bims-medebr 2024-05-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒05‒26
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.
Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.
Interplay between Energy Supply and Glutamate Toxicity in the Primary Cortical Culture.
Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.
The interplay between glucose and ketone bodies in neural stem cell metabolism.
Weak neuronal glycolysis sustains cognition and organismal fitness.
The importance of choosing the appropriate cholesterol quantification method: enzymatic assay versus gas chromatography.
Low-Temperature Plasma Pretreatment Enhanced Cholesterol Detection in Brain by Desorption Electrospray Ionization-Mass Spectrometry Imaging.
Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
Omega-3 fatty acid diglyceride emulsions as a novel injectable acute therapeutic in neonatal hypoxic-ischemic brain injury.
Sex-dependent differences in tissue and blood n-3 PUFA levels following ALA or ALA + DHA feeding of liver-specific Elovl2-KO and control mice.
Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.
Isoform-specific effects of neuronal inhibition of AMPK catalytic subunit on LTD impairments in a mouse model of Alzheimer's disease.
Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.
Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.
Direct Infusion Mass Spectrometry to Rapidly Map Metabolic Flux of Substrates Labeled with Stable Isotopes.
Amino acid transporters in neurological disorders and neuroprotective effects of cysteine derivatives.
NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias.
Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons.
Evidence for a role of the basolateral amygdala in regulating regional metabolism in the stressed brain.
Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury.
Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.
Elevated C5-hydroxy acylcarnitine in an infant girl as a result of holocarboxylase synthetase deficiency.
Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.
Alzheimer's disease manifests abnormal sphingolipid metabolism.

Epilepsia. 2024 May 20.

Case for supporting astrocyte energetics in glucose transporter 1 deficiency syndrome.

Weizhi Xu, Karin Borges.

  In glucose transporter 1 deficiency syndrome (Glut1DS), glucose transport into brain is reduced due to impaired Glut1 function in endothelial cells at the blood-brain barrier. This can lead to shortages of glucose in brain and is thought to contribute to seizures. Ketogenic diets are the first-line treatment and, among many beneficial effects, provide auxiliary fuel in the form of ketone bodies that are largely metabolized by neurons. However, Glut1 is also the main glucose transporter in astrocytes. Here, we review data indicating that glucose shortage may also impact astrocytes in addition to neurons and discuss the expected negative biochemical consequences of compromised astrocytic glucose transport for neurons. Based on these effects, auxiliary fuels are needed for both cell types and adding medium chain triglycerides (MCTs) to ketogenic diets is a biochemically superior treatment for Glut1DS compared to classical ketogenic diets. MCTs provide medium chain fatty acids (MCFAs), which are largely metabolized by astrocytes and not neurons. MCFAs supply energy and contribute carbons for glutamine and γ-aminobutyric acid synthesis, and decanoic acid can also block α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors. MCTs do not compete with metabolism of ketone bodies mostly occurring in neurons. Triheptanoin, an anaplerotic but also gluconeogenic uneven MCT, may be another potential addition to ketogenic diets, although maintenance of "ketosis" can be difficult. Gene therapy has also targeted both endothelial cells and astrocytes. Other approaches to increase fuel delivery to the brain currently investigated include exchange of Glut1DS erythrocytes with healthy cells, infusion of lactate, and pharmacological improvement of glucose transport. In conclusion, although it remains difficult to assess impaired astrocytic energy metabolism in vivo, astrocytic energy needs are most likely not met by ketogenic diets in Glut1DS. Thus, we propose prospective studies including monitoring of blood MCFA levels to find optimal doses for add-on MCT to ketogenic diets and assessing of short- and long-term outcomes.

Keywords:  MCT; acetazolamide; anaplerosis; astrocyte; energy deficit; triheptanoin

DOI:  https://doi.org/10.1111/epi.18013
J Biol Chem. 2024 May 21. pii: S0021-9258(24)01904-5. [Epub ahead of print] 107403

Up-regulation of cholesterol synthesis by lysosomal defects requires a functional mitochondrial respiratory chain.

Francesco Agostini, Leonardo Pereyra, Justin Dale, King Faisal Yambire, Silvia Maglioni, Alfonso Schiavi, Natascia Ventura, Ira Milosevic, Nuno Raimundo.

Mitochondria and lysosomes are two organelles that carry out both signaling and metabolic roles in cells. Recent evidence has shown that mitochondria and lysosomes are dependent on one another, as primary defects in one cause secondary defects in the other. Although there are functional impairments in both cases, the signaling consequences of primary mitochondrial dysfunction and lysosomal defects are dissimilar. Here, we used RNA sequencing to obtain transcriptomes from cells with primary mitochondrial or lysosomal defects to identify the global cellular consequences associated with mitochondrial or lysosomal dysfunction. We used these data to determine the pathways affected by defects in both organelles, which revealed a prominent role for the cholesterol synthesis pathway. We observed a transcriptional up-regulated of this pathway in cellular and murine models of lysosomal defects, while it is transcriptionally down-regulated in cellular and murine models of mitochondrial defects. We identified a role for the post-transcriptional regulation of transcription factor SREBF1, a master regulator of cholesterol and lipid biosynthesis, in models of mitochondrial respiratory chain deficiency. Furthermore, we found that retention of Ca2+ in lysosomes of cells with mitochondrial respiratory chain defects contributes to the differential regulation of the cholesterol synthesis pathway in the mitochondrial and lysosomal defects tested. Finally, we verified in vivo, using a model of mitochondria-associated disease in C. elegans, that normalization of lysosomal Ca2+ levels results in partial rescue of the developmental delay induced by the respiratory chain deficiency.

DOI: https://doi.org/10.1016/j.jbc.2024.107403
Biomolecules. 2024 Apr 30. pii: 543. [Epub ahead of print]14(5):

Interplay between Energy Supply and Glutamate Toxicity in the Primary Cortical Culture.

Annette Vaglio-Garro, Andrea Halasz, Ema Nováková, Andreas Sebastian Gasser, Sergejs Zavadskis, Adelheid Weidinger, Andrey V Kozlov.

  Limited substrate availability because of the blood-brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity, primary cortical cells were incubated in glucose- or lactate-containing media and toxic concentrations of glutamate for 24 h. Cell death was determined by immunostaining and lactate dehydrogenase (LDH) release. Mitochondrial membrane potential and nitric oxide (NO) levels were measured using Tetramethylrhodamine, methyl ester (TMRM) and 4-Amino-5-Methylamino-2',7'-Difluorofluorescein Diacetate (DAF-FM) live staining, respectively. LDH activity was quantified in single cells in the presence of lactate (LDH substrate) and oxamate (LDH inhibitor). Nuclei of cells were stained with DAPI and neurons with MAP2. Based on the distance between neurons and glial cells, they were classified as linked (<10 µm) and non-linked (>10 µm) neurons. Lactate increased cell death rate and the mean value of endogenous NO levels compared to glucose incubations. Mitochondrial membrane potential was lower in the cells cultured with lactate, but this effect was reversed when glutamate was added to the lactate medium. LDH activity was higher in linked neurons compared to non-linked neurons, supporting the hypothesis of the existence of the lactate shuttle between astrocytes and at least a portion of neurons. In conclusion, glucose or lactate can equally preserve primary cortical neurons, but those neurons having a low level of LDH activity and incubated with lactate cannot cover high energetic demand solely with lactate and become more susceptible to glutamate toxicity.

Keywords:  cellular viability; glutamate toxicity; lactate dehydrogenase activity; lactate shuttle; mitochondria membrane potential; primary cortical cultures

DOI:  https://doi.org/10.3390/biom14050543
Int J Mol Sci. 2024 May 17. pii: 5482. [Epub ahead of print]25(10):

Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.

Corina Tamas, Flaviu Tamas, Attila Kovecsi, Alina Cehan, Adrian Balasa.

  The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) takes place in the mitochondrial matrix through β-oxidation. Glioblastoma (GBM) is the most common form of primary malignant brain tumor (45.6%), with an incidence of 3.1 per 100,000. The metabolic changes found in GBM cells and in the surrounding microenvironment are associated with proliferation, migration, and resistance to treatment. Tumor cells show a remodeling of metabolism with the use of glycolysis at the expense of oxidative phosphorylation (OXPHOS), known as the Warburg effect. Specialized fatty acids (FAs) transporters such as FAT, FABP, or FATP from the tumor microenvironment are overexpressed in GBM and contribute to the absorption and storage of an increased amount of lipids that will provide sufficient energy used for tumor growth and invasion. This review provides an overview of the key enzymes, transporters, and main regulatory pathways of FAs and ketone bodies (KBs) in normal versus GBM cells, highlighting the need to develop new therapeutic strategies to improve treatment efficacy in patients with GBM.

Keywords:  carnitine; fatty acids; glioblastoma; ketone bodies; lipid metabolism; β-oxidation

DOI:  https://doi.org/10.3390/ijms25105482
J Neurosci Res. 2024 May;102(5): e25342

The interplay between glucose and ketone bodies in neural stem cell metabolism.

Joseph W Molloy, Denis Barry.

  Glucose is the primary energy source for neural stem cells (NSCs), supporting their proliferation, differentiation, and quiescence. However, the high demand for glucose during brain development often exceeds its supply, leading to the utilization of alternative energy sources including ketone bodies. Ketone bodies, including β-hydroxybutyrate, are short-chain fatty acids produced through hepatic ketogenesis and play a crucial role in providing energy and the biosynthetic components for NSCs when required. The interplay between glucose and ketone metabolism influences NSC behavior and fate decisions, and disruptions in these metabolic pathways have been linked to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Additionally, ketone bodies exert neuroprotective effects on NSCs and modulate cellular responses to oxidative stress, energy maintenance, deacetylation, and inflammation. As such, understanding the interdependence of glucose and ketone metabolism in NSCs is crucial to understanding their roles in NSC function and their implications for neurological conditions. This article reviews the mechanisms of glucose and ketone utilization in NSCs, their impact on NSC function, and the therapeutic potential of targeting these metabolic pathways in neurological disorders.

Keywords:  glycolysis; ketone bodies; metabolism; neural stem cell; neurological conditions

DOI:  https://doi.org/10.1002/jnr.25342
Nat Metab. 2024 May 24.

Weak neuronal glycolysis sustains cognition and organismal fitness.

Daniel Jimenez-Blasco, Jesús Agulla, Rebeca Lapresa, Marina Garcia-Macia, Veronica Bobo-Jimenez, Dario Garcia-Rodriguez, Israel Manjarres-Raza, Emilio Fernandez, Yannick Jeanson, Spiro Khoury, Jean-Charles Portais, Daniel Padro, Pedro Ramos-Cabrer, Peter Carmeliet, Angeles Almeida, Juan P Bolaños.

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3-6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

DOI: https://doi.org/10.1038/s42255-024-01049-0
J Lipid Res. 2024 May 16. pii: S0022-2275(24)00066-X. [Epub ahead of print] 100561

The importance of choosing the appropriate cholesterol quantification method: enzymatic assay versus gas chromatography.

Jeanne Serrano, Lucy Martine, Yaël Grosjean, Niyazi Acar, Georges Alves, Elodie A Y Masson.

  Cholesterol is a major lipid of the animal realm with many biological roles. It is an important component of cellular membranes and a precursor of steroid hormones and bile acids. It is particularly abundant in nervous tissues and dysregulation of cholesterol metabolism has been associated with neurodegenerative diseases such as Alzheimer's and Huntington's diseases. Deciphering the pathophysiological mechanisms of these disorders often involves animal models such as mouse and Drosophila. Accurate quantification of cholesterol levels in the chosen models is a critical point of these studies. In the present work, we compare two common methods, gas chromatography coupled to flame-ionization detection (GC/FID) and a cholesterol oxidase-based fluorometric assay to measure cholesterol in mouse brain and Drosophila heads. Cholesterol levels measured by the two methods were similar for mouse brain, which presents a huge majority of cholesterol in its sterol profile. On the contrary, depending on the method, measured cholesterol levels were very different for Drosophila heads, which present a complex sterol profile with a minority of cholesterol. We showed that the enzyme-based assay is not specific for cholesterol and detects other sterols as well. This method is therefore not suited for cholesterol measurement in models such as Drosophila. Alternatively, chromatographic methods, such as GC/FID, offer the required specificity for cholesterol quantification. Understanding the limitations of the quantification techniques is essential for reliable interpretation of the results in cholesterol-related research.

Keywords:  Amplex® Red Cholesterol Assay kit; Drosophila; mouse; sterol

DOI:  https://doi.org/10.1016/j.jlr.2024.100561
J Am Soc Mass Spectrom. 2024 May 22.

Low-Temperature Plasma Pretreatment Enhanced Cholesterol Detection in Brain by Desorption Electrospray Ionization-Mass Spectrometry Imaging.

Md Muedur Rahman, Ariful Islam, Md Al Mamun, Mst Sayela Afroz, Md Mahamodun Nabi, Takumi Sakamoto, Tomohito Sato, Tomoaki Kahyo, Yutaka Takahashi, Akitoshi Okino, Mitsutoshi Setou.

Cholesterol is a primary lipid molecule in the brain that contains one-fourth of the total body cholesterol. Abnormal cholesterol homeostasis is associated with neurodegenerative disorders. Mass spectrometry imaging (MSI) technique is a powerful tool for studying lipidomics and metabolomics. Among the MSI techniques, desorption electrospray ionization-MSI (DESI-MSI) has been used advantageously to study brain lipidomics due to its soft and ambient ionization nature. However, brain cholesterol is poorly ionized. To this end, we have developed a new method for detecting brain cholesterol by DESI-MSI using low-temperature plasma (LTP) pretreatment as an ionization enhancement. In this method, the brain sections were treated with LTP for 1 and 2 min prior to DESI-MSI analyses. Interestingly, the MS signal intensity of cholesterol (at m/z 369.35 [M + H - H2O]+) was more than 2-fold higher in the 1 min LTP-treated brain section compared to the untreated section. In addition, we detected cholesterol, more specifically excluding isomers by targeted-DESI-MSI in multiple reaction monitoring (MRM) mode and similar results were observed: the signal intensity of each cholesterol transition (m/z 369.4 → 95.1, 109.1, 135.1, 147.1, and 161.1) was increased by more than 2-fold due to 1 min LTP treatment. Cholesterol showed characteristic distributions in the fiber tract region, including the corpus callosum and anterior commissure, anterior part of the brain where LTP markedly (p < 0.001) enhanced the cholesterol intensity. In addition, the distributions of some unknown analytes were exclusively detected in the LTP-treated section. Our study revealed LTP pretreatment as a potential strategy to ionize molecules that show poor ionization efficiency in the MSI technique.

DOI: https://doi.org/10.1021/jasms.4c00045
J Neuromuscul Dis. 2024 May 21.

Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.

Payam Mohassel, Meher Abdullah, Florian S Eichler, Teresa M Dunn.

  Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.

Keywords:  Serine palmitoyltransferase; amyotrophic lateral sclerosis; hereditary sensory and autonomic neuropathy; hereditary spastic paraplegia; sphingolipid biosynthesis

DOI:  https://doi.org/10.3233/JND-240014
Biomed Pharmacother. 2024 May 17. pii: S0753-3322(24)00633-4. [Epub ahead of print]175 116749

Omega-3 fatty acid diglyceride emulsions as a novel injectable acute therapeutic in neonatal hypoxic-ischemic brain injury.

Hylde Zirpoli, Maria Eugenia Bernis, Hemmen Sabir, Denny Joseph Manual Kollareth, James A Hamilton, Nasi Huang, Jesse Ng, Sergey A Sosunov, Ben Gaebler, Vadim S Ten, Richard J Deckelbaum.

  Hypoxic-ischemic encephalopathy (HIE), resulting from a lack of blood flow and oxygen before or during newborn delivery, is a leading cause of cerebral palsy and neurological disability in children. Therapeutic hypothermia (TH), the current standard of care in HIE, is only beneficial in 1 of 7-8 cases. Therefore, there is a critical need for more efficient treatments. We have previously reported that omega-3 (n-3) fatty acids (FA) carried by triglyceride (TG) lipid emulsions provide neuroprotection after experimental hypoxic-ischemic (HI) injury in neonatal mice. Herein, we propose a novel acute therapeutic approach using an n-3 diglyceride (DG) lipid emulsions. Importantly, n-3 DG preparations had much smaller particle size compared to commercially available or lab-made n-3 TG emulsions. We showed that n-3 DG molecules have the advantage of incorporating at substantially higher levels than n-3 TG into an in vitro model of phospholipid membranes. We also observed that n-3 DG after parenteral administration in neonatal mice reaches the bloodstream more rapidly than n-3 TG. Using neonatal HI brain injury models in mice and rats, we found that n-3 DG emulsions provide superior neuroprotection than n-3 TG emulsions or TH in decreasing brain infarct size. Additionally, we found that n-3 DGs attenuate microgliosis and astrogliosis. Thus, n-3 DG emulsions are a superior, promising, and novel therapy for treating HIE.

Keywords:  diglycerides; gliosis; hypoxic-ischemic encephalopathy; lipid emulsion; neuroprotection; omega-3 fatty acids

DOI:  https://doi.org/10.1016/j.biopha.2024.116749
Prostaglandins Leukot Essent Fatty Acids. 2024 May 14. pii: S0952-3278(24)00015-2. [Epub ahead of print]201 102621

Sex-dependent differences in tissue and blood n-3 PUFA levels following ALA or ALA + DHA feeding of liver-specific Elovl2-KO and control mice.

Kuorosh Rezaei, Ashley M Bejoy, Ruxandra D Rotarescu, Brinley J Klievik, Adam H Metherel.

  Docosahexaenoic acid (DHA, 22:6n-3) must be consumed from the diet or synthesized from polyunsaturated fatty acid (PUFA) precursors, such as α-linolenic acid (ALA, 18:3n-3). Elongase 2 (encoded by Elovl2 gene) catalyzes two elongation reactions in the PUFA biosynthesis pathway and may be important in regulating the observed sex differences in n-3 PUFA levels. Our aim was to determine how targeted knockout of liver Elovl2 affects tissue and blood n-3 PUFA levels in male and female C57BL/6J mice. Twenty-eight-day old male and female liver Elovl2-KO and control mice were placed onto one of two dietary protocols for a total of 8 weeks (4-8 mice per genotype, per diet, per sex): 1) an 8-week 2 % ALA in total fat diet or 2) a 4-week 2 % ALA diet followed by a 4-week 2 % ALA + 2 % DHA diet. Following this 8-week feeding period, 12-week-old mice were sacrificed and serum, red blood cells (RBC), liver, heart and brain were collected and fatty acid levels measured. Significant interaction effects (p < 0.05, sex x genotype) for serum, RBC, liver and heart DHA levels were identified. In serum and liver, DHA levels were significantly different (p < 0.01) between all groups with male controls > female controls > female KO > male KO in serum and female controls > male controls > female KO > male KO in liver. In RBCs and the heart, female controls = male controls > female KO > male KO (p < 0.001). The addition of DHA to diet removed the interaction effects on DHA levels in the serum, liver and heart, yielding a significant sex effect in serum, liver (female > male, p < 0.01) and brain (male > female, p < 0.05) and genotype effect in serum and heart (control > KO, p < 0.05). Ablation of liver Elovl2 results in significantly lower blood and tissue DHA in a sex-dependent manner, suggesting a role for Elovl2 on sex differences in n-3 PUFA levels.

Keywords:  Docosahexaenoic acid; Elongation of very long-chain (Elovl); Liver; Polyunsaturated fatty acid; Tissue-specific knockout; α-linolenic acid

DOI:  https://doi.org/10.1016/j.plefa.2024.102621
Brain. 2024 May 20. pii: awae038. [Epub ahead of print]

Imbalanced mitochondrial dynamics contributes to the pathogenesis of X-linked adrenoleukodystrophy.

Nathalie Launay, Jone Lopez-Erauskin, Patrizia Bianchi, Sanjib Guha, Janani Parameswaran, Andrea Coppa, Lorenzo Torreni, Agatha Schlüter, Stéphane Fourcade, Abraham J Paredes-Fuentes, Rafael Artuch, Carlos Casasnovas, Montserrat Ruiz, Aurora Pujol.

  The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.

Keywords:  DRP1; P110; VLCFA; X-ALD; ccfmtDNA; mitochondrial dynamics

DOI:  https://doi.org/10.1093/brain/awae038
Neurobiol Aging. 2024 May 15. pii: S0197-4580(24)00100-3. [Epub ahead of print]140 116-121

Isoform-specific effects of neuronal inhibition of AMPK catalytic subunit on LTD impairments in a mouse model of Alzheimer's disease.

Qian Yang, Xueyan Zhou, Tao Ma.

  Synaptic dysfunction is highly correlated with cognitive impairments in Alzheimer's disease (AD), the most common dementia syndrome in the elderly. Long-term potentiation (LTP) and long-term depression (LTD) are two primary forms of synaptic plasticity with opposite direction of synaptic efficiency change. Both LTD and LTD are considered to mediate the cellular process of learning and memory. Substantial studies demonstrate AD-associated deficiency of both LTP and LTD. Meanwhile, the molecular signaling mechanisms underlying impairment of synaptic plasticity, particularly LTD, are poorly understood. By taking advantage of the novel transgenic mouse models recently developed in our lab, here we aimed to investigate the roles of AMP-activated protein kinase (AMPK), a central molecular senor that plays a critical role in maintaining cellular energy homeostasis, in regulation of LTD phenotypes in AD. We found that brain-specific suppression of the AMPKα1 isoform (but not AMPKα2 isoform) was able to alleviate mGluR-LTD deficits in APP/PS1 AD mouse model. Moreover, suppression of either AMPKα isoform failed to alleviate AD-related NMDAR-dependent LTD deficits. Taken together with our recent studies on roles of AMPK signaling in AD pathophysiology, the data indicate isoform-specific roles of AMPK in mediating AD-associated synaptic and cognitive impairments.

Keywords:  AMPK; Alzheimer’s disease; Energy metabolism; LTD; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.neurobiolaging.2024.05.009
Brain Commun. 2024 ;6(3): fcae138

Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Maria-Eleni Dounavi, Elizabeth McKiernan, Michael Langsen, Sarah Gregory, Graciela Muniz-Terrera, Maria Angeles Prats-Sedano, Marius Ovidiu Mada, Guy B Williams, Brian Lawlor, Lorina Naci, Clare Mackay, Ivan Koychev, Paresh Malhotra, Karen Ritchie, Craig W Ritchie, Li Su, Adam D Waldman, John T O' Brien.

  Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.

Keywords:  APOE4; Alzheimer’s disease; MRS; brain metabolism; preclinical dementia

DOI:  https://doi.org/10.1093/braincomms/fcae138
Int J Mol Sci. 2024 May 17. pii: 5466. [Epub ahead of print]25(10):

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Danielle I Aronowitz, Tracy R Geoffrion, Sarah Piel, Sarah R Morton, Jonathan Starr, Richard W Melchior, Hunter A Gaudio, Rinat Degani, Nicholas J Widmann, M Katie Weeks, Nicolina R Ranieri, Emilie Benson, Tiffany S Ko, Daniel J Licht, Marco Hefti, J William Gaynor, Todd J Kilbaugh, Constantine D Mavroudis.

  Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

Keywords:  animal models; brain injury; cardiopulmonary bypass

DOI:  https://doi.org/10.3390/ijms25105466
Metabolites. 2024 Apr 25. pii: 246. [Epub ahead of print]14(5):

Direct Infusion Mass Spectrometry to Rapidly Map Metabolic Flux of Substrates Labeled with Stable Isotopes.

Nils W F Meijer, Susan Zwakenberg, Johan Gerrits, Denise Westland, Arif I Ardisasmita, Sabine A Fuchs, Nanda M Verhoeven-Duif, Judith J M Jans, Fried J T Zwartkruis.

  Direct infusion-high-resolution mass spectrometry (DI-HRMS) allows for rapid profiling of complex mixtures of metabolites in blood, cerebrospinal fluid, tissue samples and cultured cells. Here, we present a DI-HRMS method suitable for the rapid determination of metabolic fluxes of isotopically labeled substrates in cultured cells and organoids. We adapted an automated annotation pipeline by selecting labeled adducts that best represent the majority of 13C and/or 15N-labeled glycolytic and tricarboxylic acid cycle intermediates as well as a number of their derivatives. Furthermore, valine, leucine and several of their degradation products were included. We show that DI-HRMS can determine anticipated and unanticipated alterations in metabolic fluxes along these pathways that result from the genetic alteration of single metabolic enzymes, including pyruvate dehydrogenase (PDHA1) and glutaminase (GLS). In addition, it can precisely pinpoint metabolic adaptations to the loss of methylmalonyl-CoA mutase in patient-derived liver organoids. Our results highlight the power of DI-HRMS in combination with stable isotopically labeled compounds as an efficient screening method for fluxomics.

Keywords:  TCA cycle; direct infusion–high-resolution mass spectrometry; glutaminolysis; glycolysis; isotope tracing; organoids; patient material

DOI:  https://doi.org/10.3390/metabo14050246
Neurochem Int. 2024 May 16. pii: S0197-0186(24)00098-6. [Epub ahead of print]177 105771

Amino acid transporters in neurological disorders and neuroprotective effects of cysteine derivatives.

Santosh Kumar Adla, Heinileena Virtanen, Thanavit Thongsodsaeng, Kristiina M Huttunen.

  For most diseases and disorders occurring in the brain, the full causes behind them are yet unknown, but many show signs of dysfunction of amino acid transporters or abnormalities in amino acid metabolism. The blood-brain barrier (BBB) plays a key role in supporting the function of the central nervous system (CNS). Because of its unique structure, the BBB can maintain the optimal environment for CNS by controlling the passage of hydrophilic molecules from blood to the brain. Nutrients, such as amino acids, can cross the BBB via specific transporters. Many amino acids are essential for CNS function, and dysfunction of these amino acid transporters can lead to abnormalities in amino acid levels. This has been linked to causes behind certain genetic brain diseases, such as schizophrenia, autism spectrum disorder, and Huntington's disease (HD). One example of crucial amino acids is L-Cys, the rate-limiting factor in the biosynthesis of an important antioxidant, glutathione (GSH). Deficiency of L-Cys and GSH has been linked to oxidative stress and has been shown as a plausible cause behind certain CNS diseases, like schizophrenia and HD. This review presents the current status of potential L-Cys therapies and gives future directions that can be taken to improve amino acid transportation related to distinct CNS diseases.

Keywords:  Amino acid transport; Blood-brain-barrier; Central nervous system; Glutathione; L-Cysteine therapies; L-cysteine

DOI:  https://doi.org/10.1016/j.neuint.2024.105771
Biomolecules. 2024 Apr 28. pii: 528. [Epub ahead of print]14(5):

NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias.

Calin Deleanu, Alina Nicolescu.

  Although both localized nuclear magnetic resonance spectroscopy (MRS) and non-localized nuclear magnetic resonance spectroscopy (NMR) generate the same information, i.e., spectra generated by various groups from the structure of metabolites, they are rarely employed in the same study or by the same research group. As our review reveals, these techniques have never been applied in the same study of methylmalonic acidemia (MMA), propionic acidemia (PA) or vitamin B12 deficiency patients. On the other hand, MRS and NMR provide complementary information which is very valuable in the assessment of the severity of disease and efficiency of its treatment. Thus, MRS provides intracellular metabolic information from localized regions of the brain, while NMR provides extracellular metabolic information from biological fluids like urine, blood or cerebrospinal fluid. This paper presents an up-to-date review of the NMR and MRS studies reported to date for methylmalonic and propionic acidemias. Vitamin B12 deficiency, although in most of its cases not inherited, shares similarities in its metabolic effects with MMA and it is also covered in this review.

Keywords:  B12 deficiency; MRI; MRS; NMR; methylmalonic acidemia; nuclear magnetic resonance; propionic acidemia

DOI:  https://doi.org/10.3390/biom14050528
Neurobiol Dis. 2024 May 22. pii: S0969-9961(24)00137-2. [Epub ahead of print] 106538

Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons.

Isabel Paiva, Jonathan Seguin, Iris Grgurina, Akash Kumar Singh, Brigitte Cosquer, Damien Plassard, Laura Tzeplaeff, Stephanie Le Gras, Ludovica Cotellessa, Charles Decraene, Johanne Gambi, Rafael Alcala-Vida, Muthusamy Eswaramoorthy, Luc Buée, Jean-Christophe Cassel, Paolo Giacobini, David Blum, Karine Merienne, Tapas K Kundu, Anne-Laurence Boutillier.

  Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions.

Keywords:  Aging; CSP-TTK21; Cholesterol; Epigenetics; Histone acetylation; Tauopathy

DOI:  https://doi.org/10.1016/j.nbd.2024.106538
Sci Prog. 2024 Apr-Jun;107(2):107(2): 368504241253692

Evidence for a role of the basolateral amygdala in regulating regional metabolism in the stressed brain.

Austin M Adkins, Zachary N M Luyo, Woong-Ki Kim, Laurie L Wellman, Larry D Sanford.

  The brain regulates every physiological process in the body, including metabolism. Studies investigating brain metabolism have shown that stress can alter major metabolic processes, and that these processes can vary between regions. However, no study has investigated how metabolic pathways may be altered by stressor perception, or whether stress-responsive brain regions can also regulate metabolism. The basolateral amygdala (BLA), a region important for stress and fear, has reciprocal connections to regions responsible for metabolic regulation. In this study, we investigated how BLA influences regional metabolic profiles within the hippocampus (HPC) and medial prefrontal cortex (mPFC), regions involved in regulating the stress response and stress perception, using optogenetics in male C57BL/6 mice during footshock presentation in a yoked shuttlebox paradigm based on controllable (ES) and uncontrollable (IS) stress. RNA extracted from HPC and mPFC were loaded into NanoString® Mouse Neuroinflammation Panels, which also provides a broad view of metabolic processes, for compilation of gene expression profiles. Results showed differential regulation of carbohydrate and lipid metabolism, and insulin signaling gene expression pathways in HPC and mPFC following ES and IS, and that these differences were altered in response to optogenetic excitation or inhibition of the BLA. These findings demonstrate for the first time that individual brain regions can utilize metabolites in a way that are unique to their needs and function in response to a stressor, and that vary based on stressor controllability and influence by BLA.

Keywords:  NanoString; Stressor controllability; amygdala; brain metabolism; optogenetics

DOI:  https://doi.org/10.1177/00368504241253692
Zool Res. 2024 May 18. pii: 2095-8137(2024)03-0648-15. [Epub ahead of print]45(3): 648-662

Exploring cerebral structural and functional abnormalities in a mouse model of post-traumatic headache induced by mild traumatic brain injury.

Dan Yang, Bin-Bin Nie, Jin-Gang He, Zong-Qiang Lv, Feng-Feng Mo, Si-Yi Ouyang, Jie Wang, Juxiang Chen, Tao Tao.

  Mild traumatic brain injury (mTBI)-induced post-traumatic headache (PTH) is a pressing public health concern and leading cause of disability worldwide. Although PTH is often accompanied by neurological disorders, the exact underlying mechanism remains largely unknown. Identifying potential biomarkers may prompt the diagnosis and development of effective treatments for mTBI-induced PTH. In this study, a mouse model of mTBI-induced PTH was established to investigate its effects on cerebral structure and function during short-term recovery. Results indicated that mice with mTBI-induced PTH exhibited balance deficits during the early post-injury stage. Metabolic kinetics revealed that variations in neurotransmitters were most prominent in the cerebellum, temporal lobe/cortex, and hippocampal regions during the early stages of PTH. Additionally, variations in brain functional activities and connectivity were further detected in the early stage of PTH, particularly in the cerebellum and temporal cortex, suggesting that these regions play central roles in the mechanism underlying PTH. Moreover, our results suggested that GABA and glutamate may serve as potential diagnostic or prognostic biomarkers for PTH. Future studies should explore the specific neural circuits involved in the regulation of PTH by the cerebellum and temporal cortex, with these two regions potentially utilized as targets for non-invasive stimulation in future clinical treatment.

Keywords:  Cerebellum; Metabolic kinetics; Mild traumatic brain injury (mTBI); Post-traumatic headache (PTH); fMRI

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.323
Pharmaceuticals (Basel). 2024 May 16. pii: 648. [Epub ahead of print]17(5):

Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.

Andrea Angarita-Rodríguez, J Manuel Matiz-González, Andrés Pinzón, Andrés Felipe Aristizabal, David Ramírez, George E Barreto, Janneth González.

  Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein-protein and drug-protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases.

Keywords:  astrocytes; drug-protein network; druggable cavity; metabolic switches; therapeutic targets

DOI:  https://doi.org/10.3390/ph17050648
Clin Chim Acta. 2024 May 22. pii: S0009-8981(24)01999-5. [Epub ahead of print] 119747

Elevated C5-hydroxy acylcarnitine in an infant girl as a result of holocarboxylase synthetase deficiency.

Andrew T Nelson, Patricia M Jones, Jing Cao.

  CONTEXT: Elevated 3-hydroxyisovaleryl-/2-methyl-3-hydroxybutyryl (C5-OH) acylcarnitine in blood can result from several genetic enzyme deficiencies: 3-methylcrotonyl CoA carboxylase deficiency, 3-hydroxy 3-methylglutaryl-CoA lyase deficiency, beta-ketothiolase deficiency, 2-methyl 3-hydroxybutyryl-CoA dehydrogenase deficiency, primary 3-methylglutaconic aciduria, multiple biotin-dependent carboxylase deficiencies and biotin metabolism disorders. Biochemical tests help differentiate these causes while molecular tests are usually required for definitive diagnosis.CASE DESCRIPTION: We reported an infant girl with newborn screen findings of elevated C5-OH acylcarnitine. She had further confirmational biochemical testing including plasma acylcarnitines, urine organic acids and urine acylglycines. Patient's urine organic acid profile showed markedly increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Urine acylglycine test reported a large increase of 3-methylcrotonylglycine and plasma acylcarnitine test repeated the finding of elevated C5-OH acylcarnitine together with propionyl acylcarnitine elevation. These results point to multiple biotin-dependent carboxylase deficiency. Molecular tests revealed a homozygous mutation in the holocarboxylase synthetase gene that is consistent with her biochemical test findings. This case demonstrated the critical role of newborn screen in identifying inborn errors of metabolism that may otherwise be missed and lead to severe morbidity later in life. It also showcased that both biochemical and molecular tests are essential tools in the diagnosis.

Keywords:  Biotin; C5-hydroxy acylcarnitine; Holocarboxylase synthetase deficiency; Inborn errors of metabolism

DOI:  https://doi.org/10.1016/j.cca.2024.119747
Genes (Basel). 2024 May 11. pii: 615. [Epub ahead of print]15(5):

Identification of a Novel Indel Variant in the DARS2 Gene in Russian Patients with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation.

Fatima M Bostanova, Polina G Tsygankova, Elena A Larshina, Ilya O Nagornov, Yulia V Evseeva, Irina L Krutikhina, Marina E Dzhentemirova, Marina N Kashlakova, Marina S Petukhova, Inna V Sharkova, Ekaterina Y Zakharova.

  BACKGROUND: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement.CASE PRESENTATION: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy.

Keywords:  leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL); next-generation sequencing (NGS); targeted gene sequencing; the DARS2 gene; white matter disorder

DOI:  https://doi.org/10.3390/genes15050615
Front Aging Neurosci. 2024 ;16 1368839

Alzheimer's disease manifests abnormal sphingolipid metabolism.

Baasanjav Uranbileg, Hideaki Isago, Eri Sakai, Masayuki Kubota, Yuko Saito, Makoto Kurano.

  Introduction: Alzheimer's disease (AD) is associated with disturbed metabolism, prompting investigations into specific metabolic pathways that may contribute to its pathogenesis and pathology. Sphingolipids have garnered attention due to their known physiological impact on various diseases.Methods: We conducted comprehensive profiling of sphingolipids to understand their possible role in AD. Sphingolipid levels were measured in AD brains, Cerad score B brains, and controls, as well as in induced pluripotent stem (iPS) cells (AD, PS, and control), using liquid chromatography mass spectrometry.
Results: AD brains exhibited higher levels of sphingosine (Sph), total ceramide 1-phosphate (Cer1P), and total ceramide (Cer) compared to control and Cerad-B brains. Deoxy-ceramide (Deoxy-Cer) was elevated in Cerad-B and AD brains compared to controls, with increased sphingomyelin (SM) levels exclusively in Cerad-B brains. Analysis of cell lysates revealed elevated dihydroceramide (dhSph), total Cer1P, and total SM in AD and PS cells versus controls. Multivariate analysis highlighted the relevance of Sph, Cer, Cer1P, and SM in AD pathology. Machine learning identified Sph, Cer, and Cer1P as key contributors to AD.
Discussion: Our findings suggest the potential importance of Sph, Cer1P, Cer, and SM in the context of AD pathology. This underscores the significance of sphingolipid metabolism in understanding and potentially targeting mechanisms underlying AD.

Keywords:  Alzheimer’s disease (AD); ceramide (Cer); ceramide 1-phosphate (Cer1P); sphingomyelin (SM); sphingosine (Sph)

DOI:  https://doi.org/10.3389/fnagi.2024.1368839