bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023–04–30
forty-two papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States.
  2. Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination.
  3. The effect of omega-3 fatty acids on alcohol-induced damage.
  4. Measurement of Neuro-energetics and Neurotransmission in the Rat Olfactory Bulb by 1 H and 1 H-[13 C] NMR Spectroscopy.
  5. Lipid Mediated Brain Disorders: A Perspective.
  6. The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons.
  7. Effect of aging on the cerebral metabolic mechanism of electroacupuncture treatment in rats with traumatic brain injury.
  8. Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration.
  9. Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501).
  10. NEUROBIOLOGICAL DYSFUNCTIONAL SUBSTRATES FOR THE SELF-MEDICATION HYPOTHESIS IN ADULT INDIVIDUALS WITH ADHD AND COCAINE USE DISORDER: AN 18F-FDG PET STUDY.
  11. Phenylketonuria and the brain.
  12. Acylglycine Analysis by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS).
  13. Quantitative Lipidomic Analysis of Serum Phospholipids Reveals Dissociable Markers of Alzheimer's Disease and Subcortical Cerebrovascular Disease.
  14. Glutamate dehydrogenase: Potential therapeutic targets for neurodegenerative disease.
  15. Glycolysis mediates neuron specific histone acetylation in valproic acid-induced human excitatory neuron differentiation.
  16. Nervonic acid and its sphingolipids: Biological functions and potential food applications.
  17. New aspects for the brain in Hartnup disease based on mining of high-resolution cellular mRNA expression data for SLC6A19.
  18. A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
  19. Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
  20. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.
  21. Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases.
  22. Developmental Stage-Dependent Changes in Mitochondrial Function in the Brain of Offspring Following Prenatal Maternal Immune Activation.
  23. Increased levels of lipid and protein oxidation in rat prefrontal cortex after treatment by lithium, valproic acid, and olanzapine.
  24. Rescue of long-term spatial memory by 7,8-dihydroxyflavone in mice with reduced oligodendrogenesis.
  25. Ketolysis is required for the proper development and function of the somatosensory nervous system.
  26. Mitochondrial Bioenergy in Neurodegenerative Disease: Huntington and Parkinson.
  27. APOE4 dysregulates cholesterol homeostasis in human microglia and astrocytes.
  28. The role of cholesterol metabolism in tumor therapy, from bench to bed.
  29. "MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression".
  30. Protective effect of resveratrol on mitochondrial biogenesis during hyperoxia-induced brain injury in neonatal pups.
  31. Mitochondrial dysfunction, oxidative stress, ER stress and mitochondria-ER crosstalk alterations in a chemical rat model of Huntington's disease: potential benefits of bezafibrate.
  32. The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.
  33. Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury.
  34. Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases.
  35. Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.
  36. Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.
  37. Chloroquine Protects Hypoxia/Ischemia-Induced Neonatal Brain Injury in Rats by Mitigating Blood-Brain Barrier Disruption.
  38. Functional Magnetic Resonance Spectroscopy of Lactate in Alzheimer Disease: A Comprehensive Review of Alzheimer Disease Pathology and the Role of Lactate.
  39. Sarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle-Brain Axis.
  40. Folate deprivation induced neuroinflammation impairs cognition.
  41. Increased white matter glycolysis in humans with cerebral small vessel disease.
  42. Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins.
  1. Metabolites. 2023 Apr 19. pii: 577. [Epub ahead of print]13(4):
    Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States.
    Pandichelvam Veeraiah, Jacobus F A Jansen.
      The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. 1H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, 13C, 2H, 17O, and 31P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (1H, 13C, 2H, 17O, and 31P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states.
    Keywords:  7T; 9.4T; MRS; UHF; X-nuclei MRS; cerebral metabolism; multinuclear MRS
    DOI:  https://doi.org/10.3390/metabo13040577
  2. J Clin Invest. 2023 Apr 27. pii: e164118. [Epub ahead of print]
    Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination.
    Vetrivel Sengottuvel, Monalisa Hota, Jeongah Oh, Dwight L Galam, Bernice H Wong, Markus R Wenk, Sujoy Ghosh, Federico Torta, David L Silver.
      Patients with Autosomal Recessive Microcephaly 15 caused by deficiency in the sodium-dependent lysophosphatidylcholine (LPC) transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) present with both microcephaly and hypomyelination, suggesting an important role of LPC uptake by oligodendrocytes in the process of myelination. Here, we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPC) and is critical for oligodendrocyte development. Single cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a KO mice (2aOKO) underwent precocious differentiation into immature oligodendrocytes (iOLs) and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, consistent with microcephaly being consequential to absence of LPC uptake at the blood-brain barrier and not from deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased phospholipids containing omega-3 fatty acids with an opposite increase in unsaturated fatty acids, that latter being products of de novo synthesis governed by Srebp-1. RNA sequencing indicated activation of the Srebp-1 pathway and defective expression of regulators of oligodendrocyte development. Taken together, these findings indicate that the transport of LPCs by Mfsd2a in OPCs is important for maintaining OPC cell state to regulate postnatal brain myelination.
    Keywords:  Demyelinating disorders; Metabolism; Monogenic diseases; Neurodevelopment; Neuroscience
    DOI:  https://doi.org/10.1172/JCI164118
  3. Front Nutr. 2023 ;10 1068343
    The effect of omega-3 fatty acids on alcohol-induced damage.
    Maitane Serrano, Irantzu Rico-Barrio, Pedro Grandes.
      Alcohol is the most widely consumed psychoactive substance in the world that has a severe impact on many organs and bodily systems, particularly the liver and nervous system. Alcohol use during pregnancy roots long-lasting changes in the newborns and during adolescence has long-term detrimental effects especially on the brain. The brain contains docosahexaenoic acid (DHA), a major omega-3 (n-3) fatty acid (FA) that makes up cell membranes and influences membrane-associated protein function, cell signaling, gene expression and lipid production. N-3 is beneficial in several brain conditions like neurodegenerative diseases, ameliorating cognitive impairment, oxidative stress, neuronal death and inflammation. Because alcohol decreases the levels of n-3, it is timely to know whether n-3 supplementation positively modifies alcohol-induced injuries. The aim of this review is to summarize the state-of-the-art of the n-3 effects on certain conditions caused by alcohol intake, focusing primarily on brain damage and alcoholic liver disease.
    Keywords:  brain damage; ethanol; liver disease; n-3; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3389/fnut.2023.1068343
  4. NMR Biomed. 2023 Apr 23. e4957
    Measurement of Neuro-energetics and Neurotransmission in the Rat Olfactory Bulb by 1 H and 1 H-[13 C] NMR Spectroscopy.
    Golam M I Chowdhury, Kevin L Behar, Graeme F Mason, Douglas L Rothman, Robin A de Graaf.
      The olfactory bulb (OB) plays a fundamental role in the sense of smell and has been implicated in several pathologies, including Alzheimer's disease. Despite its importance, high metabolic activity, and unique laminar architecture, the OB is not frequently studied by magnetic resonance spectroscopy (MRS) methods, likely due to the small size and challenging location. Here we present a detailed metabolic characterization of OB metabolism, both in terms of static metabolite concentrations using 1 H MRS and metabolic fluxes associated with neuro-energetics and neurotransmission by tracing the dynamic 13 C flow from intravenously administered [1,6-13 C2 ]-glucose, [2-13 C]-glucose and [2-13 C]-acetate to downstream metabolites, including [4-13 C]-glutamate, [4-13 C]-glutamine and [2-13 C]-GABA. The unique laminar architecture and associated metabolism of the OB, distinctly different from the cerebral cortex, is characterized by elevated GABA and glutamine levels, as well as increased GABAergic and astroglial energy metabolism and neurotransmission. The results show that, despite the technical challenges, high-quality 1 H and 1 H-[13 C] MR spectra can be obtained from the rat OB in vivo. The derived metabolite concentrations and metabolic rates demonstrate a unique metabolic profile for the OB. The metabolic model provides a solid basis for future OB studies on functional activation or pathological conditions.
    Keywords:  1H MRS; GABA; dynamic metabolism; olfactory bulb
    DOI:  https://doi.org/10.1002/nbm.4957
  5. Prostaglandins Other Lipid Mediat. 2023 Apr 20. pii: S1098-8823(23)00034-5. [Epub ahead of print] 106737
    Lipid Mediated Brain Disorders: A Perspective.
    Anju Singh, Samiksha Kukal, Neha Kanojia, Mahak Singh, Luciano Saso, Shrikant Kukreti, Ritushree Kukreti.
      The brain, one of the most resilient organs of the body is highly enriched in lipid content, suggesting the essential role of lipids in brain physiological activities. Lipids constitute an important structural part of the brain and act as a rich source of metabolic energy. Besides, lipids in their bioactive form (known as bioactive lipids) play an essential signaling and regulatory role, facilitating neurogenesis, synaptogenesis, and cell-cell communication. Brain lipid metabolism is thus a tightly regulated process. Any alteration/dysregulation of lipid metabolism greatly impact brain health and activity. Moreover, since central nervous system (CNS) is the most metabolically active system and lacks an efficient antioxidative defence system, it acts as a hub for the production of reactive oxygen species (ROS) and subsequent lipid peroxidation. These peroxidation events are reported during pathological changes such as neuronal tissue injury and inflammation. Present review is a modest attempt to gain insights into the role of dysregulated bioactive lipid levels and lipid oxidation status in the pathogenesis and progression of neurodegenerative disorders. This may open up new avenues exploiting lipids as the therapeutic targets for improving brain health, and treatment of nervous system disorders.
    Keywords:  Brain disorder; Lipid Mediators; Lipid Peroxidation; Neurodegenerative diseases; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106737
  6. Neurochem Res. 2023 Apr 25.
    The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons.
    Mengjie Chen, Ruyu Yan, Jiansheng Luo, Jiaqi Ning, Ruiling Zhou, Lingling Ding.
      Neurons are highly dependent on mitochondrial ATP production and Ca2+ buffering. Neurons have unique compartmentalized anatomy and energy requirements, and each compartment requires continuously renewed mitochondria to maintain neuronal survival and activity. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a key factor in the regulation of mitochondrial biogenesis. It is widely accepted that mitochondria are synthesized in the cell body and transported via axons to the distal end. However, axonal mitochondrial biogenesis is necessary to maintain axonal bioenergy supply and mitochondrial density due to limitations in mitochondrial axonal transport rate and mitochondrial protein lifespan. In addition, impaired mitochondrial biogenesis leading to inadequate energy supply and neuronal damage has been observed in neurological disorders. In this review, we focus on the sites where mitochondrial biogenesis occurs in neurons and the mechanisms by which it maintains axonal mitochondrial density. Finally, we summarize several neurological disorders in which mitochondrial biogenesis is affected.
    Keywords:  Axons; Cell body; Mitochondrial biogenesis; Neurological disorders; Neurons; PGC-1α
    DOI:  https://doi.org/10.1007/s11064-023-03934-8
  7. Front Neurosci. 2023 ;17 1081515
    Effect of aging on the cerebral metabolic mechanism of electroacupuncture treatment in rats with traumatic brain injury.
    Bei-Bei Huo, Mou-Xiong Zheng, Xu-Yun Hua, Jia-Jia Wu, Xiang-Xin Xing, Jie Ma, Min Fang, Jian-Guang Xu.
       Objective: Aging has great influence on the clinical treatment effect of cerebrovascular diseases, and evidence suggests that the effect may be associated with age-related brain plasticity. Electroacupuncture is an effective alternative treatment for traumatic brain injury (TBI). In the present study, we aimed to explore the effect of aging on the cerebral metabolic mechanism of electroacupuncture to provide new evidence for developing age-specific rehabilitation strategies.
    Methods: Both aged (18 months) and young (8 weeks) rats with TBI were analyzed. Thirty-two aged rats were randomly divided into four groups: aged model, aged electroacupuncture, aged sham electroacupuncture, and aged control group. Similarly, 32 young rats were also divided into four groups: young model, young electroacupuncture, young sham electroacupuncture, and young control group. Electroacupuncture was applied to "Bai hui" (GV20) and "Qu chi" (LI11) for 8 weeks. CatWalk gait analysis was then performed at 3 days pre- and post-TBI, and at 1, 2, 4, and 8 weeks after intervention to observe motor function recovery. Positron emission computed tomography (PET/CT) was performed at 3 days pre- and post-TBI, and at 2, 4, and 8 weeks after intervention to detect cerebral metabolism.
    Results: Gait analysis showed that electroacupuncture improved the forepaw mean intensity in aged rats after 8 weeks of intervention, but after 4 weeks of intervention in young rats. PET/CT revealed increased metabolism in the left (the injured ipsilateral hemisphere) sensorimotor brain areas of aged rats during the electroacupuncture intervention, and increased metabolism in the right (contralateral to injury hemisphere) sensorimotor brain areas of young rats.
    Results: This study demonstrated that aged rats required a longer electroacupuncture intervention duration to improve motor function than that of young rats. The influence of aging on the cerebral metabolism of electroacupuncture treatment was mainly focused on a particular hemisphere.
    Keywords:  aging; brain plasticity; electroacupuncture; metabolic mechanism; small animal 18F-FDG PET/CT; traumatic brain injury (TBI)
    DOI:  https://doi.org/10.3389/fnins.2023.1081515
  8. Neurobiol Dis. 2023 Apr 22. pii: S0969-9961(23)00146-8. [Epub ahead of print] 106132
    Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration.
    Robert Zorec, Nina Vardjan.
      Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connectivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a protective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hypothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.
    Keywords:  Alzheimer's disease; Cognitive decline; L-Lactate production; Lipid droplet; Neurodegeneration; Warburg effect
    DOI:  https://doi.org/10.1016/j.nbd.2023.106132
  9. Mol Psychiatry. 2023 Apr 28.
    Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501).
    Yang Du, Lei Chen, Mei-Chen Yan, Yan-Li Wang, Xiao-Lin Zhong, Chen-Xi Xv, Yao-Bo Li, Yong Cheng.
      Evidence suggests that neurometabolite alterations may be involved in the pathophysiology of autism spectrum disorders (ASDs). We performed a meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies to examine the neurometabolite levels in the brains of patients with ASD. A systematic search of PubMed and Web of Science identified 54 studies for the meta-analysis. A random-effects meta-analysis demonstrated that compared with the healthy controls, patients with ASD had lower N-acetyl-aspartate-containing compound (NAA) and choline-containing compound (Cho) levels and NAA/(creatine-containing compound) Cr ratios in the gray matter and lower NAA and glutamate + glutamine (Glx) levels in the white matter. Furthermore, NAA and gamma-aminobutyric acid (GABA) levels, NAA/Cr ratios, and GABA/Cr ratios were significantly decreased in the frontal cortex of patients with ASD, whereas glutamate (Glu) levels were increased in the prefrontal cortex. Additionally, low NAA levels and GABA/Cr ratios in the temporal cortex, low NAA levels and NAA/Cr ratios in the parietal and dorsolateral prefrontal cortices, and low NAA levels in the cerebellum and occipital cortex were observed in patients with ASD. Meta-regression analysis revealed that age was positively associated with effect size in studies analyzing the levels of gray matter NAA and white matter Glx. Taken together, these results provide strong clinical evidence that neurometabolite alterations in specific brain regions are associated with ASD and age is a confounding factor for certain neurometabolite levels in patients with ASD.
    DOI:  https://doi.org/10.1038/s41380-023-02079-y
  10. Brain Connect. 2023 Apr 25.
    NEUROBIOLOGICAL DYSFUNCTIONAL SUBSTRATES FOR THE SELF-MEDICATION HYPOTHESIS IN ADULT INDIVIDUALS WITH ADHD AND COCAINE USE DISORDER: AN 18F-FDG PET STUDY.
    Giulia Carli, Marco Cavicchioli, Anna Lisa Martini, Matteo Bruscoli, Antonella Mafredi, Luca Presotto, Christian Mazzeo, Stelvio Sestini, Daniela Perani.
       OBJECTIVES: Attention-deficit hyperactivity disorder (ADHD) in adulthood shows high co-occurrence rates with cocaine use disorder (CoUD). The self-medication hypothesis (SMH) provides a theoretical explanation for this comorbidity. This study investigates the neurobiological mechanisms that could support SMH in adult patients with ADHD-CoUD.
    MATERIALS AND METHODS: We included 19 ADHD-CoUD (84.2% male; age: 32.11 [7.18]) and 16 CoUD (68.7% male; age: 36.63 [8.12]). All subjects underwent an 18F-FDG-PET brain scan. We tested brain metabolism differences between ADHD-CoUD and CoUD patients using voxel-based and regions of interest (ROIs)-based analyses. The correlation between dependence/abstinence duration and regional brain metabolism was also assessed in the two groups. Lastly, we investigated the integrity of brain metabolic connectivity of mesocorticolimbic and nigrostriatal dopaminergic systems, and large-scale brain networks involved in ADHD and addictions.
    RESULTS: The voxel-wise and ROIs-based approaches showed that ADHD-CoUD patients had a lower metabolism in the thalamus and increased metabolism in the amygdala and parahippocampus, bilaterally, compared to CoUD subjects and HC. Metabolism in the thalamus negatively correlated with years of dependence in ADHD-CoUD patients. Moreover, connectivity analyses revealed that ADHD-CoUD had a more preserved metabolic connectivity than CoUD in the dopaminergic networks and large-scale networks involved in self-regulation mechanisms of attention and behaviours (i.e., ADMN, ECN, SAN).
    CONCLUSIONS: We demonstrated distinct neuropathological substrates underlying substance-use behaviours in ADHD-CoUD and CoUD. Furthermore, we provided neurobiological evidence in support of SMH, demonstrating that ADHD-CoUD might experience short-term advantages of cocaine assumption (i.e., compensation of dopaminergic deficiency and related cognitive-behavioural deficits).
    Keywords:  Attention deficit hyperactivity disorder (ADHD); Substance abuse
    DOI:  https://doi.org/10.1089/brain.2022.0076
  11. Mol Genet Metab. 2023 Apr 15. pii: S1096-7192(23)00213-5. [Epub ahead of print]139(1): 107583
    Phenylketonuria and the brain.
    Valentina Rovelli, Nicola Longo.
      Classic phenylketonuria (PKU) is caused by defective activity of phenylalanine hydroxylase (PAH), the enzyme that coverts phenylalanine (Phe) to tyrosine. Toxic accumulation of phenylalanine and its metabolites, left untreated, affects brain development and function depending on the timing of exposure to elevated levels. The specific mechanisms of Phe-induced brain damage are not completely understood, but they correlate to phenylalanine levels and on the stage of brain growth. During fetal life, high levels of phenylalanine such as those seen in maternal PKU can result in microcephaly, neuronal loss and corpus callosum hypoplasia. Elevated phenylalanine levels during the first few years of life can cause acquired microcephaly, severe cognitive impairment and epilepsy, likely due to the impairment of synaptogenesis. During late childhood, elevated phenylalanine can cause alterations in neurological functioning, leading to ADHD, speech delay and mild IQ reduction. In adolescents and adults, executive function and mood are affected, with some of the abnormalities reversed by better control of phenylalanine levels. Altered brain myelination can be present at this stage. In this article, we review the current knowledge about the consequences of high phenylalanine levels in PKU patients and animal models through different stages of brain development and its effect on cognitive, behavioural and neuropsychological function.
    Keywords:  Brain; Hyperphenylalaninemia; Neurocognitive function; Neurologic; Psychomotor delay; phenylketonuria
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107583
  12. Curr Protoc. 2023 Apr;3(4): e758
    Acylglycine Analysis by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS).
    Judith A Hobert, Rebecca Guymon, Tatiana Yuzyuk, Marzia Pasquali.
      Quantitative analysis of urine acylglycines has shown to be a highly sensitive and specific method with proven clinical utility for the diagnosis of several inherited metabolic disorders including: medium chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, short chain acyl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, 2-methylbutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, propionic academia, and isobutyryl-CoA dehydrogenase deficiency. Here, a method that is currently performed using ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) is described. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary acylglycine analysis by UPLC-MS/MS Support Protocol 1: Quality control preparation Support Protocol 2: Internal standard (ISTD) preparation Support Protocol 3: Standard (STD)/calibrator preparation.
    Keywords:  UPLC-MS/MS; acylglycine; fatty acid β-oxidation; glycine N-acylase; organic acidemia
    DOI:  https://doi.org/10.1002/cpz1.758
  13. J Alzheimers Dis. 2023 Apr 17.
    Quantitative Lipidomic Analysis of Serum Phospholipids Reveals Dissociable Markers of Alzheimer's Disease and Subcortical Cerebrovascular Disease.
    Yurika Otoki, Di Yu, Qing Shen, Demetrios J Sahlas, Joel Ramirez, Fuqiang Gao, Mario Masellis, Richard H Swartz, Pak Cheung Chan, Jacqueline A Pettersen, Shunji Kato, Kiyotaka Nakagawa, Sandra E Black, Walter Swardfager, Ameer Y Taha.
       BACKGROUND: Circulating phospholipid species have been shown to predict Alzheimer's disease (AD) prognosis but the link between phospholipid disturbances and subcortical small vessel cerebrovascular disease (CeVD) common in AD patients is not known.
    OBJECTIVE: This study used quantitative lipidomics to measure serum diacyl, alkenyl (ether), alkyl, and lyso phospholipid species in individuals with extensive CeVD (n = 29), AD with minimal CeVD (n = 16), and AD with extensive CeVD (n = 14), and compared them to age-matched controls (n = 27). Memory was assessed using the California Verbal Learning Test. 3.0T MRI was used to assess hippocampal volume, atrophy, and white matter hyperintensity (WMH) volumes as manifestations of CeVD.
    RESULTS: AD was associated with significantly higher concentrations of choline plasmalogen 18:0_18:1 and alkyl-phosphocholine 18:1. CeVD was associated with significantly lower lysophospholipids containing 16:0. Phospholipids containing arachidonic acid (AA) were associated with poorer memory in controls, whereas docosahexaenoic acid (DHA)-containing phospholipids were associated with better memory in individuals with AD+CeVD. In controls, DHA-containing phospholipids were associated with more atrophy and phospholipids containing linoleic acid and AA were associated with less atrophy. Lysophospholipids containing 16:0, 18:0, and 18:1 were correlated with less atrophy in controls, and of these, alkyl-phosphocholine 18:1 was correlated with smaller WMH volumes. Conversely, 16:0_18:1 choline plasmalogen was correlated with greater WMH volumes in controls.
    CONCLUSION: This study demonstrates discernable differences in circulating phospholipids in individuals with AD and CeVD, as well as new associations between phospholipid species with memory and brain structure that were specific to contexts of commonly comorbid vascular and neurodegenerative pathologies.
    Keywords:  Alkylphospholipids; lysophospholipid; plasmalogens; small vessel disease; vascular cognitive impairment; white matter hyperintensity
    DOI:  https://doi.org/10.3233/JAD-220795
  14. Eur J Pharmacol. 2023 Apr 26. pii: S0014-2999(23)00244-3. [Epub ahead of print] 175733
    Glutamate dehydrogenase: Potential therapeutic targets for neurodegenerative disease.
    Chuqiao Pan, Shijie Mao, Zeping Xiong, Zhao Chen, Ning Xu.
      Glutamate dehydrogenase (GDH) is a key enzyme in mammalian glutamate metabolism. It is located at the intersection of multiple metabolic pathways and participates in a variety of cellular activities. GDH activity is strictly regulated by a variety of allosteric compounds. Here, we review the unique distribution and expressions of GDH in the brain nervous system. GDH plays an essential role in the glutamate-glutamine-GABA cycle between astrocytes and neurons. The dysfunction of GDH may induce the occurrence of many neurodegenerative diseases, such as Parkinson's disease, epilepsy, Alzheimer's disease, schizophrenia, and frontotemporal dementia. GDH activators and gene therapy have been found to protect neurons and improve motor disorders in neurodegenerative diseases caused by glutamate metabolism disorders. To date, no medicine has been discovered that specifically targets neurodegenerative diseases, although several potential medicines are used clinically. Targeting GDH to treat neurodegenerative diseases is expected to provide new insights and treatment strategies.
    Keywords:  Glutamate dehydrogenase; Glutamate-glutamine-GABA cycle; Neurodegenerative diseases; Neuroprotection
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175733
  15. Front Mol Neurosci. 2023 ;16 1151162
    Glycolysis mediates neuron specific histone acetylation in valproic acid-induced human excitatory neuron differentiation.
    Andi Chen, Mengmeng Wang, Chao Xu, Youyi Zhao, Panpan Xian, Yuqian Li, Weian Zheng, Xuyang Yi, Shengxi Wu, Yazhou Wang.
      Pregnancy exposure of valproic acid (VPA) is widely adopted as a model of environmental factor induced autism spectrum disorder (ASD). Increase of excitatory/inhibitory synaptic transmission ratio has been proposed as the mechanism of VPA induced ASD. How this happened, particularly at the level of excitatory neuron differentiation in human neural progenitor cells (NPCs) remains largely unclear. Here, we report that VPA exposure remarkably inhibited human NPC proliferation and induced excitatory neuronal differentiation without affecting inhibitory neurons. Following VPA treatment, mitochondrial dysfunction was observed before neuronal differentiation, as showed by ultrastructural changes, respiratory complex activity, mitochondrial membrane potential and oxidation levels. Meanwhile, extracellular acidification assay revealed an elevation of glycolysis by VPA stimulation. Interestingly, inhibiting glycolysis by 2-deoxy-d-glucose-6-phosphate (2-DG) efficiently blocked the excitatory neuronal differentiation of human NPCs induced by VPA. Furthermore, 2-DG treatment significantly compromised the VPA-induced expression of H3ac and H3K9ac, and the VPA-induced binding of H3K9ac on the promoter of Ngn2 and Mash1, two key transcription factors of excitatory neuron fate determination. These data, for the first time, demonstrated that VPA biased excitatory neuron differentiation by glycolysis-mediated histone acetylation of neuron specific transcription factors.
    Keywords:  differentiation; glycolysis; histone acetylation; human embryonic stem cells; valproic acid
    DOI:  https://doi.org/10.3389/fnmol.2023.1151162
  16. Crit Rev Food Sci Nutr. 2023 Apr 28. 1-20
    Nervonic acid and its sphingolipids: Biological functions and potential food applications.
    Nghi Van Phung, Fei Rong, Wan Yue Xia, Yong Fan, Xian Yu Li, Shi An Wang, Fu Li Li.
      Nervonic acid, a 24-carbon fatty acid with only one double bond at the 9th carbon (C24:1n-9), is abundant in the human brain, liver, and kidney. It not only functions in free form but also serves as a critical component of sphingolipids which participate in many biological processes such as cell membrane formation, apoptosis, and neurotransmission. Recent studies show that nervonic acid supplementation is not only beneficial to human health but also can improve the many medical conditions such as neurological diseases, cancers, diabetes, obesity, and their complications. Nervonic acid and its sphingomyelins serve as a special material for myelination in infants and remyelination patients with multiple sclerosis. Besides, the administration of nervonic acid is reported to reduce motor disorder in mice with Parkinson's disease and limit weight gain. Perturbations of nervonic acid and its sphingolipids might lead to the pathogenesis of many diseases and understanding these mechanisms is critical for investigating potential therapeutic approaches for such diseases. However, available studies about this aspect are limited. In this review, relevant findings about functional mechanisms of nervonic acid have been comprehensively and systematically described, focusing on four interconnected functions: cellular structure, signaling, anti-inflammation, lipid mobilization, and their related diseases.
    Keywords:  Signal transduction; anti-inflammation; lipid mobilization; neurological disease; very-long-chain fatty acid
    DOI:  https://doi.org/10.1080/10408398.2023.2203753
  17. IBRO Neurosci Rep. 2023 Jun;14 393-397
    New aspects for the brain in Hartnup disease based on mining of high-resolution cellular mRNA expression data for SLC6A19.
    Zachary Kravetz, Rainald Schmidt-Kastner.
      Hartnup disease is an autosomal recessive, metabolic disorder caused by mutations of the neutral amino acid transporter, SLC6A19/B0AT1. Reduced absorption in the intestine and kidney results in deficiencies in neutral amino acids and their down-stream metabolites, including niacin, associated with skin lesions and neurological symptoms. The effects on the nervous system such as ataxia have been related to systemic deficiencies of tryptophan (and other neutral amino acids) as no expression of the B0AT1 transporter was found in the brain. In the intestine, SLC6A19 cooperates with ACE2 which has received major attention as the cellular receptor for SARS-CoV-2. When transcriptomics data for ACE2 and its partner proteins were examined, a previously unrecognized expression of Slc6a19 mRNA in the ependymal cells of the mouse brain was encountered that is set into the context of neurological manifestations of Hartnup disease with this communication. A novel role for SLC6A19/B0AT1 in amino acid transport from CSF into ependymal cells is proposed and a role of niacin in ependymal cells highlighted.
    Keywords:  ACE2; Amino acid transporter; Ependyma; Hartnup disease; SLC6A19; Tryptophan
    DOI:  https://doi.org/10.1016/j.ibneur.2023.03.010
  18. Nat Aging. 2022 Aug;2(8): 726-741
    A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
    Eunbeol Lee, Yeon-Joo Jung, Yu Rim Park, Seongjoon Lim, Young-Jin Choi, Se Young Lee, Chan Hyuk Kim, Ji Young Mun, Won-Suk Chung.
      The aging brain exhibits a region-specific reduction in synapse number and plasticity. Although astrocytes play central roles in regulating synapses, it is unclear how changes in astrocytes contribute to age-dependent cognitive decline and vulnerability to neurodegenerative diseases. Here, we identified a unique astrocyte subtype that exhibits dysregulated autophagy and morphology in aging hippocampus. In these autophagy-dysregulated astrocytes (APDAs), autophagosomes abnormally accumulate in swollen processes, impairing protein trafficking and secretion. We found that reduced mammalian target of rapamycin (mTOR) and proteasome activities with lysosomal dysfunction generate APDAs in an age-dependent manner. Secretion of synaptogenic molecules and astrocytic synapse elimination were significantly impaired in APDAs, suggesting that APDAs have lost their ability to control synapse number and homeostasis. Indeed, excitatory synapses and dendritic spines associated with APDAs were significantly reduced. Finally, we found that mouse brains with Alzheimer's disease showed a significantly accelerated increase in APDAs, suggesting potential roles for APDAs in age- and Alzheimer's disease-related cognitive decline and synaptic pathology.
    DOI:  https://doi.org/10.1038/s43587-022-00257-1
  19. Nat Aging. 2022 Apr;2(4): 317-331
    Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
    Giorgio Fedele, Samantha H Y Loh, Ivana Celardo, Nuno Santos Leal, Susann Lehmann, Ana C Costa, L Miguel Martins.
      The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson's disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut-brain communication modulates neurotoxicity in a fly model of Parkinson's disease through a mechanism involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s43587-022-00194-z
  20. Nat Aging. 2023 Mar;3(3): 275-296
    Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.
    Nicole Koutsodendris, Jessica Blumenfeld, Ayushi Agrawal, Michela Traglia, Brian Grone, Misha Zilberter, Oscar Yip, Antara Rao, Maxine R Nelson, Yanxia Hao, Reuben Thomas, Seo Yeon Yoon, Patrick Arriola, Yadong Huang.
      Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.
    DOI:  https://doi.org/10.1038/s43587-023-00368-3
  21. Antioxidants (Basel). 2023 Apr 06. pii: 895. [Epub ahead of print]12(4):
    Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases.
    Vishal Chavda, Bingwei Lu.
      Stroke is one of the leading causes of morbidity and mortality worldwide. A main cause of brain damage by stroke is ischemia-reperfusion (IR) injury due to the increased production of reactive oxygen species (ROS) and energy failure caused by changes in mitochondrial metabolism. Ischemia causes a build-up of succinate in tissues and changes in the mitochondrial NADH: ubiquinone oxidoreductase (complex I) activity that promote reverse electron transfer (RET), in which a portion of the electrons derived from succinate are redirected from ubiquinol along complex I to reach the NADH dehydrogenase module of complex I, where matrix NAD+ is converted to NADH and excessive ROS is produced. RET has been shown to play a role in macrophage activation in response to bacterial infection, electron transport chain reorganization in response to changes in the energy supply, and carotid body adaptation to changes in the oxygen levels. In addition to stroke, deregulated RET and RET-generated ROS (RET-ROS) have been implicated in tissue damage during organ transplantation, whereas an RET-induced NAD+/NADH ratio decrease has been implicated in aging, age-related neurodegeneration, and cancer. In this review, we provide a historical account of the roles of ROS and oxidative damage in the pathogenesis of ischemic stroke, summarize the latest developments in our understanding of RET biology and RET-associated pathological conditions, and discuss new ways to target ischemic stroke, cancer, aging, and age-related neurodegenerative diseases by modulating RET.
    Keywords:  Alzheimer’s disease (AD); FOXO; NAD+/NADH ratio; RET inhibitor; aging; cancer; mitochondrial complex I; reactive oxygen species (ROS); reverse electron transport (RET); sirtuin
    DOI:  https://doi.org/10.3390/antiox12040895
  22. Int J Mol Sci. 2023 Apr 14. pii: 7243. [Epub ahead of print]24(8):
    Developmental Stage-Dependent Changes in Mitochondrial Function in the Brain of Offspring Following Prenatal Maternal Immune Activation.
    Magdalena Cieślik, Aleksandra Zawadzka, Grzegorz A Czapski, Anna Wilkaniec, Agata Adamczyk.
      Maternal immune activation (MIA) is an important risk factor for neurodevelopmental disorders such as autism. The aim of the current study was to investigate the development-dependent changes in the mitochondrial function of MIA-exposed offspring, which may contribute to autism-like deficits. MIA was evoked by the single intraperitoneal administration of lipopolysaccharide to pregnant rats at gestation day 9.5, and several aspects of mitochondrial function in fetuses and in the brains of seven-day-old pups and adolescent offspring were analyzed along with oxidative stress parameters measurement. It was found that MIA significantly increased the activity of NADPH oxidase (NOX), an enzyme generating reactive oxygen species (ROS) in the fetuses and in the brain of seven-day-old pups, but not in the adolescent offspring. Although a lower mitochondrial membrane potential accompanied by a decreased ATP level was already observed in the fetuses and in the brain of seven-day-old pups, persistent alterations of ROS, mitochondrial membrane depolarization, and lower ATP generation with concomitant electron transport chain complexes downregulation were observed only in the adolescent offspring. We suggest that ROS observed in infancy are most likely of a NOX activity origin, whereas in adolescence, ROS are produced by damaged mitochondria. The accumulation of dysfunctional mitochondria leads to the intense release of free radicals that trigger oxidative stress and neuroinflammation, resulting in an interlinked vicious cascade.
    Keywords:  NADPH oxidase; ROS; animal model; autism; maternal immune activation; mitochondria; neurodevelopmental disorders
    DOI:  https://doi.org/10.3390/ijms24087243
  23. Naunyn Schmiedebergs Arch Pharmacol. 2023 Apr 24.
    Increased levels of lipid and protein oxidation in rat prefrontal cortex after treatment by lithium, valproic acid, and olanzapine.
    Mehmet Alper Arslan, Özgür Korhan Tunçel, Birşen Bilgici, Arzu Karaustaoğlu, Taner İlker Gümrükçüoğlu.
      Oxidative stress is widely accepted to contribute to the pathogenesis of several psychiatric diseases. Many antipsychotic drugs and mood stabilizers act through restoration of the dysregulated oxidative homeostasis in the brain. However, the long-term effect of these drugs per se in terms of their potential to interfere with the oxidative status in the brain remains largely controversial. The present study aimed to investigate the sole effect of three commonly used psychoactive drugs, lithium, valproic acid, and olanzapine, on lipid and protein oxidation status in the prefrontal cortex of healthy rats. A total of 80 adult male albino Wistar rats were used, and groups were treated with saline (control), lithium, valproic acid, or olanzapine daily for 30 days. Following sacrification, right prefrontal cortexes were dissected and homogenized. Lipid peroxidation (LPO) and protein oxidation (AOPP) assays were performed by ELISA. LPO levels were significantly higher in lithium and valproic acid-treated rats by 45% and 40%, respectively. Olanzapine treatment caused a mild 26% increase in LPO levels, but the effect was non-significant. Lithium, valproic acid, and olanzapine treatments significantly increased AOPP levels by 58%, 54%, and 36.5%, respectively. There was a strong positive correlation between the lipid peroxidation and protein oxidation levels. Our results call attention to the need to consider the pro-oxidative capacity of antipsychotic drugs per se and their potential to disturb the oxidative homeostasis in the brain during long-term medication for psychiatric diseases.
    Keywords:  Lithium; Olanzapine; Oxidative stress; Rat brain; Valproic acid
    DOI:  https://doi.org/10.1007/s00210-023-02494-6
  24. eNeuro. 2023 Apr 21. pii: ENEURO.0498-22.2023. [Epub ahead of print]
    Rescue of long-term spatial memory by 7,8-dihydroxyflavone in mice with reduced oligodendrogenesis.
    Florence Rawlings-Mortimer, Heidi Johansen-Berg.
      Oligodendrogenesis is the process by which new oligodendrocytes are produced in the central nervous system. Oligodendrocytes form myelin, which has a vital role in neural signal transmission and integration. Here we tested mice with reduced adult oligodendrogenesis in the Morris watermaze, a test of spatial learning. These mice were found to have impaired long-term (28-day) spatial memory. However, when 7,8-dihydroxyflavone (7,8-DHF) was administered immediately after each training session, their long-term spatial memory impairment was rescued. An increase in the number of newly formed oligodendrocytes in the corpus callosum was also observed. 7,8-DHF has previously been shown to improve spatial memory in animal models of Alzheimer's diseases, post-traumatic stress disorder (PTSD), Wolfran and Down syndrome, as well as in normal aging. Understanding the underlying mechanisms of this drug on spatial memory is therefore helpful in assessing it for clinical relevance and development.Significance Statement7,8-dihydroxyflavone (7,8-DHF) is a drug that has been shown to improve the symptoms of numerous brain disorders including Alzheimer's disease and post-traumatic stress disorder (PTSD) in mouse models. It is therefore of great interest clinically to understand the impact of this drug on the brain and assess behavioural changes over longer time periods. Here, we show that 7,8-DHF improves spatial memory one month after administration in mice with reduced numbers of oligodendrocytes in adulthood. We also found an increase of newly formed oligodendrocytes in the corpus callosum providing insights into the long-term effects of this drug.
    DOI:  https://doi.org/10.1523/ENEURO.0498-22.2023
  25. Exp Neurol. 2023 Apr 24. pii: S0014-4886(23)00113-9. [Epub ahead of print] 114428
    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 sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT 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 Adv-KO-SCOT 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.
    Keywords:  Friedreich's ataxia; Ketolysis; Ketone; Myelination; Neuropathy; Peripheral nervous system; Sensation
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114428
  26. Int J Mol Sci. 2023 Apr 13. pii: 7221. [Epub ahead of print]24(8):
    Mitochondrial Bioenergy in Neurodegenerative Disease: Huntington and Parkinson.
    Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Paola Bonsi, Tommaso Schirinzi, Giuseppina Martella.
      Strong evidence suggests a correlation between degeneration and mitochondrial deficiency. Typical cases of degeneration can be observed in physiological phenomena (i.e., ageing) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have the dyshomeostasis of mitochondrial bioenergy as a common denominator. Neurodegenerative diseases show bioenergetic imbalances in their pathogenesis or progression. Huntington's chorea and Parkinson's disease are both neurodegenerative diseases, but while Huntington's disease is genetic and progressive with early manifestation and severe penetrance, Parkinson's disease is a pathology with multifactorial aspects. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early-onset diseases linked to gene mutations, while others could be idiopathic, appear in young adults, or be post-injury senescence conditions. Although Huntington's is defined as a hyperkinetic disorder, Parkinson's is a hypokinetic disorder. However, they both share a lot of similarities, such as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In this review, we will describe the start and development of both diseases in relation to mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.
    Keywords:  Huntington’s disease; Parkinson’s disease; basal ganglia; calcium; energy metabolism; mitochondria; movement disorders; synaptic plasticity
    DOI:  https://doi.org/10.3390/ijms24087221
  27. Nat Aging. 2022 Jul;2(7): 565-566
    APOE4 dysregulates cholesterol homeostasis in human microglia and astrocytes.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-022-00256-2
  28. Front Pharmacol. 2023 ;14 928821
    The role of cholesterol metabolism in tumor therapy, from bench to bed.
    Wenhao Xia, Hao Wang, Xiaozhu Zhou, Yan Wang, Lixiang Xue, Baoshan Cao, Jiagui Song.
      Cholesterol and its metabolites have important biological functions. Cholesterol is able to maintain the physical properties of cell membrane, play an important role in cellular signaling, and cellular cholesterol levels reflect the dynamic balance between biosynthesis, uptake, efflux and esterification. Cholesterol metabolism participates in bile acid production and steroid hormone biosynthesis. Increasing evidence suggests a strict link between cholesterol homeostasis and tumors. Cholesterol metabolism in tumor cells is reprogrammed to differ significantly from normal cells, and disturbances of cholesterol balance also induce tumorigenesis and progression. Preclinical and clinical studies have shown that controlling cholesterol metabolism suppresses tumor growth, suggesting that targeting cholesterol metabolism may provide new possibilities for tumor therapy. In this review, we summarized the metabolic pathways of cholesterol in normal and tumor cells and reviewed the pre-clinical and clinical progression of novel tumor therapeutic strategy with the drugs targeting different stages of cholesterol metabolism from bench to bedside.
    Keywords:  cholesterol; cholesterol metabolism; clinical trial; pharmacological targets; tumor therapy
    DOI:  https://doi.org/10.3389/fphar.2023.928821
  29. Biochim Biophys Acta Gene Regul Mech. 2023 Apr 21. pii: S1874-9399(23)00033-0. [Epub ahead of print]1866(2): 194938
    "MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression".
    Mario Fernández-de Frutos, Virginia Pardo-Marqués, Marta Torrecilla-Parra, Patricia Rada, Ana Pérez-García, Yolanda Martín-Martín, Gema de la Peña, Ana Gómez, Ana Toledano-Zaragoza, Diego Gómez-Coronado, María José Casarejos, José M Solís, Noemí Rotllan, Óscar Pastor, María Dolores Ledesma, Ángela M Valverde, Rebeca Busto, Cristina M Ramírez.
      Dysregulation of cholesterol homeostasis is associated with several pathologies including cardiovascular diseases and neurological disorders such as Alzheimer's disease (AD). MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of cholesterol metabolism. We previously established the role of miR-7 in regulating insulin resistance and amyloidosis, which represents a common pathological feature between type 2 diabetes and AD. We show here an additional metabolic function of miR-7 in cholesterol biosynthesis. We found that miR-7 blocks the last steps of the cholesterol biosynthetic pathway in vitro by targeting relevant genes including DHCR24 and SC5D posttranscriptionally. Intracranial infusion of miR-7 on an adeno-associated viral vector reduced the expression of DHCR24 in the brain of wild-type mice, supporting in vivo miR-7 targeting. We also found that cholesterol regulates endogenous levels of miR-7 in vitro, correlating with transcriptional regulation through SREBP2 binding to its promoter region. In parallel to SREBP2 inhibition, the levels of miR-7 and hnRNPK (the host gene of miR-7) were concomitantly reduced in brain in a mouse model of Niemann Pick type C1 disease and in murine fatty liver, which are both characterized by intracellular cholesterol accumulation. Taken together, the results establish a novel regulatory feedback loop by which miR-7 modulates cholesterol homeostasis at the posttranscriptional level, an effect that could be exploited for therapeutic interventions against prevalent human diseases.
    Keywords:  Cholesterol biosynthesis; DHCR24; Posttranscriptional regulation; miR-7
    DOI:  https://doi.org/10.1016/j.bbagrm.2023.194938
  30. BMC Neurosci. 2023 Apr 25. 24(1): 27
    Protective effect of resveratrol on mitochondrial biogenesis during hyperoxia-induced brain injury in neonatal pups.
    Menghan Yang, Yunchuan Shen, Shuai Zhao, Rong Zhang, Wenbin Dong, Xiaoping Lei.
       BACKGROUND: Neonatal hyperoxic brain injury is caused by exposure to hyperphysiological oxygen content during the period of incomplete development of the oxidative stress defence system, resulting in a large number of reactive oxygen species (ROS) and causing damage to brain tissue. Mitochondrial biogenesis refers to the synthesis of new mitochondria from existing mitochondria, mostly through the PGC-1α/Nrfs/TFAM signalling pathway. Resveratrol (Res), a silencing information regulator 2-related enzyme 1 (Sirt1) agonist, has been shown to upregulate the level of Sirt1 and the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We speculate that Res has a protective effect on hyperoxia-induced brain injury through mitochondrial biogenesis.
    METHODS: Sprague-Dawley (SD) pups were randomly divided into the nonhyperoxia (NN) group, the nonhyperoxia with dimethyl sulfoxide (ND) group, the nonhyperoxia with Res (NR) group, the hyperoxia (HN) group, the hyperoxia with dimethyl sulfoxide (HD) group, and the hyperoxia with Res (HR) group within 12 h after birth. The HN, HD, and HR groups were placed in a high-oxygen environment (80‒85%), and the other three groups were placed in the standard atmosphere. The NR and HR groups were given 60 mg/kg Res every day, the ND and HD groups were given the same dose of dimethyl sulfoxide (DMSO) every day, and the NN and HN groups were given the same dose of normal saline every day. On postnatal day (PN) 1, PN7, and PN14, brain samples were acquired for HE staining to assess pathology, TUNEL to detect apoptosis, and real-time quantitative polymerase chain reaction and immunoblotting to detect the expression levels of Sirt1, PGC-1α, nuclear respiratory factor 1 (Nrf1), nuclear respiratory factor 2 (Nrf2) and mitochondrial transcription factor A (TFAM) in brain tissue.
    RESULTS: Hyperoxia induced brain tissue injury; increased brain tissue apoptosis; inhibited Sirt1, PGC-1α, Nrf1, Nrf2, TFAM mRNA expression in mitochondria; diminished the ND1 copy number and ND4/ND1 ratio; and decreased Sirt1, PGC-1α, Nrf1, Nrf2, and TFAM protein levels in the brain. In contrast, Res reduced brain injury and attenuated brain tissue apoptosis in neonatal pups and increased the levels of the corresponding indices.
    CONCLUSION: Res has a protective effect on hyperoxia-induced brain injury in neonatal SD pups by upregulating Sirt1 and stimulating the PGC-1α/Nrfs/TFAM signalling pathway for mitochondrial biogenesis.
    Keywords:  Brain; Hyperoxia; Mitochondrial biogenesis; Neonatal rats; PGC-1α; Resveratrol
    DOI:  https://doi.org/10.1186/s12868-023-00797-1
  31. Toxicol Lett. 2023 Apr 26. pii: S0378-4274(23)00169-8. [Epub ahead of print]
    Mitochondrial dysfunction, oxidative stress, ER stress and mitochondria-ER crosstalk alterations in a chemical rat model of Huntington's disease: potential benefits of bezafibrate.
    Morgana Brondani, Ana Cristina Roginski, Rafael Teixeira Ribeiro, Maria Paula de Medeiros, Chrístofer Ian Hernandez Hoffmann, Moacir Wajner, Guilhian Leipnitz, Bianca Seminotti.
      Redox homeostasis, mitochondrial functions, and mitochondria-endoplasmic reticulum (ER) communication were evaluated in the striatum of rats after 3-nitropropionic acid (3-NP) administration, a recognized chemical model of Huntington's disease (HD). 3-NP impaired redox homeostasis by increasing malondialdehyde levels at 28 days, decreasing glutathione (GSH) concentrations at 21 and 28 days, and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione S-transferase at 7, 21, and 28 days, catalase at 21 days, and glutathione reductase at 21 and 28 days. Impairment of mitochondrial respiration at 7 and 28 days after 3-NP administration was also observed, as well as reduced activities of succinate dehydrogenase (SDH) and respiratory chain complexes. 3-NP also impaired mitochondrial dynamics and the interactions between ER and mitochondria and induced ER-stress by increasing the levels of mitofusin-1, and of DRP1, VDAC1, Grp75 and Grp78. Synaptophysin levels were augmented at 7 days but reduced at 28 days after 3-NP injection. Finally, bezafibrate prevented 3-NP-induced alterations of the activities of SOD, GPx, SDH and respiratory chain complexes, DCFH oxidation and on the levels of GSH, VDAC1 and synaptophysin. Mitochondrial dysfunction and synaptic disruption may contribute to the pathophysiology of HD and bezafibrate may be considered as an adjuvant therapy for this disorder.
    Keywords:  3-Nitropropionic acid; Bezafibrate; Huntington’s disease; Mitochondrial function; Redox homeostasis; Striatum
    DOI:  https://doi.org/10.1016/j.toxlet.2023.04.011
  32. Life (Basel). 2023 Apr 08. pii: 970. [Epub ahead of print]13(4):
    The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.
    Reem M Farsi.
      Alzheimer's disease (AD), a progressive and chronic neurodegenerative syndrome, is categorized by cognitive and memory damage caused by the aggregations of abnormal proteins, specifically including Tau proteins and β-amyloid in brain tissue. Moreover, mitochondrial dysfunctions are the principal causes of AD, which is associated with mitophagy impairment. Investigations exploring pharmacological therapies alongside AD have explicitly concentrated on molecules accomplished in preventing/abolishing the gatherings of the abovementioned proteins and mitochondria damages. Mitophagy is the removal of dead mitochondria by the autophagy process. Damages in mitophagy, the manner of diversified mitochondrial degeneracy by autophagy resulting in an ongoing aggregation of malfunctioning mitochondria, were also suggested to support AD. Recently, plentiful reports have suggested a link between defective mitophagy and AD. This treaty highlights updated outlines of modern innovations and developments on mitophagy machinery dysfunctions in AD brains. Moreover, therapeutic and nanotherapeutic strategies targeting mitochondrial dysfunction are also presented in this review. Based on the significant role of diminished mitophagy in AD, we suggest that the application of different therapeutic approaches aimed at stimulating mitophagy in AD would be beneficial for targeting or reducing the mitochondrial dysfunction induced by AD.
    Keywords:  Alzheimer’s disease; mitochondrial dysfunction; mitophagy; therapeutic and nanotherapeutic approaches
    DOI:  https://doi.org/10.3390/life13040970
  33. J Stroke Cerebrovasc Dis. 2023 Apr 25. pii: S1052-3057(23)00165-9. [Epub ahead of print]32(7): 107142
    Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury.
    Xiaoyu Kang, Lixu Liu, Wenzhu Wang, Yunlei Wang.
       OBJECTIVE: To explore the effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potential in rats with global cerebral ischemia-reperfusion injury.
    METHODS: A total of 75 SPF Sprague-Dawley male rats were randomly divided into sham group (n=20), model group (n=20), pramipexole administration group (n=35). The rat model of global cerebral ischemia-reperfusion injury was prepared by the modified Pulsinelli's four-vessel occlusion method. Pramipexole administration group was administered intraperitoneally in rats with global cerebral ischemia-reperfusion injury at different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, once a day for 14 consecutive days. Based on the results of modified neurological severity scores, open field test and morphology by Nissl's staining to determine the optimal dose of pramipexole. Mitochondrial membrane potential in the optimal dose of pramipexole administration group were measured by the JC-1 fluorescent probe staining method.
    RESULTS: 1. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, were used as drug administration in rats with global cerebral ischemia-reperfusion injury for 14 consecutive days, and we found that all four doses of pramipexole could improve the modified neurological severity scores of rats with global cerebral ischemia-reperfusion injury to varying degrees, but only 0.5 mg/kg pramipexole at 1, 3, 7 and 14 days consistently reduced modified neurological severity scores and improved neurological function in rats with global cerebral ischemia-reperfusion injury. In the open-field test, only 0.5 mg/kg pramipexole increased the number of entries into the central zone, duration spent in the central zone, total distance travelled in the open field and average velocity, which improved the spontaneous activities and reduced anxiety and depression of rats with global cerebral ischemia-reperfusion injury. 2. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg for 14 consecutive days significantly increased the number of surviving neurons in the hippocampal CA1 subfield in rats with global cerebral ischemia-reperfusion injury to varying degrees. Based on these results, we tentatively found that 0.5 mg/kg pramipexole may be the optimal dose in all of the above. 3. We found that 0.5 mg/kg pramipexole significantly increased the mitochondrial membrane potential in rats after global cerebral ischemia-reperfusion injury.
    CONCLUSION: Different doses of dopamine receptor agonist pramipexole improved neurological function of rats with global cerebral ischemia-reperfusion injury to varying degrees, and 0.5 mg/kg pramipexole may be the optimal dose in all of the above. Pramipexole may produce neuroprotective effects by protecting neurons in the hippocampus and improving the mitochondrial membrane potential after global cerebral ischemia-reperfusion injury.
    Keywords:  Brain protection; Global cerebral ischemia-reperfusion injury; Mitochondrial membrane potential; Pramipexole
    DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.107142
  34. Antioxidants (Basel). 2023 Apr 15. pii: 934. [Epub ahead of print]12(4):
    Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases.
    Yun Haeng Lee, Myeong Uk Kuk, Moon Kyoung So, Eun Seon Song, Haneur Lee, Soon Kil Ahn, Hyung Wook Kwon, Joon Tae Park, Sang Chul Park.
      Mitochondria are one of the organelles undergoing rapid alteration during the senescence process. Senescent cells show an increase in mitochondrial size, which is attributed to the accumulation of defective mitochondria, which causes mitochondrial oxidative stress. Defective mitochondria are also targets of mitochondrial oxidative stress, and the vicious cycle between defective mitochondria and mitochondrial oxidative stress contributes to the onset and development of aging and age-related diseases. Based on the findings, strategies to reduce mitochondrial oxidative stress have been suggested for the effective treatment of aging and age-related diseases. In this article, we discuss mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. Then, the causal role of mitochondrial oxidative stress on aging is investigated by examining how aging and age-related diseases are exacerbated by induced stress. Furthermore, we assess the importance of targeting mitochondrial oxidative stress for the regulation of aging and suggest different therapeutic strategies to reduce mitochondrial oxidative stress. Therefore, this review will not only shed light on a new perspective on the role of mitochondrial oxidative stress in aging but also provide effective therapeutic strategies for the treatment of aging and age-related diseases through the regulation of mitochondrial oxidative stress.
    Keywords:  ROS; aging control; mitochondria; mitochondrial oxidative stress
    DOI:  https://doi.org/10.3390/antiox12040934
  35. Nat Rev Mol Cell Biol. 2023 Apr 27.
    Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.
    Takaharu Sakuragi, Shigekazu Nagata.
      Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed of glycerophospholipids, sphingolipids and cholesterol, in which proteins are embedded. Glycerophospholipids and sphingolipids freely move laterally, whereas transverse movement between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins - flippases and scramblases - mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00604-z
  36. Acta Neuropathol. 2023 Apr 28.
    Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.
    Fabia Filipello, Shih-Feng You, Farzaneh S Mirfakhar, Sidhartha Mahali, Bryan Bollman, Mariana Acquarone, Olena Korvatska, Jacob A Marsh, Anirudh Sivaraman, Rita Martinez, Claudia Cantoni, Luca De Feo, Laura Ghezzi, Miguel A Minaya, Arun Renganathan, Anil G Cashikar, Jun-Ichi Satoh, Wandy Beatty, Abhirami K Iyer, Marina Cella, Wendy H Raskind, Laura Piccio, Celeste M Karch.
      TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
    Keywords:  Induced pluripotent stem cells; Lysosome; Microglia; Nasu-Hakola disease; TREM2; Transcriptomics
    DOI:  https://doi.org/10.1007/s00401-023-02568-y
  37. ACS Chem Neurosci. 2023 Apr 28.
    Chloroquine Protects Hypoxia/Ischemia-Induced Neonatal Brain Injury in Rats by Mitigating Blood-Brain Barrier Disruption.
    Mingchu Fang, Jian Liu, Zhiwei Zhang, Yueqi Li, Jianghu Zhu, Zhenlang Lin.
      Neonatal hypoxic-ischemic (H/I) brain damage (HIBD) is a devastating condition for which there are presently no effective therapeutic strategies against its severe neurological deficits in neonates and young children. Traditionally, H/I induces the compromise of the blood-brain barrier (BBB), which causes neuronal cell death, eventually resulting in brain secondary injury. In addition to neonatal HIBD, chloroquine (CQ) has been proved to exert a protective effect on BBB disruption in several brain injury models. The main purpose of this research was to study whether CQ protects the BBB from H/I insult and confers beneficial neuroprotection in the neonatal Rice-Vannucci rat model. Herein, we reported that CQ administration significantly reduced brain damage and improved behavioral dysplasia after H/I injury. Moreover, we demonstrated the protective effects of CQ on BBB integrity, evidenced by ameliorating brain edema and Evans blue extravasation, inhibiting the degeneration of the tight junction and adherens junction proteins, and improving pericyte survival in neonatal rats after HIBD. These findings indicated that CQ administration protected the BBB against H/I injury, thereby ameliorating brain damage and promoting neurofunctional recovery. Collectively, our data demonstrated that CQ played a crucial role in BBB integrity after neonatal H/I injury, which sheds light on the development of therapeutic agents to treat HIBD.
    Keywords:  blood−brain barrier; chloroquine; neonatal hypoxic-ischemic (H/I) brain damage; neurofunctional recovery
    DOI:  https://doi.org/10.1021/acschemneuro.2c00650
  38. Top Magn Reson Imaging. 2023 04 01. 32(2): 15-26
    Functional Magnetic Resonance Spectroscopy of Lactate in Alzheimer Disease: A Comprehensive Review of Alzheimer Disease Pathology and the Role of Lactate.
    Kiarash Shirbandi, Reza Rikhtegar, Mohammad Khalafi, Mohammad Mirza Aghazadeh Attari, Farzaneh Rahmani, Pouya Javanmardi, Sajjad Iraji, Zahra Babaei Aghdam, Amir Mohammad Rezaei Rashnoudi.
       ABSTRACT: Functional 1H magnetic resonance spectroscopy (fMRS) is a derivative of dynamic MRS imaging. This modality links physiologic metabolic responses with available activity and measures absolute or relative concentrations of various metabolites. According to clinical evidence, the mitochondrial glycolysis pathway is disrupted in many nervous system disorders, especially Alzheimer disease, resulting in the activation of anaerobic glycolysis and an increased rate of lactate production. Our study evaluates fMRS with J-editing as a cutting-edge technique to detect lactate in Alzheimer disease. In this modality, functional activation is highlighted by signal subtractions of lipids and macromolecules, which yields a much higher signal-to-noise ratio and enables better detection of trace levels of lactate compared with other modalities. However, until now, clinical evidence is not conclusive regarding the widespread use of this diagnostic method. The complex machinery of cellular and noncellular modulators in lactate metabolism has obscured the potential roles fMRS imaging can have in dementia diagnosis. Recent developments in MRI imaging such as the advent of 7 Tesla machines and new image reconstruction methods, coupled with a renewed interest in the molecular and cellular basis of Alzheimer disease, have reinvigorated the drive to establish new clinical options for the early detection of Alzheimer disease. Based on the latter, lactate has the potential to be investigated as a novel diagnostic and prognostic marker for Alzheimer disease.
    DOI:  https://doi.org/10.1097/RMR.0000000000000303
  39. Nutrients. 2023 Apr 12. pii: 1853. [Epub ahead of print]15(8):
    Sarcopenia and Cognitive Decline in Older Adults: Targeting the Muscle-Brain Axis.
    Beatrice Arosio, Riccardo Calvani, Evelyn Ferri, Hélio José Coelho-Junior, Angelica Carandina, Federica Campanelli, Veronica Ghiglieri, Emanuele Marzetti, Anna Picca.
      Declines in physical performance and cognition are commonly observed in older adults. The geroscience paradigm posits that a set of processes and pathways shared among age-associated conditions may also serve as a molecular explanation for the complex pathophysiology of physical frailty, sarcopenia, and cognitive decline. Mitochondrial dysfunction, inflammation, metabolic alterations, declines in cellular stemness, and altered intracellular signaling have been observed in muscle aging. Neurological factors have also been included among the determinants of sarcopenia. Neuromuscular junctions (NMJs) are synapses bridging nervous and skeletal muscle systems with a relevant role in age-related musculoskeletal derangement. Patterns of circulating metabolic and neurotrophic factors have been associated with physical frailty and sarcopenia. These factors are mostly related to disarrangements in protein-to-energy conversion as well as reduced calorie and protein intake to sustain muscle mass. A link between sarcopenia and cognitive decline in older adults has also been described with a possible role for muscle-derived mediators (i.e., myokines) in mediating muscle-brain crosstalk. Herein, we discuss the main molecular mechanisms and factors involved in the muscle-brain axis and their possible implication in cognitive decline in older adults. An overview of current behavioral strategies that allegedly act on the muscle-brain axis is also provided.
    Keywords:  brain-derived neurotrophic factor (BDNF); cognition; cytokine; inflammation; mitochondria; myokines; neuromuscular junction; neurotrophins; nutrition; physical performance
    DOI:  https://doi.org/10.3390/nu15081853
  40. Neurosci Lett. 2023 Apr 20. pii: S0304-3940(23)00223-9. [Epub ahead of print]807 137264
    Folate deprivation induced neuroinflammation impairs cognition.
    Afridi Shaikh, Hetal Roy.
      Nutritional status is associated with many neurocognitive diseases. Folate is one of the micronutrients, and its deficiency is associated with clinical outcomes of neurological diseases. Nevertheless, molecular mechanism behind the folate deficiency induced neurological disorders are not well-known. We have hypothesized that folate-deficiency is a cardinal determinant responsible for manifestation of cognitive impairment through inflammation mediated neurodegenerative pathologies. Objective of the current study was to assess whether folate deficiency is associated with cognitive dysfunction or is merely an epiphenomenon and to identify the underlying mechanisms. We developed folate insufficient zebrafish model through intra-peritoneal treatment of methotrexate. T-maze test was carried to assess the spatial learning and memory of the fish. Higher latency of the folate-deprived zebrafishes in the T-maze test is a reflection of altered cognition. This result is supported by declined levels of dopamine and serotonin, neurotransmitters linked with learning and memory. Elevated IL-6 and CRP in peripheral blood, along with increased expression of NF-ĸB in brain indicates manifestation of neuroinflammation. Indeed, together with upregulation of maptb gene it can be implied that folate deficiency acts as a risk factor for neurodegeneration in the form of tauopathies. Furthermore, diminished localisation of synaptopodin, a protein linked to neural plasticity, suggests that neuroinflammation caused by folate deprivation hampers the plasticity of brain. Histological analysis of brain revealed the development of histopathological features including spongiform degeneration and neuronal loss in folate deprived condition. We thus conclude that folate deficiency results in NF-ĸB activation, which through multiple processes mediated by neuroinflammation could lead to cognitive decline.
    Keywords:  Cognition; Folate deficiency; NF-ĸB; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neulet.2023.137264
  41. Nat Aging. 2022 Nov;2(11): 991-999
    Increased white matter glycolysis in humans with cerebral small vessel disease.
    Matthew R Brier, Tyler Blazey, Marcus E Raichle, John C Morris, Tammie L S Benzinger, Andrei G Vlassenko, Abraham Z Snyder, Manu S Goyal.
      White matter lesions in cerebral small vessel disease are related to ischemic injury and increase the risk of stroke and cognitive decline. Pathological changes due to cerebral small vessel disease are increasingly recognized outside of discrete lesions, but the metabolic alterations in nonlesional tissue has not been described. Aerobic glycolysis is critical to white matter myelin homeostasis and repair. In this study, we examined cerebral metabolism of glucose and oxygen as well as blood flow in individuals with and without cerebral small vessel disease using multitracer positron emission tomography. We show that glycolysis is relatively elevated in nonlesional white matter in individuals with small vessel disease relative to healthy, age-matched controls. On the other hand, in young healthy individuals, glycolysis is relatively low in areas of white matter susceptible to lesion formation. These results suggest that increased white matter glycolysis is a marker of pathology associated with small vessel disease.
    DOI:  https://doi.org/10.1038/s43587-022-00303-y
  42. Neuropharmacology. 2023 Apr 24. pii: S0028-3908(23)00152-1. [Epub ahead of print] 109562
    Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins.
    J R Swann, R Diaz Heijtz, J Mayneris-Perxachs, A Arora, J Isaksson, S Bölte, K Tammimies.
      Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins' models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder.
    Keywords:  ADHD; Attention deficit hyperactivity disorder; Gut microbiota; Hippurate; Metabolomics; Microbial metabolites; Twin study
    DOI:  https://doi.org/10.1016/j.neuropharm.2023.109562
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