bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024‒02‒25
47 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Modulation of Pyruvate Export and Extracellular Pyruvate Concentration in Primary Astrocyte Cultures.
  2. Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease.
  3. Metabolomic Investigation of Brain and Liver in Rats Fed Docosahexaenoic Acid in Regio- and Enantiopure Triacylglycerols.
  4. Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.
  5. High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage.
  6. Mitochondria in Alzheimer's Disease Pathogenesis.
  7. Lipid imaging of Alzheimer's disease pathology.
  8. Lipid Droplets Accumulation in the Brain of HIV Transgenic Rat: Implication in the Accelerated Aging of HIV Infected Individuals.
  9. The role of ApoE in fatty acid transport from neurons to astrocytes under ischemia/hypoxia conditions.
  10. Lipid organization and turnover in the plasma membrane of human differentiating neural progenitor cells revealed by time-of-flight secondary ion mass spectrometry imaging.
  11. Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial β-oxidation disorders.
  12. Effects of Chronic Hypertension on the Energy Metabolism of Cerebral Cortex Mitochondria in Normotensive and in Spontaneously Hypertensive Rats During Aging.
  13. Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases.
  14. Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.
  15. Advancements in the study of synaptic plasticity and mitochondrial autophagy relationship.
  16. Insertases scramble lipids: Molecular simulations of MTCH2.
  17. Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.
  18. New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment.
  19. Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity.
  20. Distinct changes in brain metabolism in patients with dementia and hearing loss.
  21. Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
  22. Role of Succinylation Modification in Central Nervous System Diseases.
  23. Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aβ plaques in mouse and human brains.
  24. Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
  25. Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.
  26. Unveiling the Role of iPLA2β in Neurodegeneration: From Molecular Mechanisms to Advanced Therapies.
  27. Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats.
  28. Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.
  29. Methodological Pitfalls of Investigating Lipid Rafts in the Brain: What Are We Still Missing?
  30. Non-Targeted Metabolomics Investigation of a Sub-Chronic Variable Stress Model Unveils Sex-Dependent Metabolic Differences Induced by Stress.
  31. A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities.
  32. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
  33. IL-10 constrains sphingolipid metabolism to limit inflammation.
  34. Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline.
  35. A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice.
  36. Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder.
  37. Tissue Microarray Lipidomic Imaging Mass Spectrometry Method: Application to the Study of Alcohol-Related White Matter Neurodegeneration.
  38. Novel Approaches to Studying SLC13A5 Disease.
  39. Blood-Derived Metabolic Signatures as Biomarkers of Injury Severity in Traumatic Brain Injury: A Pilot Study.
  40. Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie the Allan-Herndon-Dudley syndrome.
  41. APOE ε4 allele status modulates the spatial patterns of progressive atrophy in the temporal lobes after mild traumatic brain injury.
  42. Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?
  43. APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure.
  44. Nacc1 mutation in mice models rare neurodevelopmental disorder with underlying synaptic dysfunction.
  45. Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA).
  46. Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.
  47. Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
  1. Neurochem Res. 2024 Feb 20.
    Modulation of Pyruvate Export and Extracellular Pyruvate Concentration in Primary Astrocyte Cultures.
    Nadine Denker, Ralf Dringen.
      Astrocyte-derived pyruvate is considered to have neuroprotective functions. In order to investigate the processes that are involved in astrocytic pyruvate release, we used primary rat astrocyte cultures as model system. Depending on the incubation conditions and medium composition, astrocyte cultures established extracellular steady state pyruvate concentrations in the range between 150 µM and 300 µM. During incubations for up to 2 weeks in DMEM culture medium, the extracellular pyruvate concentration remained almost constant for days, while the extracellular lactate concentration increased continuously during the incubation into the millimolar concentration range as long as glucose was present. In an amino acid-free incubation buffer, glucose-fed astrocytes released pyruvate with an initial rate of around 60 nmol/(h × mg) and after around 5 h an almost constant extracellular pyruvate concentration was established that was maintained for several hours. Extracellular pyruvate accumulation was also observed, if glucose had been replaced by mannose, fructose, lactate or alanine. Glucose-fed astrocyte cultures established similar extracellular steady state concentrations of pyruvate by releasing pyruvate into pyruvate-free media or by consuming excess of extracellular pyruvate. Inhibition of the monocarboxylate transporter MCT1 by AR-C155858 lowered extracellular pyruvate accumulation, while inhibition of mitochondrial pyruvate uptake by UK5099 increased the extracellular pyruvate concentration. Finally, the presence of the uncoupler BAM15 or of the respiratory chain inhibitor antimycin A almost completely abolished extracellular pyruvate accumulation. The data presented demonstrate that cultured astrocytes establish a transient extracellular steady state concentration of pyruvate which is strongly affected by modulation of the mitochondrial pyruvate metabolism.
    Keywords:  Astrocytes; MCT1; Metabolism; Mitochondria; Pyruvate; Transport
    DOI:  https://doi.org/10.1007/s11064-024-04120-0
  2. Philos Trans R Soc Lond B Biol Sci. 2024 Apr 08. 379(1899): 20220388
    Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease.
    Mariagiovanna Malara, Matthias Prestel, Sabina Tahirovic.
      Niemann-Pick type C (NPC) disease is a rare progressive lysosomal lipid storage disorder that manifests with a heterogeneous spectrum of clinical syndromes, including visceral, neurological and psychiatric symptoms. This monogenetic autosomal recessive disease is largely caused by mutations in the NPC1 gene, which controls intracellular lipid homeostasis. Vesicle-mediated endo-lysosomal lipid trafficking and non-vesicular lipid exchange via inter-organelle membrane contact sites are both regulated by the NPC1 protein. Loss of NPC1 function therefore triggers intracellular accumulation of diverse lipid species, including cholesterol, glycosphingolipids, sphingomyelin and sphingosine. The NPC1-mediated dysfunction of lipid transport has severe consequences for all brain cells, leading to neurodegeneration. Besides the cell-autonomous contribution of neuronal NPC1, aberrant NPC1 signalling in other brain cells is critical for the pathology. We discuss here the importance of endo-lysosomal dysfunction and a tight crosstalk between neurons, oligodendrocytes, astrocytes and microglia in NPC pathology. We strongly believe that a cell-specific rescue may not be sufficient to counteract the severity of the NPC pathology, but targeting common mechanisms, such as endo-lysosomal and lipid trafficking dysfunction, may ameliorate NPC pathology. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.
    Keywords:  NPC1; cholesterol; endo-lysosomal trafficking; glia; neurons
    DOI:  https://doi.org/10.1098/rstb.2022.0388
  3. Mol Nutr Food Res. 2024 Feb 23. e2300341
    Metabolomic Investigation of Brain and Liver in Rats Fed Docosahexaenoic Acid in Regio- and Enantiopure Triacylglycerols.
    Raghunath Pariyani, Yumei Zhang, Gudmundur G Haraldsson, Kang Chen, Kaisa M Linderborg, Baoru Yang.
      SCOPE: N-3 polyunsaturated fatty acids (n-3 PUFAs) play important roles in cognitive functions. However, there is a lack of knowledge on the metabolic impact of regio- and stereo-specific positioning of n-3 PUFAs in dietary triacylglycerols.METHODS AND RESULTS: Rats in a state of mild n-3 PUFA deficiency are fed daily with 360 mg triacylglycerols containing DHA (docosahexaenoic acid) at sn (stereospecific numbering)-1, 2, or 3 positions and 18:0 at remaining positions, or an equal amount of tristearin for 5 days. Groups fed with n-3 deficient diet and normal n-3 adequate diet are included as controls. The metabolic profiles of the brain and liver are studied using NMR (nuclear magnetic resonance)-based metabolomics. Several metabolites of significance in membrane integrity and neurotransmission, and glutamate, in particular, are significantly lower in the brain of the groups fed with sn-1 and sn-3 DHA compared to the sn-2 DHA group. Further, the tristearin and DHA groups show a lower lactate level compared to the groups fed on normal or n-3 deficient diet, suggesting a prominent role of C18:0 in regulating energy metabolism.
    CONCLUSION: This study sheds light on the impact of stereospecific positioning of DHA in triacylglycerols and the role of dietary stearic acid on metabolism in the brain and liver.
    Keywords:  Docosahexaenoic acid; brain and liver; metabolomics; stearic acid; structured lipids
    DOI:  https://doi.org/10.1002/mnfr.202300341
  4. Nutrients. 2024 Feb 17. pii: 553. [Epub ahead of print]16(4):
    Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.
    Shruthi H Iyer, Mary Y Yeh, Lauren Netzel, Molly G Lindsey, McKenzie Wallace, Kristina A Simeone, Timothy A Simeone.
      Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.
    Keywords:  MCT; PUFA; affective disorder; autism; calorie restriction; cognitive impairment; ketogenic diet; ketone; low glycemic index; triheptanoin
    DOI:  https://doi.org/10.3390/nu16040553
  5. Antioxidants (Basel). 2024 Jan 26. pii: 161. [Epub ahead of print]13(2):
    High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage.
    Rebeca Berdún, Èlia Obis, Natàlia Mota-Martorell, Anna Bassols, Daniel Valent, José C E Serrano, Meritxell Martín-Garí, María Rodríguez-Palmero, José Antonio Moreno-Muñoz, Joan Tibau, Raquel Quintanilla, Reinald Pamplona, Manuel Portero-Otín, Mariona Jové.
      Obesity is a risk factor for highly prevalent age-related neurodegenerative diseases, the pathogenesis of whichinvolves mitochondrial dysfunction and protein oxidative damage. Lipoxidation, driven by high levels of peroxidizable unsaturated fatty acids and low antioxidant protection of the brain, stands out as a significant risk factor. To gain information on the relationship between obesity and brain molecular damage, in a porcine model of obesity we evaluated (1) the level of mitochondrial respiratory chain complexes, as the main source of free radical generation, by Western blot; (2) the fatty acid profile by gas chromatography; and (3) the oxidative modification of proteins by mass spectrometry. The results demonstrate a selectively higher amount of the lipoxidation-derived biomarker malondialdehyde-lysine (MDAL) (34% increase) in the frontal cortex, and positive correlations between MDAL and LDL levels and body weight. No changes were observed in brain fatty acid profile by the high-fat diet, and the increased lipid peroxidative modification was associated with increased levels of mitochondrial complex I (NDUFS3 and NDUFA9 subunits) and complex II (flavoprotein). Interestingly, introducing n3 fatty acids and a probiotic in the high-fat diet prevented the observed changes, suggesting that dietary components can modulate protein oxidative modification at the cerebral level and opening new possibilities in neurodegenerative diseases' prevention.
    Keywords:  age-related neurodegenerative diseases; lipoxidation; mitochondrial complexes; n3 PUFA; obesity; probiotics
    DOI:  https://doi.org/10.3390/antiox13020161
  6. Life (Basel). 2024 Jan 30. pii: 196. [Epub ahead of print]14(2):
    Mitochondria in Alzheimer's Disease Pathogenesis.
    Allison B Reiss, Shelly Gulkarov, Benna Jacob, Ankita Srivastava, Aaron Pinkhasov, Irving H Gomolin, Mark M Stecker, Thomas Wisniewski, Joshua De Leon.
      Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.
    Keywords:  Alzheimer’s disease; electron transport chain; inflammation; mitochondria
    DOI:  https://doi.org/10.3390/life14020196
  7. J Neurochem. 2024 Feb 19.
    Lipid imaging of Alzheimer's disease pathology.
    Jörg Hanrieder.
      Alzheimer's disease (AD) affects one in eight individuals over 65 and poses an immense societal challenge. AD pathology is characterized by the formation of beta-amyloid plaques and Tau tangles in the brain. While some disease-modifying treatments targeting beta-amyloid are emerging, the exact chain of events underlying the pathogenesis of this disease remains unclear. Brain lipids have long been implicated in AD pathology, though their role in AD pathogenesis remains not fully resolved. Significant advancements in mass spectrometry imaging (MSI) allow to detail spatial lipid regulations in biological tissues at the low um scale. In this issue, Huang et al. resolve spatial lipid patterns in human AD brain and genetic mouse models using desorption electrospray ionization (DESI)-based MSI integrated with other spatial techniques such as imaging mass cytometry of correlative protein signatures. Those spatial multiomics experiments identify plaque-associated lipid regulations that are dependent on progressing plaque pathology in both mouse models and the human brain. Of those lipid species, particularly pro-inflammatory lysophospholipids have been implicated in AD pathology through their interaction with both aggregating Aβ and microglial activation through lipid sensing surface receptors. Together, this study provides further insight into how brain lipid homeostasis is linked to progressing AD pathology, and thereby highlights the potential of MSI-based spatial lipidomics as an emerging spatial biology technology for biomedical research.
    Keywords:  Alzheimerʼs disease; beta-amyloid plaque pathology; desorption electrospray ionization; lipidomics; mass spectrometry imaging; spatial biology
    DOI:  https://doi.org/10.1111/jnc.16079
  8. Aging Dis. 2024 Feb 15.
    Lipid Droplets Accumulation in the Brain of HIV Transgenic Rat: Implication in the Accelerated Aging of HIV Infected Individuals.
    Ming-Lei Guo, Yan Cheng, Damian Martinez Pineda, Rachael E Dempsey, Lifang Yang.
      Abnormal microglial activation has been suggested as "driven force" promoting brain aging. Lipid droplets accumulating microglia (LDAM), identified as a novel inflammatory phenotype, elevate neuroinflammation and exaggerate neuronal injuries in aging and multiple neurodegenerative diseases. Since chronic HIV (human immunodeficiency virus) (+) individuals show an accelerated brain aging and higher incidence of neurological symptoms compared to age-matched HIV (-) population, we hypothesize that LDAM are also involved in such phenomenon. For validating the hypothesis, we employed HIV transgenic (HIV-Tg) and wilt type (WT) rats to check lipid droplets (LDs) accumulation in the brains at mature (6 months) and middle age (12 months). Our results showed that HIV-Tg rats possess higher levels of LDs formation in the hippocampus (HP) and prefrontal cortex (PFc) than controls at middle age. Increased LDs are mainly presented in microglia in the HP but largely co-localized with astrocytes in the PFc. Interestingly, increased LDs are associated with upregulation on Iba1 but not with GFAP levels. HIV-Tg rats reveal an accelerated LDs accumulation during normal aging. Purified microglia from HIV-Tg rats (12 month) show higher expression of neuroimmune signaling than microglia from controls. HIV-Tg rats showed dysregulation on cholesterol synthesis in the brain HP as well as deficiency on locomotion coordination compared to controls. Overall, our results demonstrate substantial LDs accumulation in the brains of HIV-Tg rats which is associated with abnormal microglial activation and accelerated decline on locomotion coordination during aging. Dysregulation on lipid metabolism might underlie accelerated brain aging in the context of chronic HIV infection.
    DOI:  https://doi.org/10.14336/AD.2024.0125
  9. Mol Biol Rep. 2024 Feb 23. 51(1): 320
    The role of ApoE in fatty acid transport from neurons to astrocytes under ischemia/hypoxia conditions.
    Hongyan Chen, Shaozhi Zhao, Qiang Jian, Yinfang Yan, Simin Wang, Xinwen Zhang, Yuqiang Ji.
      BACKGROUND: The aim of this study was to investigate whether ischemia/hypoxia conditions induce fatty acid transport from neurons to astrocytes and whether this mechanism is affected by ApoE isoforms.METHODS AND RESULTS: A neonatal rat model of hypoxic-ischemic brain damage was established. Excessive accumulation of lipid droplets and upregulation of ApoE expression occurred in the hippocampus and cerebral cortex after hypoxia-ischemia, which implied the occurrence of abnormal fatty acid metabolism. Lipid peroxidation was induced in an oxygen-glucose deprivation and reperfusion (OGDR) model of ApoE-/- primary neurons. The number of BODIPY 558/568 C12-positive particles (fatty acid markers) transferred from neurons to astrocytes was significantly increased with the addition of human recombinant ApoE compared with that in the OGDR group, which significantly increased the efficiency of fatty acid transport from neurons to astrocytes and neuronal viability. However, ApoE4 was found to be associated with lower efficiency in fatty acid transport and less protective effects in OGDR-induced neuronal cell death than both ApoE2 and ApoE3. COG133, an ApoE-mimetic peptide, partially compensated for the adverse effects of ApoE4. FABP5 and SOD1 gene and protein expression levels were upregulated in astrocytes treated with BODIPY 558/568 C12 particles.
    CONCLUSIONS: In conclusion, ApoE plays an important role in mediating the transport of fatty acids from neurons to astrocytes under ischemia/hypoxia conditions, and this transport mechanism is ApoE isoform dependent. ApoE4 has a low transfer efficiency and may be a potential target for the clinical treatment of neonatal hypoxic-ischemic encephalopathy.
    Keywords:  ApoE; Astrocyte; Fatty acid transport; Hypoxic-ischemic brain damage; Lipid droplet; Neuron
    DOI:  https://doi.org/10.1007/s11033-023-08921-4
  10. Talanta. 2024 Feb 14. pii: S0039-9140(24)00141-3. [Epub ahead of print]272 125762
    Lipid organization and turnover in the plasma membrane of human differentiating neural progenitor cells revealed by time-of-flight secondary ion mass spectrometry imaging.
    Emmanuel Berlin, Alicia A Lork, Martin Bornecrantz, Carl Ernst, Nhu T N Phan.
      Membrane lipids have been known to influence multiple signalling and cellular processes. Dysregulation of lipids at the neuronal membrane is connected to a significant alteration of the brain function and morphology, leading to brain diseases and neurodegeneration. Understanding the lipid composition and turnover of neuronal membrane will provide a significant insight into the molecular events underlying the regulatory effects of these biomolecules in a neuronal system. In this study, we aimed to characterize the composition and turnover of the plasma membrane lipids in human neural progenitor cells (NPCs) at an early differentiation stage into midbrain neurons using ToF-SIMS imaging. Lipid composition of the native plasma membrane was explored, followed by an examination of the lipid turnover using different isotopically labelled lipid precursors, including 13C-choline, 13C-lauric acid, 15N-linoleic, and 13C-stearic. Our results showed that differentiating NPCs contain a high abundance of ceramides, glycerophosphoserines, neutral glycosphingolipids, diradylglycerols, and glycerophosphocholines at the plasma membrane. In addition, different precursors were found to incorporate into different membrane lipids which are specific for the short- or long-carbon chains, and the unsaturation or saturation stage of the precursors. The lipid structure of neuronal membrane reflects the differentiation status of NPCs, and it can be altered significantly using a particular lipid precursor. Our study illustrates a potential of ToF-SIMS imaging to study native plasma membrane lipids and elucidate complex cellular processes by providing molecular -rich information at a single cell level.
    Keywords:  Lipids; Mass spectrometry imaging; Neural stem cells; Plasma membrane; ToF-SIMS; Turnover
    DOI:  https://doi.org/10.1016/j.talanta.2024.125762
  11. FASEB J. 2024 Feb 29. 38(4): e23478
    Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial β-oxidation disorders.
    Marit Schwantje, Signe Mosegaard, Suzan J G Knottnerus, Jan Bert van Klinken, Ronald J Wanders, Henk van Lenthe, Jill Hermans, Lodewijk IJlst, Simone W Denis, Yorrick R J Jaspers, Sabine A Fuchs, Riekelt H Houtkooper, Sacha Ferdinandusse, Frédéric M Vaz.
      Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid β-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.
    Keywords:  biomarkers; inborn errors; lipid metabolism; lipid metabolism disorders; lipidomics; lipolysis and fatty acids; lysophospholipids; mitochondria
    DOI:  https://doi.org/10.1096/fj.202302163R
  12. Neuromolecular Med. 2024 Feb 23. 26(1): 2
    Effects of Chronic Hypertension on the Energy Metabolism of Cerebral Cortex Mitochondria in Normotensive and in Spontaneously Hypertensive Rats During Aging.
    Roberto Federico Villa, Federica Ferrari, Antonella Gorini.
      In this study the subcellular modifications undergone by cerebral cortex mitochondrial metabolism in chronic hypertension during aging were evaluated. The catalytic properties of regulatory energy-linked enzymes of Tricarboxylic Acid Cycle (TCA), Electron Transport Chain (ETC) and glutamate metabolism were assayed on non-synaptic mitochondria (FM, located in post-synaptic compartment) and on intra-synaptic mitochondria of pre-synaptic compartment, furtherly divided in "light" (LM) and "heavy" (HM) mitochondria, purified form cerebral cortex of normotensive Wistar Kyoto Rats (WKY) versus Spontaneously Hypertensive Rats (SHR) at 6, 12 and 18 months. During physiological aging, the metabolic machinery was differently expressed in pre- and post-synaptic compartments: LM and above all HM were more affected by aging, displaying lower ETC activities. In SHR at 6 months, FM and LM showed an uncoupling between TCA and ETC, likely as initial adaptive response to hypertension. During pathological aging, HM were particularly affected at 12 months in SHR, as if the adaptive modifications in FM and LM at 6 months granted a mitochondrial functional balance, while at 18 months all the neuronal mitochondria displayed decreased metabolic fluxes versus WKY. This study describes the effects of chronic hypertension on cerebral mitochondrial energy metabolism during aging through functional proteomics of enzymes at subcellular levels, i.e. in neuronal soma and synapses. In addition, this represents the starting point to envisage an experimental physiopathological model which could be useful also for pharmacological studies, to assess drug actions during the development of age-related pathologies that could coexist and/or are provoked by chronic hypertension.
    Keywords:  Aging; Brain energy metabolism; Intra-synaptic mitochondria; Functional proteomics; Non-synaptic mitochondria; Spontaneously Hypertensive Rats
    DOI:  https://doi.org/10.1007/s12017-023-08772-z
  13. Biomedicines. 2024 Feb 18. pii: 457. [Epub ahead of print]12(2):
    Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases.
    Shabnam Nohesara, Hamid Mostafavi Abdolmaleky, Sam Thiagalingam.
      Multiple lines of evidence have shown that lactate-mediated pH alterations in the brains of patients with neuropsychiatric diseases such as schizophrenia (SCZ), Alzheimer's disease (AD) and autism may be attributed to mitochondrial dysfunction and changes in energy metabolism. While neuronal activity is associated with reduction in brain pH, astrocytes are responsible for rebalancing the pH to maintain the equilibrium. As lactate level is the main determinant of brain pH, neuronal activities are impacted by pH changes due to the binding of protons (H+) to various types of proteins, altering their structure and function in the neuronal and non-neuronal cells of the brain. Lactate and pH could affect diverse types of epigenetic modifications, including histone lactylation, which is linked to histone acetylation and DNA methylation. In this review, we discuss the importance of pH homeostasis in normal brain function, the role of lactate as an essential epigenetic regulatory molecule and its contributions to brain pH abnormalities in neuropsychiatric diseases, and shed light on lactate-based and pH-modulating therapies in neuropsychiatric diseases by targeting epigenetic modifications. In conclusion, we attempt to highlight the potentials and challenges of translating lactate-pH-modulating therapies to clinics for the treatment of neuropsychiatric diseases.
    Keywords:  DNA methylation; histone acetylation; lactate; lactylation; microbiome; neuropsychiatric diseases; pH
    DOI:  https://doi.org/10.3390/biomedicines12020457
  14. Glia. 2024 Feb 19.
    Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration.
    Ernesto Miquel, Rosalía Villarino, Laura Martínez-Palma, Adriana Cassina, Patricia Cassina.
      Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.
    Keywords:  ALS; PDK2; astrocytes; mitochondria
    DOI:  https://doi.org/10.1002/glia.24516
  15. J Neurosci Res. 2024 Feb;102(2): e25309
    Advancements in the study of synaptic plasticity and mitochondrial autophagy relationship.
    Yousong Zhu, Qinlong Hui, Zheng Zhang, Hao Fu, Yali Qin, Qiong Zhao, Qinqing Li, Junlong Zhang, Lei Guo, Wenbin He, Cheng Han.
      Synapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through the release and reception of neurotransmitters. Synaptic plasticity, the ability of synapses to undergo structural and functional changes, is influenced by proteins such as growth-associated proteins, synaptic vesicle proteins, postsynaptic density proteins, and neurotrophic growth factors. Furthermore, maintaining synaptic plasticity consumes more than half of the brain's energy, with a significant portion of this energy originating from ATP generated through mitochondrial energy metabolism. Consequently, the quantity, distribution, transport, and function of mitochondria impact the stability of brain energy metabolism, thereby participating in the regulation of fundamental processes in synaptic plasticity, including neuronal differentiation, neurite outgrowth, synapse formation, and neurotransmitter release. This article provides a comprehensive overview of the proteins associated with presynaptic plasticity, postsynaptic plasticity, and common factors between the two, as well as the relationship between mitochondrial energy metabolism and synaptic plasticity.
    Keywords:  interrelationships; mitochondria; mitochondrial autophagy; related proteins; synaptic plasticity
    DOI:  https://doi.org/10.1002/jnr.25309
  16. Structure. 2024 Feb 17. pii: S0969-2126(24)00036-4. [Epub ahead of print]
    Insertases scramble lipids: Molecular simulations of MTCH2.
    Ladislav Bartoš, Anant K Menon, Robert Vácha.
      Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of voltage-dependent anion channel (VDAC), a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases.
    Keywords:  flip-flop rate; free energy barrier; hydrophilic groove; insertase; membrane defect; molecular dynamics; scramblase
    DOI:  https://doi.org/10.1016/j.str.2024.01.012
  17. Aging Dis. 2024 Feb 01.
    Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.
    Shao-Hua Yang, Yuanhong Sun, Raymond Berry, Gourav Roy Choudhury, Ali Winters, Kiran Chaudhari, Ran Liu.
      Glutamate-mediated excitotoxicity has been extensively explored as a therapeutic target for the development of potential treatments of neurological disorders including stroke. However, the effect of glutamate on astrocytes under pathological conditions has been less studied. Using primary astrocyte culture, we determined the effect of glutamate on astrocytes against ischemic insult. Glutamate provided a cytoprotective effect and acted as an alternative substrate for ATP production in primary astrocytes against oxygen glucose deprivation reoxygenation insult, which was blocked by glutamate uptake inhibition. The cytoprotective effect of glutamate appears to be astrocyte-specific, as glutamate dose-dependently induces cytotoxic action in murine hippocampal HT-22 cell line. Interestingly, the cytoprotective effect of glutamate against glucose deprivation was short-last, as no protection was observed after 3-day glucose deprivation. We determined the metabolic phenotype of primary astrocyte cultured in glucose or glutamate. Primary astrocytes cultured in glutamate displayed a different metabolic phenotype when compared to those cultured in glucose, evidenced by higher basal and maximal oxygen consumption rate (OCR), higher ATP production and proton leak-coupled OCR, as well as lower glycolysis. Furthermore, glutamate exposure resulted in astrocyte activation, evidenced by an increase in astrocyte size and GFAP expression. Our study demonstrated that glutamate exerts a dual effect on astrocytes under ischemic condition. Glutamate provides an alternative substrate for energy metabolism in the absence of glucose, thereby protecting astrocytes against ischemic insults. On the other hand, glutamate exposure induces astrogliosis. Modulation of glutamate uptake and metabolism in astrocytes may provide novel targets for alleviating ischemic injury and improving function recovery after ischemic stroke.
    DOI:  https://doi.org/10.14336/AD.2023.0726
  18. Redox Biol. 2024 Feb 05. pii: S2213-2317(24)00050-8. [Epub ahead of print]71 103074
    New insights on neurodegeneration triggered by iron accumulation: Intersections with neutral lipid metabolism, ferroptosis, and motor impairment.
    Athina Maniscalchi, Oriana N Benzi Juncos, Melisa A Conde, Melania I Funk, María E Fermento, María M Facchinetti, Alejandro C Curino, Romina M Uranga, Natalia P Alza, Gabriela A Salvador.
      Brain iron accumulation constitutes a pathognomonic indicator in several neurodegenerative disorders. Metal accumulation associated with dopaminergic neuronal death has been documented in Parkinson's disease. Through the use of in vivo and in vitro models, we demonstrated that lipid dysregulation manifests as a neuronal and glial response during iron overload. In this study, we show that cholesterol content and triacylglycerol (TAG) hydrolysis were strongly elevated in mice midbrain. Lipid cacostasis was concomitant with the loss of dopaminergic neurons, astrogliosis and elevated expression of α-synuclein. Exacerbated lipid peroxidation and markers of ferroptosis were evident in the midbrain from mice challenged with iron overload. An imbalance in the activity of lipolytic and acylation enzymes was identified, favoring neutral lipid hydrolysis, and consequently reducing TAG and cholesteryl ester levels. Notably, these observed alterations were accompanied by motor impairment in iron-treated mice. In addition, neuronal and glial cultures along with their secretomes were used to gain further insight into the mechanism underlying TAG hydrolysis and cholesterol accumulation as cellular responses to iron accumulation. We demonstrated that TAG hydrolysis in neurons is triggered by astrocyte secretomes. Moreover, we found that the ferroptosis inhibitor, ferrostatin-1, effectively prevents cholesterol accumulation both in neurons and astrocytes. Taken together, these results indicate that lipid disturbances occur in iron-overloaded mice as a consequence of iron-induced oxidative stress and depend on neuron-glia crosstalk. Our findings suggest that developing therapies aimed at restoring lipid homeostasis may lead to specific treatment for neurodegeneration associated with ferroptosis and brain iron accumulation.
    Keywords:  Cholesterol accumulation; Ferroptosis; Iron accumulation; Lipid cacostasis; Midbrain neurodegeneration; Movement disorders
    DOI:  https://doi.org/10.1016/j.redox.2024.103074
  19. Int J Mol Sci. 2024 Feb 14. pii: 2276. [Epub ahead of print]25(4):
    Pathological Interplay between Inflammation and Mitochondria Aggravates Glutamate Toxicity.
    Annette Vaglio-Garro, Andrey V Kozlov, Yuliya D Smirnova, Adelheid Weidinger.
      Mitochondrial dysfunction and glutamate toxicity are associated with neural disorders, including brain trauma. A review of the literature suggests that toxic and transmission actions of neuronal glutamate are spatially and functionally separated. The transmission pathway utilizes synaptic GluN2A receptors, rapidly released pool of glutamate, evoked release of glutamate mediated by Synaptotagmin 1 and the amount of extracellular glutamate regulated by astrocytes. The toxic pathway utilizes extrasynaptic GluN2B receptors and a cytoplasmic pool of glutamate, which results from the spontaneous release of glutamate mediated by Synaptotagmin 7 and the neuronal 2-oxoglutarate dehydrogenase complex (OGDHC), a tricarboxylic acid (TCA) cycle enzyme. Additionally, the inhibition of OGDHC observed upon neuro-inflammation is due to an excessive release of reactive oxygen/nitrogen species by immune cells. The loss of OGDHC inhibits uptake of glutamate by mitochondria, thus facilitating its extracellular accumulation and stimulating toxic glutamate pathway without affecting transmission. High levels of extracellular glutamate lead to dysregulation of intracellular redox homeostasis and cause ferroptosis, excitotoxicity, and mitochondrial dysfunction. The latter affects the transmission pathway demanding high-energy supply and leading to cell death. Mitochondria aggravate glutamate toxicity due to impairments in the TCA cycle and become a victim of glutamate toxicity, which disrupts oxidative phosphorylation. Thus, therapies targeting the TCA cycle in neurological disorders may be more efficient than attempting to preserve mitochondrial oxidative phosphorylation.
    Keywords:  TCA cycle; ferroptosis; glutamate; mitochondrial dysfunction; neuronal death
    DOI:  https://doi.org/10.3390/ijms25042276
  20. Brain Behav. 2024 Jan;14(1): e3374
    Distinct changes in brain metabolism in patients with dementia and hearing loss.
    Ji Hyuk Han, Sangwon Lee, Seong Hoon Bae, Mijin Yun, Byung Seok Ye, Jinsei Jung.
      INTRODUCTION: Previous studies have reported that hearing loss (HL) is associated with dementia, although the mechanistic underpinnings remain elusive. This study aimed to evaluate the changes in brain metabolism in patients with HL and different types of dementia.METHODS: Patients with cognitive impairment (CI) and HL treated at the university-based memory clinic from May 2016 to October 2021 were included. In total, 108 patients with CI and HL prospectively underwent audiometry, neuropsychological test, magnetic resonance imaging, and 18 F-fluorodeoxyglucose positron emission tomography. Twenty-seven individuals without cognitive impairment and hearing loss were enrolled as a control group. Multivariable regression was performed to evaluate brain regions correlated with each pathology type after adjusting for confounding factors.
    RESULTS: Multivariable regression analyses revealed that Alzheimer's disease-related CI (ADCI) was associated with hypometabolic changes in the right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and bilateral medial temporal lobe. Lewy body disease-related CI (LBDCI) and vascular CI were associated with hypermetabolic and hypometabolic changes in the ascending auditory pathway, respectively. In the pure ADCI group, the degree of HL was positively associated with abnormal increase of brain metabolism in the right MTG, whereas it was negatively associated with decreased brain metabolism in the right STG in the pure LBDCI group.
    CONCLUSION: Each dementia type is associated with distinct changes in brain metabolism in patients with HL.
    Keywords:  FDG-PET; brain metabolism; cognitive impairment; dementia; hearing loss
    DOI:  https://doi.org/10.1002/brb3.3374
  21. Mol Neurobiol. 2024 Feb 17.
    Mitochondrial Transportation, Transplantation, and Subsequent Immune Response in Alzheimer's Disease: An Update.
    Pegah Javadpour, Fatemeh Abbaszadeh, Abolhassan Ahmadiani, Mohsen Rezaei, Rasoul Ghasemi.
      Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by memory impairment and a progressive decline in cognitive function. Mitochondrial dysfunction has been identified as an important contributor to the development of AD, leading to oxidative stress and energy deficits within the brain. While current treatments for AD aim to alleviate symptoms, there is an urgent need to target the underlying mechanisms. The emerging field of mitotherapy, which involves the transplantation of healthy mitochondria into damaged cells, has gained substantial attention and has shown promising results. However, research in the context of AD remains limited, necessitating further investigations. In this review, we summarize the mitochondrial pathways that contribute to the progression of AD. Additionally, we discuss mitochondrial transfer among brain cells and mitotherapy, with a focus on different administration routes, various sources of mitochondria, and potential modifications to enhance transplantation efficacy. Finally, we review the limited available evidence regarding the immune system's response to mitochondrial transplantation in damaged brain regions.
    Keywords:  Alzheimer’s disease; Energy metabolism; Mitochondria; Mitochondrial transplantation; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-024-04009-7
  22. Ageing Res Rev. 2024 Feb 20. pii: S1568-1637(24)00060-6. [Epub ahead of print] 102242
    Role of Succinylation Modification in Central Nervous System Diseases.
    Chao Wang, Weigang Cui, Bing Yu, Han Zhou, Zhenwen Cui, Pin Guo, Tao Yu, Yugong Feng.
      Diseases of the central nervous system (CNS), including stroke, brain tumors, and neurodegenerative diseases, have a serious impact on human health worldwide, especially in elderly patients. The brain, which is one of the body's most metabolically dynamic organs, lacks fuel stores and therefore requires a continuous supply of energy substrates. Metabolic abnormalities are closely associated with the pathogenesis of CNS disorders. Post-translational modifications (PTMs) are essential regulatory mechanisms that affect the functions of almost all proteins. Succinylation, a broad-spectrum dynamic PTM, primarily occurs in mitochondria and plays a crucial regulatory role in various diseases. In addition to directly affecting various metabolic cycle pathways, succinylation serves as an efficient and rapid biological regulatory mechanism that establishes a connection between metabolism and proteins, thereby influencing cellular functions in CNS diseases. This review offers a comprehensive analysis of succinylation and its implications in the pathological mechanisms of CNS diseases. The objective is to outline novel strategies and targets for the prevention and treatment of CNS conditions.
    Keywords:  central nervous system diseases; epigenetics; post-translational modifications; succinylation
    DOI:  https://doi.org/10.1016/j.arr.2024.102242
  23. J Neurochem. 2024 Feb 19.
    Mass spectrometry imaging highlights dynamic patterns of lipid co-expression with Aβ plaques in mouse and human brains.
    Helen Xuexia Huang, Paolo Inglese, Jiabin Tang, Riad Yagoubi, Gonçalo D S Correia, Verena M Horneffer-van der Sluis, Stephane Camuzeaux, Vincen Wu, Maksym V Kopanitsa, Nanet Willumsen, Johanna S Jackson, Anna M Barron, Takashi Saito, Takaomi C Saido, Steve Gentlemen, Zoltan Takats, Paul M Matthews.
      Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL-G-F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid-expressing (h-Aβ) and WT mouse brains controls. We observed age-dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aβ plaques in AppNL-G-F mice. Immunohistology-based co-localization identified associations between focal pro-inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co-expression of lysophospholipids and ceramides around Aβ plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aβ-related pathologies evolve. Observing similar lipidomic changes associated with pathological Aβ plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.
    Keywords:  Alzheimer's disease; Aβ plaques; autophagic disruption; network analysis; pro-inflammatory lipids; spatial lipidomics
    DOI:  https://doi.org/10.1111/jnc.16042
  24. EMBO J. 2024 Feb 21.
    Hyperacetylated histone H4 is a source of carbon contributing to lipid synthesis.
    Evelina Charidemou, Roberta Noberini, Chiara Ghirardi, Polymnia Georgiou, Panayiota Marcou, Andria Theophanous, Katerina Strati, Hector Keun, Volker Behrends, Tiziana Bonaldi, Antonis Kirmizis.
      Histone modifications commonly integrate environmental cues with cellular metabolic outputs by affecting gene expression. However, chromatin modifications such as acetylation do not always correlate with transcription, pointing towards an alternative role of histone modifications in cellular metabolism. Using an approach that integrates mass spectrometry-based histone modification mapping and metabolomics with stable isotope tracers, we demonstrate that elevated lipids in acetyltransferase-depleted hepatocytes result from carbon atoms derived from deacetylation of hyperacetylated histone H4 flowing towards fatty acids. Consistently, enhanced lipid synthesis in acetyltransferase-depleted hepatocytes is dependent on histone deacetylases and acetyl-CoA synthetase ACSS2, but not on the substrate specificity of the acetyltransferases. Furthermore, we show that during diet-induced lipid synthesis the levels of hyperacetylated histone H4 decrease in hepatocytes and in mouse liver. In addition, overexpression of acetyltransferases can reverse diet-induced lipogenesis by blocking lipid droplet accumulation and maintaining the levels of hyperacetylated histone H4. Overall, these findings highlight hyperacetylated histones as a metabolite reservoir that can directly contribute carbon to lipid synthesis, constituting a novel function of chromatin in cellular metabolism.
    Keywords:  Acetylation; Epigenetics; Histone Reservoirs; Lipid Metabolism
    DOI:  https://doi.org/10.1038/s44318-024-00053-0
  25. Eur J Paediatr Neurol. 2024 Feb 07. pii: S1090-3798(24)00010-2. [Epub ahead of print]49 60-65
    Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.
    Emilie Everard, Hilde Laeremans, François Boemer, Sandrine Marie, Marie-Françoise Vincent, Joseph P Dewulf, François-Guillaume Debray, Corinne De Laet, Marie-Cécile Nassogne.
      Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.
    Keywords:  CPT 2 deficiency; LCHAD deficiency; MCAD deficiency; MTP deficiency; Mitochondrial fatty acid oxidation disorders; VLCAD deficiency
    DOI:  https://doi.org/10.1016/j.ejpn.2024.02.003
  26. Pharmacol Res. 2024 Feb 21. pii: S1043-6618(24)00058-6. [Epub ahead of print] 107114
    Unveiling the Role of iPLA2β in Neurodegeneration: From Molecular Mechanisms to Advanced Therapies.
    Jiabin Liu, Jieqiong Tan, Beisha Tang, Jifeng Guo.
      Calcium-independent phospholipase A2β (iPLA2β), a member of the phospholipase A2 (PLA2s) superfamily, is encoded by the PLA2G6 gene. Mutations in the PLA2G6 gene have been identified as the primary cause of infantile neuroaxonal dystrophy (INAD) and, less commonly, as a contributor to Parkinson's disease (PD). Recent studies have revealed that iPLA2β deficiency leads to neuroinflammation, iron accumulation, mitochondrial dysfunction, lipid dysregulation, and other pathological changes, forming a complex pathogenic network. These discoveries shed light on potential mechanisms underlying PLA2G6-associated neurodegeneration (PLAN) and offer valuable insights for therapeutic development. This review provides a comprehensive analysis of the fundamental characteristics of iPLA2β, its association with neurodegeneration, the pathogenic mechanisms involved in PLAN, and potential targets for therapeutic intervention. It offers an overview of the latest advancements in this field, aiming to contribute to ongoing research endeavors and facilitate the development of effective therapies for PLAN.
    Keywords:  PLA2G6; iPLA(2)β; lipid; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.1016/j.phrs.2024.107114
  27. Int J Mol Sci. 2024 Feb 11. pii: 2188. [Epub ahead of print]25(4):
    Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats.
    Karin Fehsel, Marie-Luise Bouvier.
      Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism.
    Keywords:  clozapine; glucose; glucose transporter-4; haloperidol; insulin receptor-ß; lipid; perilipin-A hormone-sensitive lipase; perirenal adipose tissue
    DOI:  https://doi.org/10.3390/ijms25042188
  28. Brain Struct Funct. 2024 Feb 21.
    Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.
    Palkin Arora, Richa Trivedi, Megha Kumari, Kavita Singh, Rajat Sandhir, Maria M D'Souza, Poonam Rana.
      Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aβ positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.
    Keywords:  Astrocytes; Aβ deposition; Closed head injury; Diffusion tensor imaging; Microglia
    DOI:  https://doi.org/10.1007/s00429-024-02758-8
  29. Biomolecules. 2024 Jan 28. pii: 156. [Epub ahead of print]14(2):
    Methodological Pitfalls of Investigating Lipid Rafts in the Brain: What Are We Still Missing?
    Kristina Mlinac-Jerkovic, Svjetlana Kalanj-Bognar, Marija Heffer, Senka Blažetić.
      The purpose of this review is to succinctly examine the methodologies used in lipid raft research in the brain and to highlight the drawbacks of some investigative approaches. Lipid rafts are biochemically and biophysically different from the bulk membrane. A specific lipid environment within membrane domains provides a harbor for distinct raftophilic proteins, all of which in concert create a specialized platform orchestrating various cellular processes. Studying lipid rafts has proved to be arduous due to their elusive nature, mobility, and constant dynamic reorganization to meet the cellular needs. Studying neuronal lipid rafts is particularly cumbersome due to the immensely complex regional molecular architecture of the central nervous system. Biochemical fractionation, performed with or without detergents, is still the most widely used method to isolate lipid rafts. However, the differences in solubilization when various detergents are used has exposed a dire need to find more reliable methods to study particular rafts. Biochemical methods need to be complemented with other approaches such as live-cell microscopy, imaging mass spectrometry, and the development of specific non-invasive fluorescent probes to obtain a more complete image of raft dynamics and to study the spatio-temporal expression of rafts in live cells.
    Keywords:  Brij O20; Triton X-100; cholesterol; detergent-resistant membranes; gangliosides; glycosphingolipids; imaging mass spectrometry; neuronal membranes
    DOI:  https://doi.org/10.3390/biom14020156
  30. Int J Mol Sci. 2024 Feb 19. pii: 2443. [Epub ahead of print]25(4):
    Non-Targeted Metabolomics Investigation of a Sub-Chronic Variable Stress Model Unveils Sex-Dependent Metabolic Differences Induced by Stress.
    Seulgi Kang, Woonhee Kim, Jimin Nam, Ke Li, Yua Kang, Boyeon Bae, Kwang-Hoon Chun, ChiHye Chung, Jeongmi Lee.
      Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). The SCVS model of male and female mice was established in discovery and validation sets. The stress-induced behavioral phenotypic changes were similar in both sexes, however, the metabolic profiles of female plasma and brain became substantially different after stress, whereas those of males did not. Four stress-differential plasma metabolites-β-hydroxybutyric acid (BHB), L-serine, glycerol, and myo-inositol-could yield biomarker panels with excellent performance to discern the stressed individuals only for females. Disturbances in BHB, glucose, 1,5-anhydrosorbitol, lactic acid, and several fatty acids in the plasma of stressed females implied a systemic metabolic shift to β-oxidation in females. The plasma levels of BHB and corticosterone only in stressed females were observed not only in SCVS but also in an acute stress model. These results collectively suggest a sex difference in the metabolic responses by stress, possibly involving the energy metabolism shift to β-oxidation and the HPA axis dysregulation in females.
    Keywords:  energy metabolism; hypothalamic-pituitary-adrenal axis; metabolomics; rodent stress model; sex-dependent depression
    DOI:  https://doi.org/10.3390/ijms25042443
  31. Front Pharmacol. 2024 ;15 1348410
    A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities.
    Yun Pan, Jieying Li, Panjie Lin, Lihua Wan, Yiqian Qu, Lingyong Cao, Lei Wang.
      The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.
    Keywords:  Alzheimer's disease; ceramide; comorbidity; inflammation; insulin signaling; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fphar.2024.1348410
  32. Int J Biol Sci. 2024 ;20(4): 1194-1217
    The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease.
    Yu Hong, Zhuoyuan Zhang, Tsering Yangzom, Anbin Chen, Bjørn Christian Lundberg, Evandro Fei Fang, Richard Siller, Gareth John Sullivan, Jiri Zeman, Charalampos Tzoulis, Laurence A Bindoff, Kristina Xiao Liang.
      Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.
    Keywords:  Alpers' disease; NAD+; NR; cortical organoids; induced pluripotent stem cells; mitochondrial function
    DOI:  https://doi.org/10.7150/ijbs.91624
  33. Nature. 2024 Feb 21.
    IL-10 constrains sphingolipid metabolism to limit inflammation.
    Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell.
      Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
    DOI:  https://doi.org/10.1038/s41586-024-07098-5
  34. Aging Dis. 2024 Feb 17.
    Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline.
    Tanya H Butt, Makoto Tobiume, Diane B Re, Shingo Kariya.
      In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer's disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging.
    DOI:  https://doi.org/10.14336/AD.2024.0216
  35. J Prev Alzheimers Dis. 2024 ;11(2): 382-401
    A Cholecystokinin Analogue Ameliorates Cognitive Deficits and Regulates Mitochondrial Dynamics via the AMPK/Drp1 Pathway in APP/PS1 Mice.
    L Hao, M Shi, J Ma, S Shao, Y Yuan, J Liu, Z Yu, Z Zhang, C Hölscher, Z Zhang.
      BACKGROUND: There are no drugs on the market that can reverse or slow Alzheimer's disease (AD) progression. A protease-resistant Cholecystokinin (CCK) analogue used in this study is based on the basic structure of CCK, which further increases the stability of the peptide fragment and prolongs its half-life in vivo. We observed a neuroprotective effect of CCK-8L in APPswe/PS1dE9 (APP/PS1) AD mice. However, its corresponding mechanisms still need to be elucidated.OBJECTIVE: This study examined CCK-8L's neuroprotective effects in enhancing cognitive impairment by regulating mitochondrial dynamics through AMPK/Drp1 pathway in the APP/PS1 AD mice.
    METHODS: Behavioural tests are applied to assess competence in cognitive functions. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria of hippocampal neurons, Immunofluorescent staining was employed to assay for Aβ1-42, APP, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and dynamin-related protein1 (Drp1). CRISPR/Cas9 was utilized for targeted knockout of the CCKB receptor (CCKBR) in the mouse APP/PS1 hippocampal CA1 region. A model of lentiviral vector-mediated overexpression of APP in N2a cells was constructed.
    RESULTS: In vivo, experiments revealed that CCK analogue and liraglutide significantly alleviated cognitive deficits in APP/PS1 mice, reduced Aβ1-42 expression, and ameliorated l damage, which is associated with CCKBR activation in the hippocampal CA1 region of mice. In vitro tests showed that CCK inhibited mitochondrial fission and promoted fusion through AMPK/Drp1 pathway.
    CONCLUSIONS: CCK analogue ameliorates cognitive deficits and regulates mitochondrial dynamics by activating the CCKB receptor and the AMPK/Drp1 pathway in AD mice.
    Keywords:  AMPK/Drp1 pathway; Alzheimer’s disease; CCK analogue ; CCKB receptor; cognitive deficits; mitochondrial dynamics
    DOI:  https://doi.org/10.14283/jpad.2024.6
  36. Transl Psychiatry. 2024 Feb 23. 14(1): 112
    Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder.
    Selena Aranda, Gerard Muntané, Elisabet Vilella.
      DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.
    DOI:  https://doi.org/10.1038/s41398-024-02823-0
  37. Appl Biosci (Basel). 2023 Jun;2(2): 173-193
    Tissue Microarray Lipidomic Imaging Mass Spectrometry Method: Application to the Study of Alcohol-Related White Matter Neurodegeneration.
    Isabel Gameiro-Ros, Lelia Noble, Ming Tong, Emine B Yalcin, Suzanne M de la Monte.
      Central nervous system (CNS) white matter pathologies accompany many diseases across the lifespan, yet their biochemical bases, mechanisms, and consequences have remained poorly understood due to the complexity of myelin lipid-based research. However, recent advances in matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) have minimized or eliminated many technical challenges that previously limited progress in CNS disease-based lipidomic research. MALDI-IMS can be used for lipid identification, semi-quantification, and the refined interpretation of histopathology. The present work illustrates the use of tissue micro-arrays (TMAs) for MALDI-IMS analysis of frontal lobe white matter biochemical lipidomic pathology in an experimental rat model of chronic ethanol feeding. The use of TMAs combines workload efficiency with the robustness and uniformity of data acquisition. The methods described for generating TMAs enable simultaneous comparisons of lipid profiles across multiple samples under identical conditions. With the methods described, we demonstrate significant reductions in phosphatidylinositol and increases in phosphatidylcholine in the frontal white matter of chronic ethanol-fed rats. Together with the use of a novel rapid peak alignment protocol, this approach facilitates reliable inter- and intra-group comparisons of MALDI-IMS data from experimental models and could be extended to human disease states, including using archival specimens.
    Keywords:  MALDI; alcohol; central nervous system; lipidomic; mass spectrometry; tissue micro-array; white matter
    DOI:  https://doi.org/10.3390/applbiosci2020013
  38. Metabolites. 2024 Jan 24. pii: 84. [Epub ahead of print]14(2):
    Novel Approaches to Studying SLC13A5 Disease.
    Adriana S Beltran.
      The role of the sodium citrate transporter (NaCT) SLC13A5 is multifaceted and context-dependent. While aberrant dysfunction leads to neonatal epilepsy, its therapeutic inhibition protects against metabolic disease. Notably, insights regarding the cellular and molecular mechanisms underlying these phenomena are limited due to the intricacy and complexity of the latent human physiology, which is poorly captured by existing animal models. This review explores innovative technologies aimed at bridging such a knowledge gap. First, I provide an overview of SLC13A5 variants in the context of human disease and the specific cell types where the expression of the transporter has been observed. Next, I discuss current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids. Finally, I explore the relevance of these cellular models as platforms for delving into the intricate molecular and cellular mechanisms underlying SLC13A5-related disorders.
    Keywords:  NaCT; SLC13A5; hepatocytes; iPSCs; neurons; organoids
    DOI:  https://doi.org/10.3390/metabo14020084
  39. Metabolites. 2024 Feb 02. pii: 105. [Epub ahead of print]14(2):
    Blood-Derived Metabolic Signatures as Biomarkers of Injury Severity in Traumatic Brain Injury: A Pilot Study.
    Elani A Bykowski, Jamie N Petersson, Sean P Dukelow, Chester Ho, Chantel T Debert, Tony Montina, Gerlinde A S Metz.
      Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived biomarkers as proxy measures that can provide an objective approach to TBI diagnosis and monitoring. Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined whether (1) blood-derived metabolites change during recovery in male participants with mild to severe TBI; (2) biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery; and (3) changes in metabolites correlate to initial injury severity. Eight male participants with mild to severe TBI (with intracranial lesions) provided morning blood samples within 1-4 days and again 6 months post-TBI. Following NMR analysis, the samples were subjected to multivariate statistical and machine learning-based analyses. Statistical modelling displayed metabolic changes during recovery through group separation, and eight significant metabolic pathways were affected by TBI. Metabolic changes were correlated to injury severity. L-alanine (R= -0.63, p < 0.01) displayed a negative relationship with the Glasgow Coma Scale. This study provides pilot data to support the feasibility of using blood-derived metabolites to better understand changes in biochemistry following TBI.
    Keywords:  biological pathways; blood; concussion; metabolomics; nuclear magnetic resonance (NMR) spectroscopy; precision medicine; recovery; rehabilitation; severity; symptom burden; traumatic brain injury
    DOI:  https://doi.org/10.3390/metabo14020105
  40. JCI Insight. 2024 Feb 20. pii: e174645. [Epub ahead of print]
    Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie the Allan-Herndon-Dudley syndrome.
    Federico Salas-Lucia, Sergio Escamilla, Antonio C Bianco, Alexandra Dumitrescu, Samuel Refetoff.
      Patients with mutations in the thyroid hormone (TH) cell transporter MCT8 gene develop severe neuro-psychomotor retardation known as the Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated brain organoids (BOs) using human iPSCs from MCT8-deficient patients. We found that MCT8-deficient BOs exhibit (i) impaired T3 transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (ii) reduced expression of genes involved in neurogenesis and neuronal maturation, and (iii) reduced T3-inducibility of TH-regulated genes. In contrast, the TH-analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient BOs, constituting a proof-of-concept that lack of T3 transport underlies the pathophysiology of AHDS, demonstrating the clinical potential for TH analogues to be used in treating AHDS patients. MCT8-deficient BOs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for AHDS patients.
    Keywords:  Endocrinology; Neurodevelopment; Neuroscience; Thyroid disease; Transport
    DOI:  https://doi.org/10.1172/jci.insight.174645
  41. Alzheimers Dement (Amst). 2024 Jan-Mar;16(1):16(1): e12550
    APOE ε4 allele status modulates the spatial patterns of progressive atrophy in the temporal lobes after mild traumatic brain injury.
    Shuoqiu Gan, Yingxiang Sun, Kejia Liu, Xiaoyan Jia, Xuan Li, Ming Zhang, Lijun Bai.
      INTRODUCTION: We evaluated how the apolipoprotein E (APOE) ε4 allele modulated the spatial patterns of longitudinal atrophy in the Alzheimer's disease-vulnerable brain areas of patients with mild traumatic brain injury (mTBI) from the acute to chronic phase post injury.METHODS: Fifty-nine adult patients with acute mTBI and 48 healthy controls with APOE ε4 allele testing underwent T1-weighted magnetic resonance imaging and neuropsychological assessments with 6 to 12 months of follow-up. Progressive brain volume loss was compared voxel-wise in the temporal lobes.
    RESULTS: Patients with the APOE ε4 allele presented significant longitudinal atrophy in the left superior and middle temporal gyri, where the progressive gray matter volume loss predicted longitudinal impairment in language fluency, whereas mTBI APOE ε4 allele noncarriers showed mainly significant longitudinal atrophy in the medial temporal lobes, without significant neuropsychological relevance.
    DISCUSSION: The atrophy progression observed in mTBI patients with the APOE ε4 allele may increase the possibility of developing a specific phenotype of Alzheimer's disease with language dysfunction.
    Highlights: The apolipoprotein E (APOE) ε4 allele and mild traumatic brain injury (mTBI) are risk factors for Alzheimer's disease (AD) progression.It is unclear how the interaction of mTBI with the APOE ε4 allele impacts the progressive atrophy topography in AD-vulnerable brain regions.In this study, patients with the APOE ε4 allele showed progressive atrophy patterns similar to the early stage of logopenic variant of primary progressive aphasia (lvPPA) phenotype of AD. APOE ε4 allele carriers with mTBI history may be at the risk of developing a given AD phenotype with language dysfunction.
    Keywords:  APOE ε4 allele status; Alzheimer's disease risk; longitudinal atrophy; mild traumatic brain injury; temporal lobes
    DOI:  https://doi.org/10.1002/dad2.12550
  42. Antioxidants (Basel). 2024 Feb 16. pii: 240. [Epub ahead of print]13(2):
    Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?
    Caterina Peggion, Tito Calì, Marisa Brini.
      Neurodegenerative diseases (NDs) encompass an assorted array of disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, each characterised by distinct clinical manifestations and underlying pathological mechanisms. While some cases have a genetic basis, many NDs occur sporadically. Despite their differences, these diseases commonly feature chronic neuroinflammation as a hallmark. Consensus has recently been reached on the possibility that mitochondria dysfunction and protein aggregation can mutually contribute to the activation of neuroinflammatory response and thus to the onset and progression of these disorders. In the present review, we discuss the contribution of mitochondria dysfunction and neuroinflammation to the aetiology and progression of NDs, highlighting the possibility that new potential therapeutic targets can be identified to tackle neurodegenerative processes and alleviate the progression of these pathologies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; inflammasome; mitochondrial dysfunction; neurodegeneration; oxidative stress
    DOI:  https://doi.org/10.3390/antiox13020240
  43. Brain Commun. 2024 ;6(1): fcad351
    APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure.
    PREVENT-Dementia and ALFA studies
      The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.
    Keywords:  NODDI; cognitive impairment; neurodegeneration; preclinical dementia
    DOI:  https://doi.org/10.1093/braincomms/fcad351
  44. J Neurosci. 2024 Feb 22. pii: e1610232024. [Epub ahead of print]
    Nacc1 mutation in mice models rare neurodevelopmental disorder with underlying synaptic dysfunction.
    Mark A Deehan, Josine M Kothuis, Ellen Sapp, Kathryn Chase, Yuting Ke, Connor Seeley, Maria Iuliano, Emily Kim, Lori Kennington, Rachael Miller, Adel Boudi, Kai Shing, Xueyi Li, Edith Pfister, Christelle Anaclet, Michael Brodsky, Kimberly Kegel-Gleason, Neil Aronin, Marian DiFiglia.
      A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay (Schoch et al 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram (EEG), behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In cortex, NACC1 long isoform, which harbors the mutation, increased from 3-6 months whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from P7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein (GFAP) staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed altered expression of over 1000 genes (DEGs). Glial transcripts were downregulated, and synaptic genes upregulated. Top GO terms from upregulated DEGs relate to post synapse and ion channel function while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.Significance statement A missense mutation causing an arginine to tryptophan (R>W) mutation at amino acid 298 in the Nucleus accumbens-associated protein 1 (NACC1) causes profound neurodevelopmental arrest in humans. NACC1 is a transcription repressor but how the R298W mutation causes disease in brain is unclear. We engineered the first mouse model with this mutation and found delayed weight gain, deficits in the open field signaling anxiety, motor dysfunction, and cortical EEG disturbance akin to absence seizures. Females displayed more deficits than males. NACC1 protein increased in neurons in multiple brain regions including cortex and RNA-sequencing and protein studies in postnatal mice revealed dysregulated synaptic pathways. This mouse model recapitulates patient symptoms and provides robust cellular and molecular benchmarks for therapeutic testing.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1610-23.2024
  45. Pharmacol Ther. 2024 Feb 16. pii: S0163-7258(24)00029-9. [Epub ahead of print]256 108609
    Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA).
    Jeffrey M Witkin, Hana Shafique, Rok Cerne, Jodi L Smith, Ann M Marini, Robert H Lipsky, Elizabeth Delery.
      Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.
    Keywords:  Animal models; GABA; Glutamate; Post-traumatic epilepsy (PTE); Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108609
  46. Nat Metab. 2024 Feb 20.
    Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.
    Alain J De Solis, Almudena Del Río-Martín, Jan Radermacher, Weiyi Chen, Lukas Steuernagel, Corinna A Bauder, Fynn R Eggersmann, Donald A Morgan, Anna-Lena Cremer, Michael Sué, Maximilian Germer, Christian Kukat, Stefan Vollmar, Heiko Backes, Kamal Rahmouni, Peter Kloppenburg, Jens C Brüning.
      Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons. We identify a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus, where activated AgRP neurons and inhibited POMC neurons cooperate to promote food consumption and activate Th+ neurons in the nucleus tractus solitarii. Collectively, these results unveil how food intake is precisely regulated by the simultaneous bidirectional interplay between AgRP and POMC neurocircuits.
    DOI:  https://doi.org/10.1038/s42255-024-00987-z
  47. Biomolecules. 2024 Jan 30. pii: 162. [Epub ahead of print]14(2):
    Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model.
    Jaime M Ross, Lars Olson, Giuseppe Coppotelli.
      Mitochondrial dysfunction has been implicated in aging and age-related disorders. Disturbed-protein homeostasis and clearance of damaged proteins have also been linked to aging, as well as to neurodegenerative diseases, cancers, and metabolic disorders. However, since mitochondrial oxidative phosphorylation, ubiquitin-proteasome, and autophagy-lysosome systems are tightly interdependent, it is not understood whether the facets observed in aging are the causes or consequences of one or all of these failed processes. We therefore used prematurely aging mtDNA-mutator mice and normally aging wild-type littermates to elucidate whether mitochondrial dysfunction per se is sufficient to impair cellular protein homeostasis similarly to that which is observed in aging. We found that both mitochondrial dysfunction and normal aging affect the ubiquitin-proteasome system in a tissue-dependent manner, whereas only normal aging markedly impairs the autophagy-lysosome system. Thus, our data show that the proteostasis network control in the prematurely aging mtDNA-mutator mouse differs in certain aspects from that found in normal aging. Taken together, our findings suggest that severe mitochondrial dysfunction drives an aging phenotype associated with the impairment of certain components of the protein homeostasis machinery, while others, such as the autophagy-lysosome system, are not affected or only minimally affected. Taken together, this shows that aging is a multifactorial process resulting from alterations of several integrated biological processes; thus, manipulating one process at the time might not be sufficient to fully recapitulate all changes associated with normal aging.
    Keywords:  aging; autophagy; mitochondrial dysfunction; ubiquitin–proteasome system
    DOI:  https://doi.org/10.3390/biom14020162
This page is being maintained by Thomas Krichel. It was last updated on 2024‒04‒16 at 19:16.