bims-medebr 2024-06-09 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒06‒09
thirteen papers selected by
Regina F. Fernández, Johns Hopkins University

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
Energy substrate supplementation increases ATP levels and is protective to PD neurons.
Brain development and bioenergetic changes.
Cholesterol Metabolism in Neurodegenerative Diseases.
Region-specific cerebral metabolic alterations in Parkinson's disease patients with/without mild cognitive impairment.
TANGO2 deficiency disease is predominantly caused by a lipid imbalance.
The use of ketogenic diets in children living with drug-resistant epilepsy, glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency: A scoping review.
Hyperpolarized [2-13C, 3-2H3]Pyruvate Detects Hepatic Gluconeogenesis In Vivo.
Effects of short-term supplementation with DHA-enriched phosphatidylcholine and phosphatidylserine on lipid profiles in the brain and liver of n-3 PUFA-deficient mice in early life after weaning.
Arginine, glycine, and creatine supplementation improves symptoms in a female with creatine transporter deficiency.
Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system.
Brain lipid sensing and the neural control of energy balance.
Senescent glia link mitochondrial dysfunction and lipid accumulation.

Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.

  A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
Curr Res Pharmacol Drug Discov. 2024 ;6 100187

Energy substrate supplementation increases ATP levels and is protective to PD neurons.

Andrey Y Vinokurov, Marina Y Pogonyalova, Larisa Andreeva, Andrey Y Abramov, Plamena R Angelova.

  Alteration of mitochondrial metabolism by various mutations or toxins leads to various neurological conditions. Age-related changes in energy metabolism could also play the role of a trigger for neurodegenerative disorders. Nonetheless, it is not clear if restoration of ATP production or supplementation of brain cells with substrates for energy production could be neuroprotective. Using primary neurons and astrocytes, and neurons with familial forms of neurodegenerative disorders we studied whether various substrates of energy metabolism could improve mitochondrial metabolism and stimulate ATP production, and whether increased ATP levels could protect cells against glutamate excitotoxicity and neurodegeneration. We found that supplementation of neurons with several substrates, or combination thereof, for the TCA cycle and cellular respiration, and oxidative phosphorylation resulted in an increase in mitochondrial NADH level and in mitochondrial membrane potential and led to an increased level of ATP in neurons and astrocytes. Subsequently, these cells were protected against energy deprivation during ischemia or glutamate excitotoxicity. Provision of substrates for energy metabolism to cells with familial forms of Parkinson's disease also prevented triggering of cell death. Thus, restoration of energy metabolism and increase of ATP production can play neuroprotective role in neurodegeneration. A combination of a succinate salt of choline and nicotinamide provided the best results.

Keywords:  Ageing; Brain energy metabolism; Neurodegeneration; Parkinson's disease; Substrate supplementation

DOI:  https://doi.org/10.1016/j.crphar.2024.100187
Neurobiol Dis. 2024 Jun 05. pii: S0969-9961(24)00149-9. [Epub ahead of print] 106550

Brain development and bioenergetic changes.

Arjun Rajan, Ryann M Fame.

  Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease.

Keywords:  Bioenergetic pathways; Neural progenitors; Neurodevelopmental diseases

DOI:  https://doi.org/10.1016/j.nbd.2024.106550
Antioxid Redox Signal. 2024 Jun 06.

Cholesterol Metabolism in Neurodegenerative Diseases.

Keqiang He, Zhiwei Zhao, Juan Zhang, Dingfeng Li, Sheng Wang, Qiang Liu.

SIGNIFICANCE: Cholesterol plays a crucial role in brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).RECENT ADVANCES: A significant advancement has been the identification of astrocyte-derived ApoE as a key regulator of de novo cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. Additionally, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions.
CRITICAL ISSUES: Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential.
FUTURE DIRECTION: Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. Additionally, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptom.

DOI: https://doi.org/10.1089/ars.2024.0674
Neuroscience. 2024 Jun 05. pii: S0306-4522(24)00241-0. [Epub ahead of print]

Region-specific cerebral metabolic alterations in Parkinson's disease patients with/without mild cognitive impairment.

Mingming Huang, Hui Yu, Xinyue Lyu, Wei Pu, Jianhong Yin, Bo Gao.

  N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) are brain metabolites involved in some key neuronal functions within the brain, such as cognitive function. The aim of this study was to investigate whether parkinson's disease (PD) with different cognitive status induces regional brain metabolite differences. 38 diagnosed PD patients, including 18 PD patients with normal cognitive (PDN), 20 PD subjects with cognitive impairment (PDMCI) and 25 healthy controls (HC) participated in this study. All subjects underwent a single-voxel proton MR spectroscopy (1H-MRS) on a 3T scanner. 1H-MRS were obtained from bilateral PCC, left thalamus and PFC regions in all subjects, respectively. Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. PDMCI patients showed a significant reduction of NAA, Cho and tCr in the PCC and left thalamus, compared to healthy controls; whereas lower levels of NAA and Cho in thalamus were found in PDN patients. Moreover, Cho and tCr levels were positively correlated with MMSE scores. Both NAA and tCr in PCC levels were positively correlated with MMSE and MoCA scores. The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. This study provides preliminary evidence that thalamic, PCC and PFC neurometabolic alterations occur in PD patients with cognition decline. . Findings of this study indicate that NAA and tCr abnormalities in PCC and thalamus might be used as a biomarker to track cognitive decline in Parkinson's disease in clinical settings.

Keywords:  Cerebral metabolic; Cognitive impairment; Parkinson’s disease; Posterior cingulate cortex; Thalamus

DOI:  https://doi.org/10.1016/j.neuroscience.2024.05.039
Dis Model Mech. 2024 Jun 01. pii: dmm050662. [Epub ahead of print]17(6):

TANGO2 deficiency disease is predominantly caused by a lipid imbalance.

Michael Sacher, Jay DeLoriea, Mahsa Mehranfar, Cody Casey, Aaliya Naaz, Chiara Gamberi.

  TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

Keywords:  Lipid imbalance; Metabolic crises; Neurodevelopmental disease; TANGO2 deficiency disease

DOI:  https://doi.org/10.1242/dmm.050662
J Hum Nutr Diet. 2024 Jun 04.

The use of ketogenic diets in children living with drug-resistant epilepsy, glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency: A scoping review.

Tracy Cameron, Karen Allan, Kay Cooper.

  BACKGROUND: The ketogenic diet (KD) is a high fat, moderate protein and very low carbohydrate diet. It can be used as a medical treatment for drug-resistant epilepsy (DRE), glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency. The aim of this scoping review was to map the KD literature, with a focus on epilepsy and associated metabolic conditions, to summarise the current evidence-base and identify any gaps.METHODS: This review was conducted using JBI scoping review methodological guidance and the PRISMA extension for scoping reviews reporting guidance. A comprehensive literature search was conducted in September 2021 and updated in February 2024 using MEDLINE, CINAHL, AMED, EmBASE, CAB Abstracts, Scopus and Food Science Source databases.
RESULTS: The initial search yielded 2721 studies and ultimately, data were extracted from 320 studies that fulfilled inclusion criteria for the review. There were five qualitative studies, and the remainder were quantitative, including 23 randomised controlled trials (RCTs) and seven quasi-experimental studies. The USA published the highest number of KD studies followed by China, South Korea and the UK. Most studies focused on the classical KD and DRE. The studies key findings suggest that the KD is efficacious, safe and tolerable.
CONCLUSIONS: There are opportunities available to expand the scope of future KD research, particularly to conduct high-quality RCTs and further qualitative research focused on the child's needs and family support to improve the effectiveness of KDs.

Keywords:  children; epilepsy; glucose transporter 1 deficiency syndrome; ketogenic diet; pyruvate dehydrogenase deficiency; scoping review

DOI:  https://doi.org/10.1111/jhn.13324
ACS Sens. 2024 Jun 05.

Hyperpolarized [2-13C, 3-2H3]Pyruvate Detects Hepatic Gluconeogenesis In Vivo.

Mai T Huynh, Zohreh Erfani, Zoltán Kovács, Jae Mo Park.

  The feasibility of hyperpolarized [2-13C, 3-2H3]pyruvate for probing gluconeogenesis in vivo was investigated in this study. Whereas hyperpolarized [1-13C]pyruvate has clear access to metabolic pathways that convert pyruvate to lactate, alanine, and bicarbonate, its utility for assessing pyruvate carboxylation and gluconeogenesis has been limited by technical challenges, including spectral overlap and an obscure enzymatic step that decarboxylates the labeled carbon. To achieve unambiguous detection of gluconeogenic products, the carbonyl carbon in pyruvate was labeled with 13C. To prolong the T1 relaxation time, [2-13C, 3-2H3]pyruvate was synthesized and dissolved with D2O after dynamic nuclear polarization. The T1 of [2-13C, 3-2H3]pyruvate in D2O could be improved by 76.9% (79.6 s at 1 T and 74.5 s at 3 T) as compared to [2-13C]pyruvate in water. Hyperpolarized [2-13C, 3-2H3]pyruvate with D2O dissolution was applied to rat livers in vivo under normal feeding and fasting conditions. A gluconeogenic product, [2-13C]phosphoenolpyruvate, was observed at 149.9 ppm from fasted rats only, highlighting the utility of [2-13C, 3-2H3]pyruvate in detecting key gluconeogenic enzyme activities such as pyruvate carboxylase and phosphoenolpyruvate carboxykinase in vivo.

Keywords:  carbon-13 MRS; gluconeogenesis; hyperpolarization; liver metabolism; phosphoenolpyruvate carboxykinase; pyruvate carboxylase

DOI:  https://doi.org/10.1021/acssensors.4c00734
J Sci Food Agric. 2024 Jun 06.

Effects of short-term supplementation with DHA-enriched phosphatidylcholine and phosphatidylserine on lipid profiles in the brain and liver of n-3 PUFA-deficient mice in early life after weaning.

Wei-Ya Zuo, Min Wen, Ying-Cai Zhao, Xiao-Yue Li, Chang-Hu Xue, Teruyoshi Yanagita, Yu-Ming Wang, Tian-Tian Zhang.

  BACKGROUND: Lack of n-3 polyunsaturated fatty acids during the period of maternity drastically lowers the docosahexaenoic acid (DHA) level in the brain of offspring and studies have demonstrated that different molecular forms of DHA are beneficial to brain development. The aim of this study was to investigate the effect of short-term supplementation with DHA-enriched phosphatidylserine (PS) and phosphatidylcholine (PC) on DHA levels in the liver and brain of congenital n-3-deficient mice.RESULTS: Dietary supplementation with DHA significantly changed the fatty acid composition of various phospholipid molecules in the cerebral cortex and liver while DHA-enriched phospholipid was more effective than DHA triglyceride (TG) in increasing brain and liver DHA. Both DHA-PS and DHA-PC could effectively increase the DHA levels, but DHA in the PS form was superior to PC in the contribution of DHA content in the brain ether-linked PC (ePC) and liver lyso-phosphatidylcholine molecular species. DHA-PC showed more significant effects on the increase of DHA in liver TG, PC, ePC, phosphatidylethanolamine (PE) and PE plasmalogen (pPE) molecular species and decreasing the arachidonic acid level in liver PC plasmalogen, ePC, PE and pPE molecular species compared with DHA-PS.
CONCLUSION: The effect of dietary interventions with different molecular forms of DHA for brain and liver lipid profiles is different, which may provide theoretical guidance for dietary supplementation of DHA for people. © 2024 Society of Chemical Industry.

Keywords:  DHA; lipid profiles; n‐3 PUFA; phosphatidylcholine; phosphatidylserine

DOI:  https://doi.org/10.1002/jsfa.13625
Psychiatr Genet. 2024 Jun 04.

Arginine, glycine, and creatine supplementation improves symptoms in a female with creatine transporter deficiency.

Kara Tauer, Caroline Theile, Joshua W Owens, Kim M Cecil, Amelle Shillington.

X-linked creatine transporter deficiency is caused by hemizygous or heterozygous pathogenic variants in SLC6A8 that cause neuropsychiatric symptoms because of impaired uptake of creatine into tissues throughout the body. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males, but only six cases of supplementation in females have been published. Here, we present a female with a de-novo pathogenic SLC6A8 variant who had ongoing weight loss, mild intellectual disability, and neuropsychiatric symptoms. Magnetic resonance spectroscopy of the brain showed reduced creatine on all acquired spectra. The patient was started on creatine-monohydrate, l-arginine, and l-glycine supplementation, and she had significant symptomatic improvement within the following 3 weeks. After 8 months of supplementation, magnetic resonance spectroscopy showed improved creatine concentrations with normalizing semiquantitative ratios with other brain metabolites. Current data supports clinicians trialing creatine, arginine, and glycine supplements for female patients with creatine transporter deficiency.

DOI: https://doi.org/10.1097/YPG.0000000000000372
J Neuroinflammation. 2024 Jun 05. 21(1): 151

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system.

Rasa Valiauga, Sarah Talley, Mark Khemmani, Melline Fontes Noronha, Rocco Gogliotti, Alan J Wolfe, Edward Campbell.

  BACKGROUND: Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes.METHODS: 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated.
RESULTS: The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established.
CONCLUSIONS: Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.

Keywords:  Behavior; Caspase-1; Glucose intolerance; High glycemic index diet; Inflammasome; Inflammation; Ketogenic diet; Microbiome; Neuroinflammation; Sex

DOI:  https://doi.org/10.1186/s12974-024-03140-5
Biochimie. 2024 May 31. pii: S0300-9084(24)00122-6. [Epub ahead of print]

Brain lipid sensing and the neural control of energy balance.

Céline Cruciani-Guglielmacci, Hervé Le Stunff, Christophe Magnan.

  The central nervous system continuously detects circulating concentrations of lipids such as fatty acids and troglycerides. Once information has been detected, the central nervous system can in turn participate in the control of energy balance and blood sugar levels and in particular regulate the secretion and action of insulin. Neurons capable of detecting circulating lipid variations are located in the hypothalamus and in other regions such as the nucleus accumbens, the striatum or the hippocampus. An excess of lipids will have deleterious effects and may induce central lipotoxicity, in particular following local production of ceramides and the appearance of neuroinflammation which may lead to metabolic diseases such as obesity and type 2 diabetes.

Keywords:  Ceramides; Hypothalamus; Lipoprotein lipase; Neuroinflammation; Triglycerides; saturated fatty acids

DOI:  https://doi.org/10.1016/j.biochi.2024.05.020
Nature. 2024 Jun 05.

Senescent glia link mitochondrial dysfunction and lipid accumulation.

China N Byrns, Alexandra E Perlegos, Karl N Miller, Zhecheng Jin, Faith R Carranza, Palak Manchandra, Connor H Beveridge, Caitlin E Randolph, V Sai Chaluvadi, Shirley L Zhang, Ananth R Srinivasan, F C Bennett, Amita Sehgal, Peter D Adams, Gaurav Chopra, Nancy M Bonini.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

DOI: https://doi.org/10.1038/s41586-024-07516-8