bims-medebr 2024-02-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–02–04
eleven papers selected by
Regina F. Fernández, Johns Hopkins University

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.
Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis.
Brain energetics and glucose transport in metabolic diseases: role in neurodegeneration.
NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport.
The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.
The effects of long-term lactate and high-intensity interval training (HIIT) on brain neuroplasticity of aged mice.
Metabolic stroke-like events in a girl with pyruvate dehydrogenase complex deficiency caused by a novel de novo mutation in PDHA1.
Disruption of mitochondrial pyruvate oxidation in dorsal root ganglia drives persistent nociceptive sensitization and causes pervasive transcriptomic alterations.
N-acetyl aspartate levels early after ischemic stroke accurately reflect long-term brain damage.
Newborn screening for aromatic l-amino acid decarboxylase deficiency - Strategies, results, and implication for prevalence calculations.
Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis.

Brain. 2024 Feb 01. pii: awae028. [Epub ahead of print]

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

Hazem Ahmed, Yuqin Wang, William J Griffiths, Allan I Levey, Irina Pikuleva, Steven H Liang, Ahmed Haider.

  Cholesterol homeostasis is impaired in Alzheimer's disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the formation of amyloid-β (Aβ) formation and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Further, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with positron emission tomography, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in AD patients - with the ultimate aim to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in AD. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in AD patients.

Keywords:  Alzheimer’s disease; brain cholesterol homeostasis; cholesterol lowering therapy; cytochrome P450 46A1 (CYP46A1); translational molecular imaging

DOI:  https://doi.org/10.1093/brain/awae028
J Mol Med (Berl). 2024 Jan 29.

Evidence for alterations in lipid profiles and biophysical properties of lipid rafts from spinal cord in sporadic amyotrophic lateral sclerosis.

Mario Díaz, Noemí Fabelo, M Virginia Martín, Guido Santos, Isidre Ferrer.

  Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease affecting motor neurons in the spinal cord and brainstem whose etiopathogenesis remains unclear. Recent studies have linked major neurodegenerative diseases with altered function of multimolecular lipid-protein complexes named lipid rafts. In the present study, we have isolated lipid rafts from the anterior horn of the spinal cords of controls and ALS individuals and analysed their lipid composition. We found that ALS affects levels of different fatty acids, lipid classes and related ratios and indexes. The most significant changes affected the contents of n-9/n-7 monounsaturated fatty acids and arachidonic acid, the main n-6 long-chain polyunsaturated fatty acid (LCPUFA), which were higher in ALS lipid rafts. Paralleling these findings, ALS lipid rafts lower saturates-to-unsaturates ratio compared to controls. Further, levels of cholesteryl ester (SE) and anionic-to-zwitterionic phospholipids ratio were augmented in ALS lipid rafts, while sulfatide contents were reduced. Further, regression analyses revealed augmented SE esterification to (mono)unsaturated fatty acids in ALS, but to saturates in controls. Overall, these changes indicate that lipid rafts from ALS spinal cord undergo destabilization of the lipid structure, which might impact their biophysical properties, likely leading to more fluid membranes. Indeed, estimations of membrane microviscosity confirmed less viscous membranes in ALS, as well as more mobile yet smaller lipid rafts compared to surrounding membranes. Overall, these results demonstrate that the changes in ALS lipid rafts are unrelated to oxidative stress, but to anomalies in lipid metabolism and/or lipid raft membrane biogenesis in motor neurons. KEY MESSAGES: The lipid matrix of multimolecular membrane complexes named lipid rafts are altered in human spinal cord in sporadic amyotrophic lateral sclerosis (ALS). Lipid rafts from ALS spinal cord contain higher levels of n-6 LCPUFA (but not n-3 LCPUFA), n-7/n-9 monounsaturates and lower saturates-to-unsaturates ratio. ALS lipid rafts display increased contents of cholesteryl esters, anomalous anionic-to-zwitterionic phospholipids and phospholipid remodelling and reduced sulphated and total sphingolipid levels, compared to control lipid rafts. Destabilization of the lipid structure of lipid raft affects their biophysical properties and leads to more fluid, less viscous membrane microdomains. The changes in ALS lipid rafts are unlikely related to increased oxidative stress, but to anomalies in lipid metabolism and/or raft membrane biogenesis in motor neurons.

Keywords:  Amyotrophic lateral sclerosis; Arachidonic acid; Cholesteryl esters; Domain mobility; Lipid rafts; Membrane microviscosity; Neurodegenerative diseases; Neurolipids

DOI:  https://doi.org/10.1007/s00109-024-02419-7
Nutr Neurosci. 2024 Jan 31. 1-12

Brain energetics and glucose transport in metabolic diseases: role in neurodegeneration.

Orquídea G Méndez-Flores, Luisa C Hernández-Kelly, Tatiana N Olivares-Bañuelos, Gabriel López-Ramírez, Arturo Ortega.

   OBJECTIVES: Neurons and glial cells are the main functional and structural elements of the brain, and the former depends on the latter for their nutritional, functional and structural organization, as well as for their energy maintenance.
METHODS: Glucose is the main metabolic source that fulfills energetic demands, either by direct anaplerosis or through its conversion to metabolic intermediates. Development of some neurodegenerative diseases have been related with modifications in the expression and/or function of glial glucose transporters, which might cause physiological and/or pathological disturbances of brain metabolism. In the present contribution, we summarized the experimental findings that describe the exquisite adjustment in expression and function of glial glucose transporters from physiologic to pathologic metabolism, and its relevance to neurodegenerative diseases.
RESULTS: A exhaustive literature review was done in order to gain insight into the role of brain energetics in neurodegenerative disease. This study made evident a critical involvement of glucose transporters and thus brain energetics in the development of neurodegenerative diseases.
DISCUSSION: An exquisite adjustment in the expression and function of glial glucose transporters from physiologic to pathologic metabolism is a biochemical signature of neurodegenerative diseases.

Keywords:  Glia cells; brain energetic; glucose transporters; metabolic coupling; neuropathologies

DOI:  https://doi.org/10.1080/1028415X.2024.2306427
Mol Neurodegener. 2024 Jan 29. 19(1): 13

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport.

Sen Yang, Zhen-Xian Niou, Andrea Enriquez, Jacob LaMar, Jui-Yen Huang, Karen Ling, Paymaan Jafar-Nejad, Jonathan Gilley, Michael P Coleman, Jason M Tennessen, Vidhya Rangaraju, Hui-Chen Lu.

BACKGROUND: Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer's, Parkinson's, and Huntington's disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function.
METHODS: We generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of techniques, including genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos.
RESULTS: We provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide "on-board" ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons.
CONCLUSION: NMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

DOI: https://doi.org/10.1186/s13024-023-00690-9
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00018-8. [Epub ahead of print]1870(3): 167033

The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.

Valeria Balmaceda, Timea Komlódi, Marten Szibor, Erich Gnaiger, Anthony L Moore, Erika Fernandez-Vizarra, Carlo Viscomi.

  Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.

Keywords:  Coenzyme Q redox state; Complex I deficiency; Complex III deficiency; Isolated mitochondria; Oxygen consumption; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbadis.2024.167033
Heliyon. 2024 Jan 30. 10(2): e24421

The effects of long-term lactate and high-intensity interval training (HIIT) on brain neuroplasticity of aged mice.

Zhou Lei, Soroosh Mozaffaritabar, Takuji Kawamura, Atsuko Koike, Attila Kolonics, Johanna Kéringer, Ricardo A Pinho, Jingquan Sun, Ruonan Shangguan, Zsolt Radák.

  Extensive research has confirmed numerous advantages of exercise for promoting brain health. More recent studies have proposed the potential benefits of lactate, the by-product of exercise, in various aspects of brain function and disorders. However, there remains a gap in understanding the effects of lactate dosage and its impact on aged rodents. The present study first examined the long-term effects of three different doses of lactate intervention (2000 mg/kg, 1000 mg/kg, and 500 mg/kg) and high-intensity interval training (HIIT) on aging mice (20-22 months) as the 1st experiment. Subsequently, in the 2nd experiment, we investigated the long-term effects of 500 mg/kg lactate intervention and HIIT on brain neuroplasticity in aged mice (25-27 months). The results of the 1st experiment demonstrated that both HIIT and different doses of lactate intervention (500 mg/kg and 2000 mg/kg) positively impacted the neuroplasticity biomarker VEGF in the hippocampus of aging mice. Subsequently, the 2nd experiment revealed that long-term HIIT significantly improved the performance of mice in open-field, novel object recognition, and passive avoidance tests. However, lactate intervention did not significantly affect these behavioral tests. Moreover, compared to the control group, both HIIT and lactate intervention positively influenced the angiogenesis signaling pathway (p/t-AKT/ENOS/VEGF), mitochondrial biomarker (SDHA), and metabolic protein (p/t-CREB, p/t-HSL, and LDH) in the hippocampus of aged mice. Notably, only lactate intervention significantly elevated the BDNF (PGC-1α, SIRT1, and BDNF) signaling pathway and metabolic content (lactate and pyruvate). In the end, long-term HIIT and lactate intervention failed to change the protein expression of p/t-MTOR, iNOS, nNOS, HIF-1α, SYNAPSIN, SIRT3, NAMPT, CS, FNDC5 and Pan Lactic aid-Lysine in the hippocampus of aged mice. In summary, the present study proved that long-term HIIT and lactate treatment have positive effects on the brain functions of aged mice, suggesting the potential usage of lactate as a therapeutic strategy in neurodegenerative diseases in the elderly population.

Keywords:  Aging; Brain function; Exercise; Hippocampus; Lactate; Lactylation

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24421
Neurol Sci. 2024 Jan 30.

Metabolic stroke-like events in a girl with pyruvate dehydrogenase complex deficiency caused by a novel de novo mutation in PDHA1.

Simona Fecarotta, Alessandra D'Amico, Simona Di Gennaro, Marianna Alagia, Alessandro Rossi, Claudia Zuppaldi, Giancarlo Parenti, Gaetano Terrone.

DOI: https://doi.org/10.1007/s10072-024-07355-5
Pain. 2024 Jan 23.

Disruption of mitochondrial pyruvate oxidation in dorsal root ganglia drives persistent nociceptive sensitization and causes pervasive transcriptomic alterations.

Md Mamunul Haque, Panjamurthy Kuppusamy, Ohannes K Melemedjian.

ABSTRACT: Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain.

DOI: https://doi.org/10.1097/j.pain.0000000000003158
Heliyon. 2024 Jan 30. 10(2): e24233

N-acetyl aspartate levels early after ischemic stroke accurately reflect long-term brain damage.

Henrik Hasseldam, Rune Skovgaard Rasmussen, Henrik Hussein El Ali, Flemming Fryd Johansen.

   Background: Estimation of brain damage following an ischemic stroke is most often performed within the first few days after the insult, where large amounts of oedematous fluid have accumulated. This can potentially hamper correct measurement of infarcted area, since oedema formation poorly reflects infarct size. This study presents a non-invasive, easily applicable and reliable method to accurately predict long-term evolution and late-stage infarction.
Objective: We performed a longitudinal analysis of brain infarct evolution after MCAO in mice, in order to determine whether water-compensated N-Acetylaspartate (NAA) levels in the infarct area, measured 24 h after the insult, is a suitable marker for late-stage infarction and thereby prognosis.
Methods: Twenty mice were divided into 4 groups and scanned longitudinally at different time-points after MCAO, followed by euthanisation for histology: Group 1) MRI/MRS at day 1 after MCAO (n = 4), Group 2) MRI/MRS at days 1 and 7 after MCAO (n = 5), Group 3) MRI/MRS at days 1, 7, and 14 after MCAO (n = 3), and Group 4) MRI/MRS at days 1, 7, 14, and 28 after MCAO (n = 4). At days 1, 7, 14, and 28, NAA levels were correlated with histological determination of neuronal death based on Nissl and H&E stainings.
Results: Twenty-four hours after the insult, NAA levels in the infarcted area decreased by 35 %, but steadily returned to normal after 28 days. In the acute phases, NAA levels strongly correlated with loss of Nissl substance (r2 = -0.874, p = 0.002), whereas NAA levels in later stages reflect glial metabolism and tissue reorganisation. Most importantly, NAA levels 24 h after MCAO was highly correlated with late stage infarction at days 14 and 28 (r2 = 0.73, p = 0.01), in contrast to T2 (r2 = 0.06, p = 0.59).
Conclusions: By using a fixed voxel, which is easily positioned in the affected area, it is possible to obtain reliable measures of the extent of neuronal loss at early time points independent of oedema and brain deformation. Importantly, NAA levels 24 h after MCAO accurately reflects late-stage infarction, suggesting that NAA is a useful prognostic biomarker early after an ischemic stroke.

Keywords:  MCAO; MRI; NAA; Prognostic marker; infarct maturation

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24233
Mol Genet Metab. 2024 Jan 29. pii: S1096-7192(24)00033-7. [Epub ahead of print] 108148

Newborn screening for aromatic l-amino acid decarboxylase deficiency - Strategies, results, and implication for prevalence calculations.

Anna T Reischl-Hajiabadi, Jürgen G Okun, Dirk Kohlmüller, Georgi Manukjan, Sebastian Hegert, Jürgen Durner, Elfriede Schuhmann, Friederike Hörster, Ulrike Mütze, Patrik Feyh, Georg F Hoffmann, Wulf Röschinger, Nils Janzen, Thomas Opladen.

   BACKGROUND: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal-recessive neurometabolic disorder caused by variants in dopa decarboxylase (DDC) gene, resulting in a severe combined deficiency of serotonin, dopamine, norepinephrine, and epinephrine. Birth prevalence of AADCD varies by population. In pilot studies, 3-O-methyldopa (3-OMD) was shown to be a reliable biomarker for AADCD in high-throughput newborn screening (NBS) allowing an early diagnosis and access to gene therapy. To evaluate the usefulness of this method for routine NBS, 3-OMD screening results from the largest three German NBS centers were analyzed.
METHODS: A prospective, multicenter (n = 3) NBS pilot study evaluated screening for AADCD by quantifying 3-OMD in dried blood spots (DBS) using tandem mass spectrometry (MS/MS).
RESULTS: In total, 766,660 neonates were screened from January 2021 until June 2023 with 766,647 with unremarkable AADCD NBS (766,443 by 1st-tier analysis and 204 by 2nd-tier analysis) and 13 with positive NBS result recalled for confirmatory diagnostics (recall-rate about 1:59,000). Molecular genetic analysis confirmed AADCD (c.79C > T p.[Arg27Cys] in Exon 2 und c.215 A > C p.[His72Pro] in Exon 3) in one infant. Another individual was highly suspected with AADCD but died before confirmation (overall positive predictive value 0.15). False-positive results were caused by maternal L-Dopa use (n = 2) and prematurity (30th and 36th week of gestation, n = 2). However, in 63% (n = 7) the underlying etiology for false positive results remained unexplained. Estimated birth prevalence (95% confidence interval) was 1:766,660 (95% CI 1:775,194; 1:769,231) to 1:383,330 (95% CI 1:384,615; 1:383,142). The identified child remained asymptomatic until last follow up at the age of 9 months.
CONCLUSIONS: The proposed screening strategy with 3-OMD detection in DBS is feasible and effective to identify individuals with AADCD. The estimated birth prevalence supports earlier estimations and confirms AADCD as a very rare disorder. Pre-symptomatic identification by NBS allows a disease severity adapted drug support to diminish clinical complications until individuals are old enough for the application of the gene therapy.

Keywords:  3-O-methyldopa; 3-OMD; AADC deficiency; Aromatic l-amino acid decarboxylase; Neonatal screening

DOI:  https://doi.org/10.1016/j.ymgme.2024.108148
J Lipid Res. 2024 Jan 25. pii: S0022-2275(24)00013-0. [Epub ahead of print] 100508

Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis.

Natsuki Kita, Asuka Hamamoto, Siddabasave Gowda B Gowda, Hiroyuki Takatsu, Kazuhisa Nakayama, Makoto Arita, Shu-Ping Hui, Hye-Won Shin.

  Lipid transport is an essential cellular process with importance to human health, disease development, and therapeutic strategies. Type IV P-type ATPases (P4-ATPases) have been identified as membrane lipid flippases by utilizing nitrobenzoxadiazole (NBD)-labeled lipids as substrates. Among the 14 human P4-ATPases, ATP10D was shown to flip NBD-glucosylceramide (GlcCer) across the plasma membrane. Here, we found that conversion of incorporated GlcCer (d18:1/12:0) to other sphingolipids is accelerated in cells exogenously expressing ATP10D but not its ATPase-deficient mutant. These findings suggest that 1) ATP10D flips unmodified GlcCer as well as NBD-GlcCer at the plasma membrane and 2) ATP10D can translocate extracellular GlcCer which is subsequently converted to other metabolites. Notably, exogenous expression of ATP10D led to the reduction in cellular hexosylceramide (HexCer) levels. Moreover, the expression of GlcCer flippases, including ATP10D, also reduced cellular HexCer levels in fibroblasts derived from patients with Gaucher disease (GD), which is a lysosomal storage disorder with excess GlcCer accumulation. Our study highlights the contribution of ATP10D to the regulation of cellular GlcCer levels and maintaining lipid homeostasis.

Keywords:  P4-ATPase; flippase; glucosylceramide; glycosphingolipid; lipid transport; sphingolipid

DOI:  https://doi.org/10.1016/j.jlr.2024.100508