sing Stephen Lee.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA, dihomo gamma linolenic acid (DGLA), specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH, representing a new class of lipid metabolite that induces neurodegeneration via ferroptosis.

DOI: https://doi.org/10.1101/2023.01.05.522933
Metab Brain Dis. 2023 Feb 01.

Research progress of PPARγ regulation of cholesterol and inflammation in Alzheimer's disease.

Lili Gu, Yue Ju, Min Hu, Miao Zheng, Qin Li, Xinyue Zhang.

  Peroxidase proliferator receptors (PPARs) are defined as key sensors and regulators of cell metabolism, transcription factors activated by ligands, involved in lipid, glucose and amino acid metabolism, participating in the processes of cell differentiation, apoptosis, inflammation regulation, and acute and chronic nerve damage. Among them, PPARγ is expressed in different brain regions and can regulate lipid metabolism, mitochondrial disorders, oxidative stress, and cell apoptosis. It has anti-inflammatory activity and shows neuroprotection. The regulation of Aβ levels in Alzheimer's disease involves cholesterol metabolism and inflammation, so this article first analyzes the biological functions of PPARγ, then mainly focuses on the relationship between cholesterol and inflammation and Aβ, and elaborates on the regulation of PPARγ on key proteins and the corresponding molecules, which provides new ideas for the treatment of AD.

Keywords:  Alzheimer’s disease; Cholesterol; Inflammation; PPARγ

DOI:  https://doi.org/10.1007/s11011-022-01139-6
Brain Res Bull. 2023 Jan 28. pii: S0361-9230(23)00014-X. [Epub ahead of print]

Regulation of plasmalogen biosynthesis in mammalian cells and tissues.

Masanori Honsho, Yukio Fujiki.

  Plasmalogens are a unique family of cellular glycerophospholipids that contain a vinyl-ether bond. Synthesis of plasmalogens is initiated in peroxisomes and completed in the endoplasmic reticulum. The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans. Plasmalogen biosynthesis is spatiotemporally regulated by a feedback mechanism that senses the amount of plasmalogens in the inner leaflet of the plasma membrane and regulates the stability of fatty acyl-CoA reductase 1 (FAR1), the rate-limiting enzyme for plasmalogen biosynthesis. Dysregulation of plasmalogen synthesis impairs cholesterol synthesis in cells and brain, resulting in the reduced expression of genes such as mRNA encoding myelin basic protein, a phenotype found in the cerebellum of plasmalogen-deficient mice. In this review, we summarize the current knowledge of molecular mechanisms underlying the regulation of plasmalogen biosynthesis and the link between plasmalogen homeostasis and cholesterol biosynthesis, and address the pathogenesis of impaired plasmalogen homeostasis in rodent and humans.

Keywords:  FAR1; cerebellum; cholesterol; peroxisome; plasmalogen homeostasis

DOI:  https://doi.org/10.1016/j.brainresbull.2023.01.011
AIDS. 2023 Jan 20.

A prospective 18F-FDG PET/CT study of the neurometabolic effects in cocaine use and HIV infection.

Ramya S Mamidi, Cyrus Ayubcha, Grant Rigney, Jason Kirschner, Oke Gerke, Thomas J Werner, Pablo Tebas, Abass Alavi, Mona-Elisabeth Revheim.

OBJECTIVES: HIV affects 36 million people globally with prevalence decreasing due to antiretroviral therapy (ART) and social awareness; transmission occurs during substance use. Cocaine usage independently affects brain activity and may result in reduced ART adherence. This study evaluates brain glucose metabolism measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in cocaine users with HIV infection.DESIGN: Sixty-three subjects were categorized into groups: 36 HIV infected (HIV+) and 27 non-HIV infected (HIV-) subjects. Each group was further split into cocaine users (CO+) and non-cocaine users (CO-). Of the HIV+, half were cocaine users and half were not. Of the HIV-, 14 were cocaine users and 13 were not. 18F-FDG-PET and low dose CT scans were performed on all subjects.
METHODS: Brain glucose metabolism was evaluated by 18F-FDG uptake in the whole brain, cortex, basal ganglia, and cerebellum 120 minutes after injection. ROVER software was used for image analysis and ROI masks were applied via an adaptive threshold system. ANOVA tests and t-tests were performed to assess the respective differences between the four groups.
RESULTS: Generally, the HIV+/CO+ group (group A) displayed the lowest levels of uptake whereas the HIV-/CO- group (group D) showed the highest; the HIV+/CO- and HIV-/CO+ groups (group B and C) showed intermediate levels of activity across the whole brain, cortex, basal ganglia, and cerebellum.
CONCLUSION: HIV infection and cocaine usage were independently associated with a decrease in brain glucose uptake as measured by 18F-FDG PET/CT. When combined, positive HIV status and cocaine patients showed the most decreased 18F-FDG uptake.

DOI: https://doi.org/10.1097/QAD.0000000000003485
J Neuroinflammation. 2023 Jan 30. 20(1): 17

Inhibition of 2-arachidonoylglycerol degradation enhances glial immunity by single-cell transcriptomic analysis.

Dexiao Zhu, Jian Zhang, Jack Hashem, Fei Gao, Chu Chen.

  BACKGROUND: 2-Arachidonoylglycerol (2-AG) is the most abundant endogenous cannabinoid. Inhibition of 2-AG metabolism by inactivation of monoacylglycerol lipase (MAGL), the primary enzyme that degrades 2-AG in the brain, produces anti-inflammatory and neuroprotective effects in neurodegenerative diseases. However, the molecular mechanisms underlying these beneficial effects are largely unclear.METHODS: Hippocampal and cortical cells were isolated from cell type-specific MAGL knockout (KO) mice. Single-cell RNA sequencing was performed by 10 × Genomics platform. Cell Ranger, Seurat (v3.2) and CellChat (1.1.3) packages were used to carry out data analysis.
RESULTS: Using single-cell RNA sequencing analysis, we show here that cell type-specific MAGL KO mice display distinct gene expression profiles in the brain. Inactivation of MAGL results in robust changes in expression of immune- and inflammation-related genes in microglia and astrocytes. Remarkably, upregulated expression of chemokines in microglia is more pronounced in mice lacking MAGL in astrocytes. In addition, expression of genes that regulate other cellular functions and Wnt signaling in astrocytes is altered in MAGL KO mice.
CONCLUSIONS: Our results provide transcriptomic evidence that cell type-specific inactivation of MAGL induces differential expression of immune-related genes and other fundamental cellular pathways in microglia and astrocytes. Upregulation of the immune/inflammatory genes suggests that tonic levels of immune/inflammatory vigilance are enhanced in microglia and astrocytes, particularly in microglia, by inhibition of 2-AG metabolism, which likely contribute to anti-inflammatory and neuroprotective effects produced by inactivation of MAGL in neurodegenerative diseases.

Keywords:  Endocannabinoid; Immunity; Monoacylglycerol lipase; Neurodegenerative disease; Neuroinflammation; Single-cell RNA sequencing; Transcriptome; Vigilance

DOI:  https://doi.org/10.1186/s12974-023-02701-4
Pharmacol Biochem Behav. 2023 Jan 28. pii: S0091-3057(23)00009-6. [Epub ahead of print]223 173522

Cholesterol metabolism pathway in autism spectrum disorder: From animal models to clinical observations.

Jaime Lin, Victória Linden de Rezende, Maiara de Aguiar da Costa, Jade de Oliveira, Cinara Ludvig Gonçalves.

  Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a persistent impairment of social skills, including aspects of perception, interpretation, and response, combined with restricted and repetitive behavior. ASD is a complex and multifactorial condition, and its etiology could be attributed to genetic and environmental factors. Despite numerous clinical and experimental studies, no etiological factor, biomarker, and specific model of transmission have been consistently associated with ASD. However, an imbalance in cholesterol levels has been observed in many patients, more specifically, a condition of hypocholesterolemia, which seems to be shared between ASD and ASD-related genetic syndromes such as fragile X syndrome (FXS), Rett syndrome (RS), and Smith- Lemli-Opitz (SLO). Furthermore, it is known that alterations in cholesterol levels lead to neuroinflammation, oxidative stress, impaired myelination and synaptogenesis. Thus, the aim of this review is to discuss the cholesterol metabolic pathways in the ASD context, as well as in genetic syndromes related to ASD, through clinical observations and animal models. In fact, SLO, FXS, and RS patients display early behavioral markers of ASD followed by cholesterol disturbances. Several studies have demonstrated the role of cholesterol in psychiatric conditions and how its levels modulate brain neurodevelopment. This review suggests an important relationship between ASD pathology and cholesterol metabolism impairment; thus, some strategies could be raised - at clinical and pre-clinical levels - to explore whether cholesterol metabolism disturbance has a generally adverse effect in exacerbating the symptoms of ASD patients.

Keywords:  Biomarker; Etiology; Lipids; Metabolism; Neurodevelopment

DOI:  https://doi.org/10.1016/j.pbb.2023.173522
Exp Mol Med. 2023 Feb 01.

TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia.

Chenfei Wang, Jia Lu, Xudong Sha, Yu Qiu, Hongzhuan Chen, Zhihua Yu.

Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer's disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1flox/flox; Cx3cr1cre-ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele.

DOI: https://doi.org/10.1038/s12276-023-00935-z
Front Mol Biosci. 2023 ;10 1120373

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis.

Amitabha Chattopadhyay, Ashwani Sharma.

  The biosynthesis of cholesterol, an essential component of higher eukaryotic membranes, was worked out by Konrad Bloch (and Feodor Lynen) in the 1960s and they received the Nobel Prize around that time in recognition of their pioneering contributions. An elegant consequence of this was a hypothesis proposed by Konrad Bloch (the Bloch hypothesis) which suggests that each subsequent intermediate in the cholesterol biosynthesis pathway is superior in supporting membrane function in higher eukaryotes relative to its precursor. In this review, we discuss an autosomal recessive metabolic disorder, known as Smith-Lemli-Opitz syndrome (SLOS), associated with a defect in the Kandutsch-Russell pathway of cholesterol biosynthesis that results in accumulation of the immediate precursor of cholesterol in its biosynthetic pathway (7-dehydrocholesterol) and an altered cholesterol to total sterol ratio. Patients suffering from SLOS have several developmental, behavioral and cognitive abnormalities for which no drug is available yet. We characterize SLOS as a manifestation of the Bloch hypothesis and review its molecular etiology and current treatment. We further discuss defective Hedgehog signaling in SLOS and focus on the role of the serotonin1A receptor, a representative neurotransmitter receptor belonging to the GPCR family, in SLOS. Notably, ligand binding activity and cellular signaling of serotonin1A receptors are impaired in SLOS-like condition. Importantly, cellular localization and intracellular trafficking of the serotonin1A receptor (which constitute an important determinant of a GPCR cellular function) are compromised in SLOS. We highlight some of the recent developments and emerging concepts in SLOS pathobiology and suggest that novel therapies based on trafficking defects of target receptors could provide new insight into treatment of SLOS.

Keywords:  7-DHC; Bloch hypothesis; SLOS; cellular trafficking; cholesterol biosynthesis; serotonin1A receptor

DOI:  https://doi.org/10.3389/fmolb.2023.1120373
Gene. 2023 Jan 27. pii: S0378-1119(23)00070-7. [Epub ahead of print] 147229

De novo frameshift variant in MT-ND1 causes a mitochondrial complex I deficiency associated with MELAS syndrome.

Xiaoting Lou, Yuwei Zhou, Zhimei Liu, Yaojun Xie, Luyi Zhang, Suzhou Zhao, Shuai Gong, Xiuwei Zhuo, Junling Wang, Lifang Dai, Xiaotun Ren, Xiao Tong, Liangliang Jiang, Hezhi Fang, Fang Fang, Jianxin Lyu.

  BACKGROUND: The variant m.3571_3572insC/MT-ND1 thus far only reported in oncocytic tumors of different tissues. However, the role of m.3571_3572insC in inherited mitochondrial diseases has yet to be elucidated.METHODS: A patient diagnosed with MELAS syndrome was recruited, and detailed medical records were collected and reviewed. The muscle was biopsied for mitochondrial respiratory chain enzyme activity. Series of fibroblast clones bearing different m.3571_3572insC variant loads were generated from patient-derived fibroblasts and subjected to functional assays.
RESULTS: Complex I deficiency was confirmed in the patient's muscle via mitochondrial respiratory chain enzyme activity assay. The m.3571_3572insC was filtered for the candidate variant of the patient according to the guidelines for mitochondrial mRNA variants interpretation. Three cell clones with different m.3571_3572insC variant loads were generated to evaluate mitochondrial function. Blue native PAGE analysis revealed that m.3571_3572insC caused a deficiency in the mitochondrial complex I. Oxygen consumption rate, ATP production, and lactate assays found an impairment of cellular bioenergetic capacity due to m.3571_3572insC. Mitochondrial membrane potential was decreased, and mitochondrial reactive oxygen species production was increased with the variant of m.3571_3572insC. According to the competitive cell growth assay, the mutant cells had impaired cell growth capacity compared to wild type.
CONCLUSIONS: A novel variant m.3571_3572insC was identified in a patient diagnosed with MELAS syndrome, and the variant impaired mitochondrial respiration by decreasing the activity of complex I. In conclusion, the genetic spectrum of mitochondrial diseases was expanded by including m.3571_3572insC/MT-ND1.

Keywords:  Heteroplasmic; MELAS syndrome; MT-ND1; de novo; m.3571_3572insC

DOI:  https://doi.org/10.1016/j.gene.2023.147229
Int J Pharm. 2023 Jan 28. pii: S0378-5173(23)00071-6. [Epub ahead of print] 122651

Oral lipid-based formulations alter delivery of cannabidiol to different anatomical regions in the brain.

Alice Brookes, Adelaide Jewell, Wanshan Feng, Tracey D Bradshaw, James Butler, Pavel Gershkovich.

  Delivery to the brain is a challenging task due to its protection by the blood-brain barrier (BBB). Lipids and fatty acids are reported to affect the permeability of the BBB, although this has not been reported following oral administration. Cannabidiol (CBD) has high therapeutic potential in the brain, therefore, tis work investigated CBD delivery to anatomical brain regions following oral administration in lipid-based and lipid-free vehicles. All formulations resulted in a short brain Tmax (1 h) and brain-plasma ratios ≥3.5, with retention up to 18 h post administration. The highest CBD delivery was observed in the olfactory bulb and striatum, and the medulla pons and cerebellum the lowest. The lipid-free vehicle led to the highest levels of CBD in the whole brain. However, when each anatomical region was assessed individually, the long chain triglyceride-rich rapeseed oil formulation commonly showed optimal performance. The medium chain triglyceride-rich coconut oil formulation did not result in the highest CBD concentration in any brain region. Overall, differences in CBD delivery to the whole brain and various brain regions were observed following administration in different formulations, indicating that the oral formulation selection may be important for optimal delivery to specific regions of the brain.

Keywords:  Blood-brain barrier; Brain regions; Cannabidiol; Lipid-based drug delivery; Oral

DOI:  https://doi.org/10.1016/j.ijpharm.2023.122651
bioRxiv. 2023 Jan 13. pii: 2023.01.11.523492. [Epub ahead of print]

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.

Jonathan Enders, Jarrid Jack, Sarah Thomas, Paige Lynch, Sarah Lasnier, Xin Cao, M Taylor Swanson, Janelle M Ryals, John P Thyfault, Patrycja Puchalska, Peter A Crawford, Douglas E Wright.

Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1 ), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated s ensory n euron-specific, A dvillin- C re k nockout of O xct1 (SNACKO) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and innervation of the skin and spinal dorsal horn. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. SNACKO mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet SNACKO mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

DOI: https://doi.org/10.1101/2023.01.11.523492
Brain Plast. 2022 ;8(2): 143-152

Nicotinamide Mononucleotide Prevents Cisplatin-Induced Mitochondrial Defects in Cortical Neurons Derived from Human Induced Pluripotent Stem Cells.

Mohammad Abdur Rashid, Alfredo Oliveros, Yu Shin Kim, Mi-Hyeon Jang.

  Background: Chemotherapy-induced cognitive impairment (CICI) is a neurotoxic side effect of chemotherapy that has yet to have an effective treatment.Objective: Using cisplatin, a platinum-based chemotherapy together with excitatory cortical neurons derived from human induced pluripotent cells (iPSCs) to model of CICI, our recent study demonstrated that dysregulation of brain NAD+ metabolism contributes to cisplatin-induced impairments in neurogenesis and cognitive function, which was prevented by administration of the NAD+ precursor, nicotinamide mononucleotide (NMN). However, it remains unclear how cisplatin causes neurogenic dysfunction and the mechanism by which NMN prevents cisplatin-induced cognitive impairment. Given that mitochondrial dysfunction is thought to play a prominent role in age-related neurodegenerative disease and chemotherapy-induced neurotoxicity, we sought to explore if NMN prevents chemotherapy-related neurotoxicity by attenuating cisplatin-induced mitochondrial damage.
Results: We demonstrate that cisplatin induces neuronal DNA damage, increases generation of mitochondrial reactive oxygen species (ROS) and decreases ATP production, all of which are indicative of oxidative DNA damage and mitochondrial functional defects. Ultrastructural analysis revealed that cisplatin caused loss of cristae membrane integrity and matrix swelling in human cortical neurons. Notably, pretreatment with NMN prevents cisplatin-induced defects in mitochondria of human cortical neurons.
Conclusion: Our results suggest that increased mitochondrial oxidative stress and functional defects play key roles in cisplatin-induced neurotoxicity. Thus, NMN may be an effective therapeutic strategy to prevent cisplatin-induced deleterious effects on mitochondria, making this organelle a key factor in amelioration of cisplatin-induced cognitive impairments.

Keywords:  Cisplatin; chemobrain; chemotherapy-induced cognitive impairment; mitochondria; nicotinamide adenine dinucleotide (NAD+); nicotinamide mononucleotide

DOI:  https://doi.org/10.3233/BPL-220143
Jpn J Radiol. 2023 Feb 02.

Neuroimaging findings of inborn errors of metabolism: urea cycle disorders, aminoacidopathies, and organic acidopathies.

Mikako Enokizono, Noriko Aida, Akira Yagishita, Yasuhiro Nakata, Reiko Ideguchi, Ryo Kurokawa, Tatsuo Kono, Toshio Moritani, Harushi Mori.

  Although there are many types of inborn errors of metabolism (IEMs) affecting the central nervous system, also referred to as neurometabolic disorders, individual cases are rare, and their diagnosis is often challenging. However, early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurological impairment or death. The clinical course of IEMs is very diverse, with some diseases progressing to acute encephalopathy following infection or fasting while others lead to subacute or slowly progressive encephalopathy. The diagnosis of IEMs relies on biochemical and genetic tests, but neuroimaging studies also provide important clues to the correct diagnosis and enable the conditions to be distinguished from other, more common causes of encephalopathy, such as hypoxia-ischemia. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful, non-invasive method of assessing neurological abnormalities at the microscopic level and can measure in vivo brain metabolites. The present review discusses neuroimaging findings, including those of 1H-MRS, of IEMs focusing on intoxication disorders such as urea cycle disorders, aminoacidopathies, and organic acidopathies, which can result in acute life-threatening metabolic decompensation or crisis.

Keywords:  Aminoacidopathy; Inborn errors of metabolism; Magnetic resonance spectroscopy; Organic acidopathy; Urea cycle disorders

DOI:  https://doi.org/10.1007/s11604-023-01396-0
Biomed Pharmacother. 2023 Jan 28. pii: S0753-3322(23)00096-3. [Epub ahead of print]160 114308

Butyrate ameliorates chronic alcoholic central nervous damage by suppressing microglia-mediated neuroinflammation and modulating the microbiome-gut-brain axis.

Huiling Wei, Chunyang Yu, Chun Zhang, Yi Ren, Li Guo, Ting Wang, Feifei Chen, Yiwei Li, Xiaoxia Zhang, Hao Wang, Juan Liu.

  BACKGROUND: Alcohol abuse triggers neuroinflammation, leading to neuronal damage and further memory and cognitive impairment. Few satisfactory advances have been made in the management of alcoholic central nervous impairment. Therefore, novel and more practical treatment options are urgently needed. Butyrate, a crucial metabolite of short-chain fatty acids (SCFAs), has been increasingly demonstrated to protect against numerous metabolic diseases. However, the impact of butyrate on chronic alcohol consumption-induced central nervous system (CNS) lesions remains unknown.METHODS: In this study, we assessed the possible effects and underlying mechanisms of butyrate on the attenuation of alcohol-induced CNS injury in mice. Firstly, sixty female C57BL/6 J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. After six weeks of feeding, the mice were euthanized and the associated indicators were investigated.
RESULTS: As indicated by the behavioral tests and brain morphology, dietary NaB administration significantly ameliorated aberrant behaviors, including locomotor hypoactivity, anxiety disorder, depressive behavior, impaired learning, spatial recognition memory, and effectively reduced chronic alcoholic central nervous system damage. To further understand the underlying mechanisms, microglia-mediated inflammation and the associated M1/M2 polarization were measured separately. Firstly, pro-inflammatory TNF-α, IL-1β, and IL-6 in brain and peripheral blood circulation were decreased, but IL-10 were increased in the AF/NaB group compared with the AF/CON group. Consistently, the abnormal proportions of activated and resting microglial cells in the hippocampus and cortex regions after excessive alcohol consumption were significantly reduced with NaB treatment. Moreover, the rectification of microglia polarization (M1/M2) imbalance was found after NaB administration via binding GPR109A, up-regulating the expression of PPAR-γ and down-regulating TLR4/NF-κB activation. In addition to the direct suppression of neuroinflammation, intriguingly, dietary NaB intervention remarkably increased the levels of intestinal tight junction protein occludin and gut morphological barrier, attenuated the levels of serum lipopolysaccharide (LPS) and dysbiosis of gut microbiota, suggesting that NaB supplementation effectively improved the integrity and permeability of gut microecology. Finally, the neurotransmitters including differential Tryptophan (Trp) and Kynurenine (Kyn) were found with dietary NaB administration, which showed significantly altered and closely correlated with the gut microbiota composition, demonstrating the complex interactions in the microbiome-gut-brain axis involved in the efficacy of dietary NaB therapy for alcoholic CNS lesions.
CONCLUSION: Dietary microbial metabolite butyrate supplementation ameliorates chronic alcoholic central nervous damage and improves related memory and cognitive functions through suppressing microglia-mediated neuroinflammation by GPR109A/PPAR-γ/TLR4-NF-κB signaling pathway and modulating microbiota-gut-brain axis.

Keywords:  Alcohol; Butyrate; Microbiota−gut− brain axis; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1016/j.biopha.2023.114308
J Mol Biol. 2023 Feb 01. pii: S0022-2836(23)00048-7. [Epub ahead of print] 167992

Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson's Disease.

Tahereh Sohrabi, Behnaz Mirzaei-Behbahani, Ramin Zadali, Mitra Pirhaghi, Ludmilla A Morozova-Roche, Ali Akbar Meratan.

  Parkinson's disease (PD) is the most common neurological movement disorder characterized by the selective and irreversible loss of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. While most cases are sporadic or environmental , about 10 % of patients have a positive family history with a genetic cause. The misfolding and aggregation of α-synuclein (α-syn) as a casual factor in the pathogenesis of PD has been supported by a great deal of literature. Extensive studies of mechanisms underpinning degeneration of the dopaminergic neurons induced by α-syn dysfunction suggest a complex process that involves multiple pathways, including mitochondrial dysfunction and increased oxidative stress, impaired calcium homeostasis through membrane permeabilization, synaptic dysfunction, impairment of quality control systems, disruption of microtubule dynamics and axonal transport, endoplasmic reticulum/Golgi dysfunction, nucleus malfunction, and microglia activation leading to neuroinflammation. Among them mitochondrial dysfunction has been considered as the most primary target of α-syn-induced toxicity, leading to neuronal cell death in both sporadic and familial forms of PD. Despite reviewing many aspects of PD pathogenesis related to mitochondrial dysfunction, a systemic study on how α-syn malfunction/aggregation damages mitochondrial functionality and leads to neurodegeneration is missing in the literature. In this review, we give a detailed molecular overview of the proposed mechanisms by which α-syn, directly or indirectly, contributes to mitochondrial dysfunction. This may provide valuable insights for development of new therapeutic approaches in relation to PD. Antioxidant-based therapy as a potential strategy to protect mitochondria against oxidative damage, its challenges, and recent developments in the field are discussed.

Keywords:  Parkinson’s disease; mitochondrial dysfunction; neurodegeneration; oxidative stress; α-synuclein

DOI:  https://doi.org/10.1016/j.jmb.2023.167992
Mitochondrion. 2023 Jan 26. pii: S1567-7249(23)00007-7. [Epub ahead of print]

Mitochondrial Oxidative Stress in Brain Microvascular Endothelial Cells: Triggering Blood-Brain Barrier Disruption.

Yi Wang, Jing Wu, Jiexin Wang, Linxi He, Han Lai, Tian Zhang, Xin Wang, Weihong Li.

  Blood-brain barrier disruption plays an important role in central nervous system diseases. This review provides information on the role of mitochondrial oxidative stress in brain microvascular endothelial cells in cellular dysfunction, the disruption of intercellular junctions, transporter dysfunction, abnormal angiogenesis, neurovascular decoupling, and the involvement and aggravation of vascular inflammation and illustrates related molecular mechanisms. In addition, recent drug and nondrug therapies targeting cerebral vascular endothelial cell mitochondria to repair the blood-brain barrier are discussed. This review shows that mitochondrial oxidative stress disorder in brain microvascular endothelial cells plays a key role in the occurrence and development of blood-brain barrier damage and may be critical in various pathological mechanisms of blood-brain barrier damage. These new findings suggest a potential new strategy for the treatment of central nervous system diseases through mitochondrial modulation of cerebral vascular endothelial cells.

Keywords:  blood-brain barrier disruption; brain microvascular endothelial cells; central nervous system diseases; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.mito.2023.01.007