bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024‒04‒28
38 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer's Disease.
  2. A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.
  3. Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.
  4. Behavioral and Metabolic Effects of ABCG4 KO in the APPswe,Ind (J9) Mouse Model of Alzheimer's Disease.
  5. Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.
  6. Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.
  7. Mice and minipigs with compromised expression of the Alzheimer's disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-13C]pyruvate and sodium MRI.
  8. Characteristic Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.
  9. Adenylate kinase 4 promotes neuronal energy metabolism and mitophagy in early cerebral ischemia via Parkin/PKM2 pathway.
  10. Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol.
  11. Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?
  12. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK.
  13. Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress.
  14. Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain.
  15. The lactate receptor HCAR1: A key modulator of epileptic seizure activity.
  16. Protective effect of increased O-GlcNAc cycling against 6-OHDA induced Parkinson's disease pathology.
  17. Measurement of Cerebral Glucose Metabolism in the Visual Cortex Predicts the Prognosis of Hemianopia.
  18. Long-Term Region-Specific Mitochondrial Functionality Changes in Both Cerebral Hemispheres after fMCAo Model of Ischemic Stroke.
  19. Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
  20. Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia.
  21. Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review.
  22. Lipidomic Analysis of Plasma Extracellular Vesicles Derived from Alzheimer's Disease Patients.
  23. Mitochondrial Dysfunction as the Major Basis of Brain Aging.
  24. Hippocampal Lactate-Infusion Enhances Spatial Memory Correlated with Monocarboxylate Transporter 2 and Lactylation.
  25. Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.
  26. Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects.
  27. Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice.
  28. The effects of cerebral pressure autoregulation status and CPP levels on cerebral metabolism in pediatric traumatic brain injury.
  29. Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
  30. Lrp8 knockout mice fed a selenium-replete diet display subtle deficits in their spatial learning and memory function.
  31. Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact.
  32. Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion.
  33. Formoterol Acting via β2-Adrenoreceptor Restores Mitochondrial Dysfunction Caused by Parkinson's Disease-Related UQCRC1 Mutation and Improves Mitochondrial Homeostasis Including Dynamic and Transport.
  34. Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders.
  35. Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.
  36. Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson's disease.
  37. Peak Resembling N-acetylaspartate (NAA) on Magnetic Resonance Spectroscopy of Brain Metastases.
  38. Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression.
  1. Antioxidants (Basel). 2024 Apr 03. pii: 435. [Epub ahead of print]13(4):
    Altered Brain Cholesterol Machinery in a Down Syndrome Mouse Model: A Possible Common Feature with Alzheimer's Disease.
    Erica Staurenghi, Gabriella Testa, Valerio Leoni, Rebecca Cecci, Lucrezia Floro, Serena Giannelli, Eugenio Barone, Marzia Perluigi, Gabriella Leonarduzzi, Barbara Sottero, Paola Gamba.
      Down syndrome (DS) is a complex chromosomal disorder considered as a genetically determined form of Alzheimer's disease (AD). Maintenance of brain cholesterol homeostasis is essential for brain functioning and development, and its dysregulation is associated with AD neuroinflammation and oxidative damage. Brain cholesterol imbalances also likely occur in DS, concurring with the precocious AD-like neurodegeneration. In this pilot study, we analyzed, in the brain of the Ts2Cje (Ts2) mouse model of DS, the expression of genes encoding key enzymes involved in cholesterol metabolism and of the levels of cholesterol and its main precursors and products of its metabolism (i.e., oxysterols). The results showed, in Ts2 mice compared to euploid mice, the downregulation of the transcription of the genes encoding the enzymes 3-hydroxy-3-methylglutaryl-CoA reductase and 24-dehydrocholesterol reductase, the latter originally recognized as an indicator of AD, and the consequent reduction in total cholesterol levels. Moreover, the expression of genes encoding enzymes responsible for brain cholesterol oxidation and the amounts of the resulting oxysterols were modified in Ts2 mouse brains, and the levels of cholesterol autoxidation products were increased, suggesting an exacerbation of cerebral oxidative stress. We also observed an enhanced inflammatory response in Ts2 mice, underlined by the upregulation of the transcription of the genes encoding for α-interferon and interleukin-6, two cytokines whose synthesis is increased in the brains of AD patients. Overall, these results suggest that DS and AD brains share cholesterol cycle derangements and altered oxysterol levels, which may contribute to the oxidative and inflammatory events involved in both diseases.
    Keywords:  Alzheimer’s disease; CYP46A1; DHCR24; Down syndrome; HMGCR; cholesterol; neuroinflammation; oxidative stress; oxysterols
    DOI:  https://doi.org/10.3390/antiox13040435
  2. Brain. 2024 Apr 25. pii: awae134. [Epub ahead of print]
    A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.
    Maali Odeh, Clara Sajrawi, Adam Majcher, Salman Zubedat, Lihi Shaulov, Alex Radzishevsky, Liron Mizrahi, Wendy K Chung, Avi Avital, Thorsten Hornemann, Daniel J Liebl, Inna Radzishevsky, Herman Wolosker.
      Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.
    Keywords:  d-serine; mitochondria; mitophagy; serine metabolism; synaptopathy
    DOI:  https://doi.org/10.1093/brain/awae134
  3. Life Sci Alliance. 2024 Jul;pii: e202302473. [Epub ahead of print]7(7):
    Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.
    Rita Soares, Diogo M Lourenço, Isa F Mota, Ana M Sebastião, Sara Xapelli, Vanessa A Morais.
      Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.
    DOI:  https://doi.org/10.26508/lsa.202302473
  4. J Mol Neurosci. 2024 Apr 26. 74(2): 49
    Behavioral and Metabolic Effects of ABCG4 KO in the APPswe,Ind (J9) Mouse Model of Alzheimer's Disease.
    Vincent Fong, Babunageswararao Kanuri, Owen Traubert, Min Lui, Shailendra B Patel.
      The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.
    Keywords:  ABCG4; Alzheimer’s disease; Behavior; Cholesterol metabolism; Glucose metabolism
    DOI:  https://doi.org/10.1007/s12031-024-02214-6
  5. Hum Brain Mapp. 2024 Apr 15. 45(6): e26686
    Whole-brain deuterium metabolic imaging via concentric ring trajectory readout enables assessment of regional variations in neuronal glucose metabolism.
    Fabian Niess, Bernhard Strasser, Lukas Hingerl, Viola Bader, Sabina Frese, William T Clarke, Anna Duguid, Eva Niess, Stanislav Motyka, Martin Krššák, Siegfried Trattnig, Thomas Scherer, Rupert Lanzenberger, Wolfgang Bogner.
      Deuterium metabolic imaging (DMI) is an emerging magnetic resonance technique, for non-invasive mapping of human brain glucose metabolism following oral or intravenous administration of deuterium-labeled glucose. Regional differences in glucose metabolism can be observed in various brain pathologies, such as Alzheimer's disease, cancer, epilepsy or schizophrenia, but the achievable spatial resolution of conventional phase-encoded DMI methods is limited due to prolonged acquisition times rendering submilliliter isotropic spatial resolution for dynamic whole brain DMI not feasible. The purpose of this study was to implement non-Cartesian spatial-spectral sampling schemes for whole-brain 2H FID-MR Spectroscopic Imaging to assess time-resolved metabolic maps with sufficient spatial resolution to reliably detect metabolic differences between healthy gray and white matter regions. Results were compared with lower-resolution DMI maps, conventionally acquired within the same session. Six healthy volunteers (4 m/2 f) were scanned for ~90 min after administration of 0.8 g/kg oral [6,6']-2H glucose. Time-resolved whole brain 2H FID-DMI maps of glucose (Glc) and glutamate + glutamine (Glx) were acquired with 0.75 and 2 mL isotropic spatial resolution using density-weighted concentric ring trajectory (CRT) and conventional phase encoding (PE) readout, respectively, at 7 T. To minimize the effect of decreased signal-to-noise ratios associated with smaller voxels, low-rank denoising of the spatiotemporal data was performed during reconstruction. Sixty-three minutes after oral tracer uptake three-dimensional (3D) CRT-DMI maps featured 19% higher (p = .006) deuterium-labeled Glc concentrations in GM (1.98 ± 0.43 mM) compared with WM (1.66 ± 0.36 mM) dominated regions, across all volunteers. Similarly, 48% higher (p = .01) 2H-Glx concentrations were observed in GM (2.21 ± 0.44 mM) compared with WM (1.49 ± 0.20 mM). Low-resolution PE-DMI maps acquired 70 min after tracer uptake featured smaller regional differences between GM- and WM-dominated areas for 2H-Glc concentrations with 2.00 ± 0.35 mM and 1.71 ± 0.31 mM, respectively (+16%; p = .045), while no regional differences were observed for 2H-Glx concentrations. In this study, we successfully implemented 3D FID-MRSI with fast CRT encoding for dynamic whole-brain DMI at 7 T with 2.5-fold increased spatial resolution compared with conventional whole-brain phase encoded (PE) DMI to visualize regional metabolic differences. The faster metabolic activity represented by 48% higher Glx concentrations was observed in GM- compared with WM-dominated regions, which could not be reproduced using whole-brain DMI with the low spatial resolution protocol. Improved assessment of regional pathologic alterations using a fully non-invasive imaging method is of high clinical relevance and could push DMI one step toward clinical applications.
    Keywords:  3D magnetic resonance spectroscopic imaging; deuterium metabolic imaging; deuterium‐labeled glucose; downstream neurotransmitter synthesis; whole‐brain metabolic mapping
    DOI:  https://doi.org/10.1002/hbm.26686
  6. J Lipid Res. 2024 Apr 20. pii: S0022-2275(24)00053-1. [Epub ahead of print] 100548
    Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.
    Adam H Metherel, Rodrigo Valenzuela, Brinley J Klievik, Giulia Cisbani, Ruxandra D Rotarescu, Melissa Gonzalez-Soto, Céline Cruciani-Guglielmacci, Sophie Layé, Christophe Magnan, David M Mutch, Richard P Bazinet.
      DHA is abundant in brain where it regulates cell survival, neurogenesis and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this paper. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis (CSIA), that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by CSIA we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long-chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 knockout was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and non-competitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.
    Keywords:  dietary fat; elongation of very long-chain; enzyme inhibition; fatty acid metabolism; kinetics; liver; nutrition; omega-3 fatty acids; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.jlr.2024.100548
  7. Brain Commun. 2024 ;6(2): fcae114
    Mice and minipigs with compromised expression of the Alzheimer's disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-13C]pyruvate and sodium MRI.
    Nikolaj Bøgh, Charlotte B Sørensen, Aage K O Alstrup, Esben S S Hansen, Olav M Andersen, Christoffer Laustsen.
      The sortilin-related receptor 1 (SORL1) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene for Alzheimer's disease. As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1 variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with Alzheimer's disease and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1 mutations, we applied two metabolic MRI technologies, sodium (23Na) MRI and MRI with hyperpolarized [1-13C]pyruvate, in minipigs and mice with compromised expression of SORL1. At the age analysed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1-13C]pyruvate to [1-13C]lactate and 13C-bicarbonate was decreased by 32 and 23%, respectively, in the cerebrum of SORL1-haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with 23Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of Alzheimer's disease and Alzheimer's disease-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1 mutations and their potential role in neurodegeneration.
    Keywords:  Alzheimer’s disease; MRI; SORL1; SORLA; metabolism
    DOI:  https://doi.org/10.1093/braincomms/fcae114
  8. medRxiv. 2024 Apr 10. pii: 2024.04.08.24303574. [Epub ahead of print]
    Characteristic Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.
    Olivier Fortin, Kelsey Christoffel, Abdullah Shoaib, Charu Venkatesan, Kate Cilli, Jason W Schroeder, Cesar Alves, Rebecca D Ganetzky, Jamie L Fraser.
      Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1 . Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.
    DOI:  https://doi.org/10.1101/2024.04.08.24303574
  9. Exp Neurol. 2024 Apr 24. pii: S0014-4886(24)00124-9. [Epub ahead of print] 114798
    Adenylate kinase 4 promotes neuronal energy metabolism and mitophagy in early cerebral ischemia via Parkin/PKM2 pathway.
    Yunxue Zhong, Bingbing Jia, Cong Xie, Hu Linghui, Zijun Liao, Wenlan Liu, Yuan Zhang, Guodong Huang.
      Mitochondrial dysfunction is closely related to brain injury and neurological dysfunction in ischemic stroke. Adenylate kinase 4 (AK4) plays a critical role in energy metabolism and mitochondrial homeostasis. However, the underlying mechanisms remain unclear. In the present study, we demonstrated an important role of AK4 in mitochondrial dysfunction in the early cerebral ischemia. Early focal cerebral ischemia induced decrease of AK4 protein expression in ischemic hemispheric brain tissue in mice. Exposure of cultured primary neuron to oxygen-glucose deprivation (OGD) also induced AK4 downregulation. Overexpression of AK4 in neuron using adeno-associated virus (AAV-AK4) in mice promoted neuronal survival reflected by decreased infarction volume and TUNEL staining. AK4 overexpression inhibited mitochondrial decline and downregulation of energy metabolism-associated proteins (p-AMPK and ATP1A3) induced by MCAO. Moreover, AK4 knock-in using lentivirus carried AK4 vector (LV-AK4) induced energy metabolism shift from glycolysis to oxidation in neuron. Using transmission electron microscope and western blot, we revealed that AK4 overexpression promoted mitophagy and mitophagy-associated proteins expression PINK1 and Parkin after MCAO. Mass spectrometry and co-immunoprecipitation revealed an interaction between AK4 and PKM2. Mechanistically, AK4 indirectly decreased PKM2 expression via enhancing its ubiquitination by increasing the interaction between PKM2 and its ubiquitin E3 ligase Parkin, and inhibits Parkin downregulation. In conclusion, our data demonstrate that AK4/ Parkin /PKM axis prevents cerebral ischemia damage via regulation of neuronal energy metabolism model and mitophagy. AK4 was a new target for intervention of early ischemic neuron injury.
    Keywords:  Adenylate kinase 4; Cerebral ischemia; Mitophagy; Pyruvate kinase M; Ubiquitination
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114798
  10. Front Cell Neurosci. 2024 ;18 1347535
    Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol.
    Fokion Spanos, Gorka Gerenu, Julen Goikolea, María Latorre-Leal, Hugo Balleza-Tapia, Karen Gomez, Laura Álvarez-Jiménez, Antonio Piras, Marta Gómez-Galán, André Fisahn, Angel Cedazo-Minguez, Silvia Maioli, Raúl Loera-Valencia.
      Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer's disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.
    Keywords:  27-hydroxycholesterol; 3D co-culture system; Alzheimer’s disease; astrocytes; cholesterol metabolism; neurospheroid; synaptic dysfunction
    DOI:  https://doi.org/10.3389/fncel.2024.1347535
  11. Lipids Health Dis. 2024 Apr 20. 23(1): 114
    Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?
    Clifford Lingwood.
      Disturbances in cholesterol homeostasis have been associated with ASD. Lipid rafts are central in many transmembrane signaling pathways (including mTOR) and changes in raft cholesterol content affect their order function. Cholesterol levels are controlled by several mechanisms, including endoplasmic reticulum associated degradation (ERAD) of the rate limiting HMGCoA reductase. A new approach to increase cholesterol via temporary ERAD blockade using a benign bacterial toxin-derived competitor for the ERAD translocon is suggested.A new lock and key model for cholesterol/lipid raft dependent signaling is proposed in which the rafts provide both the afferent and efferent 'tumblers' across the membrane to allow 'lock and key' receptor transmembrane signals.
    Keywords:  ERAD cholesterol control; Raft lock and key signaling model
    DOI:  https://doi.org/10.1186/s12944-024-02075-3
  12. Cell Metab. 2024 Apr 16. pii: S1550-4131(24)00118-9. [Epub ahead of print]
    Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK.
    Yajuan Li, Daniel Munoz-Mayorga, Yuhang Nie, Ningxin Kang, Yuren Tao, Jessica Lagerwall, Carla Pernaci, Genevieve Curtin, Nicole G Coufal, Jerome Mertens, Lingyan Shi, Xu Chen.
      The accumulation of lipid droplets (LDs) in aging and Alzheimer's disease brains is considered a pathological phenomenon with unresolved cellular and molecular mechanisms. Utilizing stimulated Raman scattering (SRS) microscopy, we observed significant in situ LD accumulation in microglia of tauopathy mouse brains. SRS imaging, combined with deuterium oxide (D2O) labeling, revealed heightened lipogenesis and impaired lipid turnover within LDs in tauopathy fly brains and human neurons derived from induced pluripotent stem cells (iPSCs). Transfer of unsaturated lipids from tauopathy iPSC neurons to microglia induced LD accumulation, oxidative stress, inflammation, and impaired phagocytosis. Neuronal AMP-activated protein kinase (AMPK) inhibits lipogenesis and promotes lipophagy in neurons, thereby reducing lipid flux to microglia. AMPK depletion in prodromal tauopathy mice increased LD accumulation, exacerbated pro-inflammatory microgliosis, and promoted neuropathology. Our findings provide direct evidence of native, aberrant LD accumulation in tauopathy brains and underscore the critical role of AMPK in regulating brain lipid homeostasis.
    Keywords:  AMPK; Alzheimer’s disease; Raman microscopy; SRS imaging; Tau; deuterium oxide; lipid droplets; lipophagy; microglia
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.014
  13. bioRxiv. 2024 Apr 20. pii: 2024.04.16.589828. [Epub ahead of print]
    Organelle-targeted Laurdans measure heterogeneity in subcellular membranes and their responses to saturated lipid stress.
    Adrian M Wong, Itay Budin.
      Cell organelles feature characteristic lipid compositions that lead to differences in membrane properties. In living cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to membrane packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells, so it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out membrane packing of individual cellular organelles. The set of Organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes and Golgi compartments with high specificity, while retaining the spectral resolution needed to detect biological changes in membrane packing. We show that ratiometric imaging with OTL can resolve membrane heterogeneity within organelles, as well as changes in membrane packing resulting from inhibition of lipid trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application to interrogating lipid dysregulation.
    DOI:  https://doi.org/10.1101/2024.04.16.589828
  14. bioRxiv. 2024 Apr 11. pii: 2024.04.10.588417. [Epub ahead of print]
    Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain.
    Jun Yin, Hsueh-Ling Chen, Anna Grigsby-Brown, Yi He, Myriam L Cotten, Jacob Short, Aidan Dermady, Jingce Lei, Mary Gibbs, Ethan S Cheng, Dean Zhang, Caixia Long, Lele Xu, Tiffany Zhong, Rinat Abzalimov, Mariam Haider, Rong Sun, Ye He, Qiangjun Zhou, Nico Tjandra, Quan Yuan.
      Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.
    DOI:  https://doi.org/10.1101/2024.04.10.588417
  15. iScience. 2024 May 17. 27(5): 109679
    The lactate receptor HCAR1: A key modulator of epileptic seizure activity.
    Maxime Alessandri, Alejandro Osorio-Forero, Anita Lüthi, Jean-Yves Chatton.
      Epilepsy affects millions globally with a significant portion exhibiting pharmacoresistance. Abnormal neuronal activity elevates brain lactate levels, which prompted the exploration of its receptor, the hydroxycarboxylic acid receptor 1 (HCAR1) known to downmodulate neuronal activity in physiological conditions. This study revealed that HCAR1-deficient mice (HCAR1-KO) exhibited lowered seizure thresholds, and increased severity and duration compared to wild-type mice. Hippocampal and whole-brain electrographic seizure analyses revealed increased seizure severity in HCAR1-KO mice, supported by time-frequency analysis. The absence of HCAR1 led to uncontrolled inter-ictal activity in acute hippocampal slices, replicated by lactate dehydrogenase A inhibition indicating that the activation of HCAR1 is closely associated with glycolytic output. However, synthetic HCAR1 agonist administration in an in vivo epilepsy model did not modulate seizures, likely due to endogenous lactate competition. These findings underscore the crucial roles of lactate and HCAR1 in regulating circuit excitability to prevent unregulated neuronal activity and terminate epileptic events.
    Keywords:  Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109679
  16. Cell Death Dis. 2024 Apr 23. 15(4): 287
    Protective effect of increased O-GlcNAc cycling against 6-OHDA induced Parkinson's disease pathology.
    Dong Yeol Kim, Sang-Min Kim, Eun-Jeong Cho, Hyo-Bum Kwak, Inn-Oc Han.
      This study aimed to elucidate the role of O-GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD)-like neurodegeneration and the underlying mechanisms. We observed dose-dependent downregulation of O-GlcNAcylation, accompanied by an increase in O-GlcNAcase following 6-OHDA treatment in both mouse brain and Neuro2a cells. Interestingly, elevating O-GlcNAcylation through glucosamine (GlcN) injection provided protection against PD pathogenesis induced by 6-OHDA. At the behavioral level, GlcN mitigated motor deficits induced by 6-OHDA, as determined using the pole, cylinder, and apomorphine rotation tests. Furthermore, GlcN attenuated 6-OHDA-induced neuroinflammation and mitochondrial dysfunction. Notably, augmented O-GlcNAcylation, achieved through O-GlcNAc transferase (OGT) overexpression in mouse brain, conferred protection against 6-OHDA-induced PD pathology, encompassing neuronal cell death, motor deficits, neuroinflammation, and mitochondrial dysfunction. These collective findings suggest that O-GlcNAcylation plays a crucial role in the normal functioning of dopamine neurons. Moreover, enhancing O-GlcNAcylation through genetic and pharmacological means could effectively ameliorate neurodegeneration and motor impairment in an animal model of PD. These results propose a potential strategy for safeguarding against the deterioration of dopamine neurons implicated in PD pathogenesis.
    DOI:  https://doi.org/10.1038/s41419-024-06670-1
  17. Neurorehabil Neural Repair. 2024 Apr 25. 15459683241247536
    Measurement of Cerebral Glucose Metabolism in the Visual Cortex Predicts the Prognosis of Hemianopia.
    Yukihisa Suzuki, Motohiro Kiyosawa, Kenji Ishii.
      BACKGROUND AND OBJECTIVE: Homonymous hemianopia caused by cerebrovascular disease may improve over time. This study investigated whether functional neuroimaging can predict the prognosis of hemianopia due to cerebral infarction.METHODS: We studied 19 patients (10 men and 9 women) with homonymous hemianopia and compared them with 34 healthy subjects (20 men and 14 women). Cerebral glucose metabolism was measured by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), 1 to 6 months after the onset. Bilateral regions of interest (ROIs) were selected from the posterior and, anterior striate cortices, extrastriate cortex, and thalamus. Furthermore, semi-quantitative data on cerebral glucose metabolism were obtained for ROIs and compared with the data obtained for homologous regions in the contralateral hemisphere by calculating the ipsilateral/contralateral (I/C) ratio.
    RESULTS: The I/C ratio for the cerebral glucose metabolism in the posterior striate cortex was high (>0.750) in 8 patients, and the central visual field of these patients improved or showed macular sparing. The I/C ratio for cerebral glucose metabolism in the anterior striate cortex was high (>0.830) in 7 patients, and the peripheral visual field of these patients improved. However, no improvement was observed in 9 patients with a low I/C ratio for cerebral glucose metabolism in both the posterior and anterior striate cortices.
    CONCLUSION: Measurement of cerebral glucose metabolism in the striate cortex is useful for estimating visual field prognosis. Furthermore, FDG-PET is useful in predicting the prognosis of hemianopia.
    Keywords:  cerebral glucose metabolism; hemianopia; macular sparing; positron emission tomography; visual field
    DOI:  https://doi.org/10.1177/15459683241247536
  18. Antioxidants (Basel). 2024 Mar 29. pii: 416. [Epub ahead of print]13(4):
    Long-Term Region-Specific Mitochondrial Functionality Changes in Both Cerebral Hemispheres after fMCAo Model of Ischemic Stroke.
    Ksenija Lūcija Bahire, Reinis Maļuhins, Fiona Bello, Jolanta Upīte, Aleksandrs Makarovs, Baiba Jansone.
      Cerebral ischemia/reperfusion (I/R) refers to a secondary brain injury that results in mitochondrial dysfunction of variable extent, leading to neuronal cell damage. The impact of this process has mainly been studied in the short term, from the early hours up to one week after blood flow reperfusion, and in the ischemic hemisphere only. The focus of this study was to assess the long-term impacts of I/R on mitochondrial functionality using high-resolution fluorespirometry to evaluate state-dependent activities in both ischemic (ipsilateral) and non-ischemic (contralateral) hemispheres of male mice 60, 90, 120, and 180 days after I/R caused by 60-min-long filament-induced middle cerebral artery occlusion (fMCAo). Our results indicate that in cortical tissues, succinate-supported oxygen flux (Complex I&II OXPHOS state) and H2O2 production (Complex II LEAK state) were significantly decreased in the fMCAo (stroke) group ipsilateral hemisphere compared to measurements in the contralateral hemisphere 60 and 90 days after stroke. In hippocampal tissues, during the Complex I&II ET state, mitochondrial respiration was generally lower in the ipsilateral compared to the contralateral hemisphere 90 days following stroke. An aging-dependent impact on mitochondria oxygen consumption following I/R injury was observed 180 days after surgery, wherein Complex I&II activities were lowest in both hemispheres. The obtained results highlight the importance of long-term studies in the field of ischemic stroke, particularly when evaluating mitochondrial bioenergetics in specific brain regions within and between separately affected cerebral hemispheres.
    Keywords:  cerebral hemispheres; high-resolution fluorespirometry; ischemia/reperfusion injury; middle cerebral artery occlusion; mitochondrial damage; oxygen consumption; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox13040416
  19. Genes (Basel). 2024 Apr 17. pii: 500. [Epub ahead of print]15(4):
    Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
    Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide, Eirik Frengen.
      Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.
    Keywords:  Alu element; COX; Complex IV; Leigh syndrome; NDUFA4/COXFA4; WGS; encephalopathy; structural variant (SV)
    DOI:  https://doi.org/10.3390/genes15040500
  20. Prog Neuropsychopharmacol Biol Psychiatry. 2024 Apr 18. pii: S0278-5846(24)00079-4. [Epub ahead of print]133 111011
    Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia.
    Shimeng Jiao, Nana Li, Ting Cao, Liwei Wang, Hui Chen, Chenquan Lin, Hualin Cai.
      Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography-mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.
    Keywords:  Clozapine; Fatty acid; Intermittent treatment; Prefrontal cortex; Schizophrenia
    DOI:  https://doi.org/10.1016/j.pnpbp.2024.111011
  21. Int J Neonatal Screen. 2024 Mar 30. pii: 29. [Epub ahead of print]10(2):
    Management and Outcomes of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD Deficiency): A Retrospective Chart Review.
    Maria Al Bandari, Laura Nagy, Vivian Cruz, Stacy Hewson, Alomgir Hossain, Michal Inbar-Feigenberg.
      Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare genetic condition affecting the mitochondrial beta-oxidation of long-chain fatty acids. This study reports on the clinical outcomes of patients diagnosed by newborn screening with VLCAD deficiency comparing metabolic parameters, enzyme activities, molecular results, and clinical management. It is a single-center retrospective chart review of VLCAD deficiency patients who met the inclusion criteria between January 2002 and February 2020. The study included 12 patients, 7 of whom had an enzyme activity of more than 10%, and 5 patients had an enzyme activity of less than 10%. The Pearson correlation between enzyme activity and the C14:1 level at newborn screening showed a p-value of 0.0003, and the correlation between enzyme activity and the C14:1 level at diagnosis had a p-value of 0.0295. There was no clear correlation between the number of documented admissions and the enzyme activity level. Patients who had a high C14:1 value at diagnosis were started on a diet with a lower percentage of energy from long-chain triglycerides. The C14:1 result at diagnosis is the value that has been guiding our initial clinical management in asymptomatic diagnosed newborns. However, the newborn screening C14:1 value is the most sensitive predictor of low enzyme activity and may help guide dietary management.
    Keywords:  newborn screening; residual enzyme activity; very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.3390/ijns10020029
  22. Cells. 2024 Apr 18. pii: 702. [Epub ahead of print]13(8):
    Lipidomic Analysis of Plasma Extracellular Vesicles Derived from Alzheimer's Disease Patients.
    Marios G Krokidis, Krishna A Pucha, Maja Mustapic, Themis P Exarchos, Panagiotis Vlamos, Dimitrios Kapogiannis.
      Analysis of blood-based indicators of brain health could provide an understanding of early disease mechanisms and pinpoint possible intervention strategies. By examining lipid profiles in extracellular vesicles (EVs), secreted particles from all cells, including astrocytes and neurons, and circulating in clinical samples, important insights regarding the brain's composition can be gained. Herein, a targeted lipidomic analysis was carried out in EVs derived from plasma samples after removal of lipoproteins from individuals with Alzheimer's disease (AD) and healthy controls. Differences were observed for selected lipid species of glycerolipids (GLs), glycerophospholipids (GPLs), lysophospholipids (LPLs) and sphingolipids (SLs) across three distinct EV subpopulations (all-cell origin, derived by immunocapture of CD9, CD81 and CD63; neuronal origin, derived by immunocapture of L1CAM; and astrocytic origin, derived by immunocapture of GLAST). The findings provide new insights into the lipid composition of EVs isolated from plasma samples regarding specific lipid families (MG, DG, Cer, PA, PC, PE, PI, LPI, LPE, LPC), as well as differences between AD and control individuals. This study emphasizes the crucial role of plasma EV lipidomics analysis as a comprehensive approach for identifying biomarkers and biological targets in AD and related disorders, facilitating early diagnosis and potentially informing novel interventions.
    Keywords:  Alzheimer’s disease; biomarkers; exosomes; extracellular vesicles; lipid profile; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells13080702
  23. Biomolecules. 2024 Mar 26. pii: 402. [Epub ahead of print]14(4):
    Mitochondrial Dysfunction as the Major Basis of Brain Aging.
    Stephen C Bondy.
      The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse changes already begin to develop early in mid-life and gradually become more pronounced with senescence. Essentially, they are reflections of the progressive decline in effectiveness of key processes, resulting in the deviation of essential biochemical trajectories to ineffective and ultimately harmful variants of these programs. The emphasis of this review is the major role played by the mitochondria in the transition of these three important processes toward more deleterious variants as brain aging proceeds. The immune system: the shift away from an efficient immune response to a more unfocused, continuing inflammatory condition. Such a state is both ineffective and harmful. Reactive oxygen species are important intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive oxygen species contribute to the removal of aberrant or dead cells and bacteria. These processes are transformed into an excessive, untargeted, and persistent generation of pro-oxidant free radicals (oxidative stress). The normal efficient neural transmission is modified to a state of undirected, chronic low-level excitatory activity. Each of these changes is characterized by the occurrence of continuous activity that is inefficient and diffused. The signal/noise ratio of several critical biological events is thus reduced as beneficial responses are gradually replaced by their impaired and deleterious variants.
    Keywords:  aging; brain; excitotoxicity; inflammation; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/biom14040402
  24. Brain Sci. 2024 Mar 28. pii: 327. [Epub ahead of print]14(4):
    Hippocampal Lactate-Infusion Enhances Spatial Memory Correlated with Monocarboxylate Transporter 2 and Lactylation.
    Yuhan Wu, Hui Hu, Weiwei Liu, Yun Zhao, Fang Xie, Zhaowei Sun, Ling Zhang, Huafeng Dong, Xue Wang, Lingjia Qian.
      Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into the mouse's hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders.
    Keywords:  HT22; MCT2; lactate; lactylation; spatial memory
    DOI:  https://doi.org/10.3390/brainsci14040327
  25. J Neurodev Disord. 2024 Apr 24. 16(1): 21
    Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.
    Itay Tokatly Latzer, Jean-Baptiste Roullet, Wardiya Afshar-Saber, Henry H C Lee, Mariarita Bertoldi, Gabrielle E McGinty, Melissa L DiBacco, Erland Arning, Melissa Tsuboyama, Alexander Rotenberg, Thomas Opladen, Kathrin Jeltsch, Àngels García-Cazorla, Natalia Juliá-Palacios, K Michael Gibson, Mustafa Sahin, Phillip L Pearl.
      BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy.METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy.
    RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation.
    CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.
    Keywords:  Development; GABA; Neurotransmitters; Succinic semialdehyde dehydrogenase
    DOI:  https://doi.org/10.1186/s11689-024-09538-9
  26. Neurobiol Dis. 2024 Apr 18. pii: S0969-9961(24)00104-9. [Epub ahead of print] 106505
    Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects.
    Bin Tong, Yaoqi Ba, Zhengyang Li, Caidi Yang, Kangtai Su, Haodong Qi, Deju Zhang, Xiao Liu, Yuting Wu, Yixuan Chen, Jitao Ling, Jing Zhang, Peng Yu, Xiaoping Yin.
      Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features of AD are memory decline and cognitive dysfunction, while PD mainly manifests as motor dysfunction such as limb tremors, muscle rigidity abnormalities, and slow gait. Abnormalities in cholesterol, sphingolipid, and glycerophospholipid metabolism have been demonstrated to directly exacerbate the progression of AD by stimulating Aβ deposition and tau protein tangles. Indirectly, abnormal lipids can increase the burden on brain vasculature, induce insulin resistance, and affect the structure of neuronal cell membranes. Abnormal lipid metabolism leads to PD through inducing accumulation of α-syn, dysfunction of mitochondria and endoplasmic reticulum, and ferroptosis. Great progress has been made in targeting lipid metabolism abnormalities for the treatment of AD and PD in recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, and monoclonal antibodies targeting apolipoprotein E (ApoE). This review comprehensively summarizes the involvement of dysregulated lipid metabolism in the pathogenesis of AD and PD, the application of Lipid Monitoring, and emerging lipid regulatory drug targets. A better understanding of the lipidological bases of AD and PD may pave the way for developing effective prevention and treatment methods for neurodegenerative disorders.
    Keywords:  Alzheimer's disease; ApoE; Lipid metabolism; Mitochondria; PPARs; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2024.106505
  27. Brain. 2024 Apr 23. pii: awae127. [Epub ahead of print]
    Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice.
    Caroline Fernandes, Leticia Forny-Germano, Mayara M Andrade, Natalia M Lyra E Silva, Angela M Ramos-Lobo, Fernanda Meireles, Fernanda Tovar-Moll, Jean Christophe Houzel, Jose Donato, Fernanda G De Felice.
      Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) are involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has critical developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems, including energy homeostasis imbalance, melanocortin and reproductive system alterations and brain mass reduction in young adult mice. Since in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early life leptin deficiency in brain structure and memory function. Here, we demonstrate that leptin-deficient mice (LepOb) exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, as well as neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signaling in adulthood.
    Keywords:  Leptin; brain atrophy; memory impairment; neurogenesis; obesity
    DOI:  https://doi.org/10.1093/brain/awae127
  28. Acta Neurochir (Wien). 2024 Apr 24. 166(1): 190
    The effects of cerebral pressure autoregulation status and CPP levels on cerebral metabolism in pediatric traumatic brain injury.
    Fartein Velle, Anders Lewén, Tim Howells, Anders Hånell, Pelle Nilsson, Per Enblad.
      BACKGROUND: Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as marker of cerebral pressure autoregulation (CPA) and optimal CPP (CPPopt) may be assessed by identifying the CPP level with best (lowest) PRx. To evaluate the potential of CPPopt guided management in children with severe TBI, cerebral microdialysis (CMD) monitoring levels of lactate and the lactate/pyruvate ratio (LPR) (indicators of ischemia) were related to actual CPP levels, autoregulatory state (PRx) and deviations from CPPopt (ΔCPPopt).METHODS: Retrospective study of 21 children ≤ 17 years with severe TBI who had both ICP and CMD monitoring were included. CPP, PRx, CPPopt and ΔCPPopt where calculated, dichotomized and compared with CMD lactate and lactate-pyruvate ratio.
    RESULTS: Median age was 16 years (range 8-17) and median Glasgow coma scale motor score 5 (range 2-5). Both lactate (p = 0.010) and LPR (p =  < 0.001) were higher when CPP ≥ 70 mmHg than when CPP < 70. When PRx ≥ 0.1 both lactate and LPR were higher than when PRx < 0.1 (p =  < 0.001). LPR was lower (p = 0.012) when CPPopt ≥ 70 mmHg than when CPPopt < 70, but there were no differences in lactate levels. When ΔCPPopt > 10 both lactate (p = 0.026) and LPR (p = 0.002) were higher than when ΔCPPopt < -10.
    CONCLUSIONS: Increased levels of CMD lactate and LPR in children with severe TBI appears to be related to disturbed CPA (PRx). Increased lactate and LPR also seems to be associated with actual CPP levels ≥ 70 mmHg. However, higher lactate and LPR values were also seen when actual CPP was above CPPopt. Higher CPP appears harmful when CPP is above the upper limit of pressure autoregulation. The findings indicate that CPPopt guided CPP management may have potential in pediatric TBI.
    Keywords:  Autoregulation; Cerebral microdialysis; Children; Optimal cerebral perfusion pressure; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s00701-024-06085-z
  29. Mol Neurobiol. 2024 Apr 23.
    Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.
    Laura Bierhansl, Lukas Gola, Venu Narayanan, Andre Dik, Sven G Meuth, Heinz Wiendl, Stjepana Kovac.
      Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca2+ transport through the inner mitochondrial membrane. Ca2+ influx is essential for mitochondrial functions, but longer elevations of intracellular Ca2+ levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU-/-ΔN), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca2+ levels but differences in intracellular Ca2+ handling. MCU-/-ΔN reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU-/-ΔN reduces ROS levels and suppresses Ca2+ overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca2+ handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy.
    Keywords:  Hyperexcitability; Metabolism; Mitochondrial calcium uniporter (MCU); Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-024-04148-x
  30. Behav Neurosci. 2024 Apr;138(2): 125-141
    Lrp8 knockout mice fed a selenium-replete diet display subtle deficits in their spatial learning and memory function.
    Odette Leiter, David Brici, Imesh Aththanayake Mudiyan, Fang Ming Choo, Anna Winkler, Tara L Walker.
      Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
    DOI:  https://doi.org/10.1037/bne0000585
  31. Biomolecules. 2024 Apr 21. pii: 505. [Epub ahead of print]14(4):
    Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact.
    Khatereh Saei Arezoumand, Chris-Tiann Roberts, Mojgan Rastegar.
      Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target "BDNF" is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome.
    Keywords:  DNA methylation; MeCP2; RTT; Rett Syndrome; adult brain; hippocampus; metformin
    DOI:  https://doi.org/10.3390/biom14040505
  32. Physiol Rev. 2024 Apr 25.
    Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion.
    Bernard Thorens.
      Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle or glucose production by the liver. The balance between the secretion of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet b-cells and a-cells can sense variations in glycemia and respond by an appropriate secretory response to restore euglycemia. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and, thus, a vital interest in ensuring that glycemic levels never fall below ~5mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cells secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we will present the autonomic innervation of the pancreatic islets; the mechanisms of neurons activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow to integrate specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function. Finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.
    Keywords:  Autonomic nervous system; glucagon; glucose sensing; hypothalamus; insulin
    DOI:  https://doi.org/10.1152/physrev.00038.2023
  33. Biology (Basel). 2024 Mar 30. pii: 231. [Epub ahead of print]13(4):
    Formoterol Acting via β2-Adrenoreceptor Restores Mitochondrial Dysfunction Caused by Parkinson's Disease-Related UQCRC1 Mutation and Improves Mitochondrial Homeostasis Including Dynamic and Transport.
    Jui-Chih Chang, Huei-Shin Chang, Yi-Chun Chao, Ching-Shan Huang, Chin-Hsien Lin, Zhong-Sheng Wu, Hui-Ju Chang, Chin-San Liu, Chieh-Sen Chuang.
      Formoterol, a β2-adrenergic receptor (β2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson's disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of β2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD.
    Keywords:  Parkinson’s disease; formoterol; mitochondrial dynamics; mitochondrial function; ubiquinol-cytochrome c reductase core protein 1
    DOI:  https://doi.org/10.3390/biology13040231
  34. Front Mol Neurosci. 2024 ;17 1268013
    Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders.
    Michele Iacomino, Nadia Houerbi, Sara Fortuna, Jennifer Howe, Shan Li, Giovanna Scorrano, Antonella Riva, Kai-Wen Cheng, Mandy Steiman, Iskra Peltekova, Afiqah Yusuf, Simona Baldassari, Serena Tamburro, Paolo Scudieri, Ilaria Musante, Armando Di Ludovico, Sara Guerrisi, Ganna Balagura, Antonio Corsello, Stephanie Efthymiou, David Murphy, Paolo Uva, Alberto Verrotti, Chiara Fiorillo, Maurizio Delvecchio, Andrea Accogli, Mayada Elsabbagh, Henry Houlden, Stephen W Scherer, Pasquale Striano, Federico Zara, Tsui-Fen Chou, Vincenzo Salpietro.
      The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.
    Keywords:  PLAA gene; SNAREopathies; de novo variants; developmental regression; neurodevelopmental disorders; synaptic transmission
    DOI:  https://doi.org/10.3389/fnmol.2024.1268013
  35. Pharmaceuticals (Basel). 2024 Apr 12. pii: 491. [Epub ahead of print]17(4):
    Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.
    Sachin P Patil, Bella R Kuehn.
      Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.
    Keywords:  ABCA1; ABCG1; Alzheimer’s disease; apolipoprotein E; astrocytes; glycolysis; lipidation; liver X receptor (LXR)
    DOI:  https://doi.org/10.3390/ph17040491
  36. Medicine (Baltimore). 2024 Apr 26. 103(17): e37960
    Interplay of human gastrointestinal microbiota metabolites: Short-chain fatty acids and their correlation with Parkinson's disease.
    Jiaji Liu, Qi Chen, Ruijun Su.
      Short-chain fatty acids (SCFAs) are, the metabolic byproducts of intestinal microbiota that, are generated through anaerobic fermentation of undigested dietary fibers. SCFAs play a pivotal role in numerous physiological functions within the human body, including maintaining intestinal mucosal health, modulating immune functions, and regulating energy metabolism. In recent years, extensive research evidence has indicated that SCFAs are significantly involved in the onset and progression of Parkinson disease (PD). However, the precise mechanisms remain elusive. This review comprehensively summarizes the progress in understanding how SCFAs impact PD pathogenesis and the underlying mechanisms. Primarily, we delve into the synthesis, metabolism, and signal transduction of SCFAs within the human body. Subsequently, an analysis of SCFA levels in patients with PD is presented. Furthermore, we expound upon the mechanisms through which SCFAs induce inflammatory responses, oxidative stress, abnormal aggregation of alpha-synuclein, and the intricacies of the gut-brain axis. Finally, we provide a critical analysis and explore the potential therapeutic role of SCFAs as promising targets for treating PD.
    DOI:  https://doi.org/10.1097/MD.0000000000037960
  37. Medicina (Kaunas). 2024 Apr 19. pii: 662. [Epub ahead of print]60(4):
    Peak Resembling N-acetylaspartate (NAA) on Magnetic Resonance Spectroscopy of Brain Metastases.
    Jelena Ostojic, Dusko Kozic, Milana Panjkovic, Biljana Georgievski-Brkic, Dusan Dragicevic, Aleksandra Lovrenski, Jasmina Boban.
      Background and Objectives: Differentiating between a high-grade glioma (HGG) and solitary cerebral metastasis presents a challenge when using standard magnetic resonance imaging (MRI) alone. Magnetic resonance spectroscopy (MRS), an advanced MRI technique, may assist in resolving this diagnostic dilemma. N-acetylaspartate (NAA), an amino acid found uniquely in the central nervous system and in high concentrations in neurons, typically suggests HGG over metastatic lesions in spectra from ring-enhancing lesions. This study investigates exceptions to this norm. Materials and Methods: We conducted an MRS study on 49 histologically confirmed and previously untreated patients with brain metastases, employing single-voxel (SVS) techniques with short and long echo times, as well as magnetic resonance spectroscopic imaging (MRSI). Results: In our cohort, 44 out of 49 (90%) patients demonstrated a typical MR spectroscopic profile consistent with secondary deposits: a Cho peak, very low or absent Cr, absence of NAA, and the presence of lipids. A peak at approximately 2 ppm, termed the "NAA-like peak", was present in spectra obtained with both short and long echo times. Among the MRS data from 49 individuals, we observed a peak at 2.0 ppm in five brain metastases from mucinous carcinoma of the breast, mucinous non-small-cell lung adenocarcinoma, two metastatic melanomas, and one metastatic non-small-cell lung cancer. Pathohistological verification of mucin in two of these five cases suggested this peak likely represents N-acetyl glycoproteins, indicative of mucin expression in cancer cells. Conclusions: The identification of a prominent peak at 2.0 ppm could be a valuable diagnostic marker for distinguishing single ring-enhancing lesions, potentially associated with mucin-expressing metastases, offering a new avenue for diagnostic specificity in challenging cases.
    Keywords:  brain; differential diagnosis; magnetic resonance spectroscopy; metastasis; mucin; neoplasm
    DOI:  https://doi.org/10.3390/medicina60040662
  38. Adv Sci (Weinh). 2024 Apr 26. e2400426
    Adaptive Metabolic Responses Facilitate Blood-Brain Barrier Repair in Ischemic Stroke via BHB-Mediated Epigenetic Modification of ZO-1 Expression.
    Ruijie Li, Yilin Liu, Jihao Wu, Xiong Chen, Qiying Lu, Kai Xia, Congyuan Liu, Xin Sui, Yixuan Liu, Yiling Wang, Yuan Qiu, Jinsi Chen, Yi Wang, Ruijun Li, Yucheng Ba, Jiayun Fang, Weijun Huang, Zhengqi Lu, Yanbing Li, Xinxue Liao, Andy Peng Xiang, Yinong Huang.
      Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta-hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood-brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO-ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO-1 by enhancing local β-hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO-ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.
    Keywords:  ZO‐1; adipose; blood brain barrier (BBB); ketone body; lysine β‐hydroxybutyrylation (Kbhb)
    DOI:  https://doi.org/10.1002/advs.202400426
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