bims-medebr 2023-02-19 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–02–19
ten papers selected by
Regina F. Fernández, Johns Hopkins University

Lipidomic analysis of brain and hippocampus from mice fed with high-fat diet and treated with fecal microbiota transplantation.
Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response.
The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging.
Chronic Administration of Δ9-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat.
Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment.
Targeting IGF1R signaling for brain aging and Alzheimer's disease.
Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.
Metabolomic, Proteomic, and Transcriptomic Changes in Adults with Epilepsy on Modified Atkins Diet.
Severity-dependent functional connectome and the association with glucose metabolism in the sensorimotor cortex of Parkinson's disease.
Long-lasting effects of very preterm birth on brain structure in adulthood: a systematic review and meta-analysis.

Nutr Metab (Lond). 2023 Feb 15. 20(1): 12

Lipidomic analysis of brain and hippocampus from mice fed with high-fat diet and treated with fecal microbiota transplantation.

Jinchen Li, Hongying Huang, Rong Fan, Yinan Hua, Weiwei Ma.

   BACKGROUND: Dietary fat intake affects brain composition and function. Different types of dietary fatty acids alter species and abundance of brain lipids in mice. The aim of this study is to explore whether the changes are effective through gut microbiota.
METHODS: In our study, 8-week-old male C57BL/6 mice were randomly divided into 7 groups and fed with high-fat diet (HFD) with different fatty acid compositions, control (CON) group, long-chain saturated fatty acid (LCSFA) group, medium-chain saturated fatty acid (MCSFA) group, n-3 polyunsaturated fatty acid (n-3 PUFA) group, n-6 polyunsaturated fatty acid (n-6 PUFA) group, monounsaturated fatty acid (MUFA) group and trans fatty acid (TFA) group. Then, the fecal microbiota transplant (FMT) was performed in other pseudo germ-free mice after antibiotic treatment. The experimental groups were orally perfused with gut microbiota that induced by HFD with different types of dietary fatty acids. The mice were fed with regular fodder before and after FMT. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to analysis the composition of fatty acids in the brain of HFD-fed mice and hippocampus of mice treated with FMT which was collected from HFD-fed mice.
RESULTS: The content of acyl-carnitines (AcCa) increased and lysophosphatidylgylcerol (LPG) decreased in all kinds of HFD groups. phosphatidic acids (PA), phosphatidylethanolamine (PE) and sphingomyelin (SM) contents were significantly increased in the n-6 PUFA-fed HFD group. The HFD elevated the saturation of brain fatty acyl (FA). Lysophosphatidylcholine (LPC), lysodi-methylphosphatidylethanolamine (LdMePE), monolysocardiolipin (MLCL), dihexosylceramides (Hex2Cer), and wax ester (WE) significantly increased after LCSFA-fed FMT. MLCL reduced and cardiolipin (CL) raised significantly after n-3 PUFA-fed FMT.
CONCLUSIONS: The study revealed, HFD and FMT in mice had certain effects on the content and composition of fatty acids in the brain, especially on glycerol phospholipid (GP). The change of AcCa content in FA was a good indicator of dietary fatty acid intake. By altering the fecal microbiota, dietary fatty acids might affect brain lipids.

Keywords:  Brain lipid; Dietary fatty acid; FMT; High-fat diet; Lipidomics

DOI:  https://doi.org/10.1186/s12986-023-00730-7
Dev Neurobiol. 2023 Feb 16.

Loss of mitochondrial Chchd10 or Chchd2 in zebrafish leads to an ALS-like phenotype and Complex I deficiency independent of the mitochondrial integrated stress response.

Virginie Petel Légaré, Christian J Rampal, Tyler J N Gurberg, Mari J Aaltonen, Alexandre Janer, Lorne Zinman, Eric A Shoubridge, Gary A B Armstrong.

  Mutations in CHCHD10 and CHCHD2, encoding two paralogous mitochondrial proteins, have been identified in cases of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and Parkinson's disease (PD). Their role in disease is unclear, though both have been linked to mitochondrial respiration and mitochondrial stress responses. Here we investigated the biological roles of these proteins during vertebrate development using knockout (KO) models in zebrafish. We demonstrate that loss of either or both proteins leads to motor impairment, reduced survival and compromised neuromuscular junction (NMJ) integrity in larval zebrafish. Compensation by Chchd10 was observed in the chchd2-/- model, but not by Chchd2 in the chchd10 -/- model. The assembly of mitochondrial respiratory chain Complex I was impaired in chchd10 -/- and chchd2 -/- zebrafish larvae, but unexpectedly not in a double chchd10 -/- & chchd2 -/- model, suggesting that reduced mitochondrial Complex I cannot be solely responsible for the observed phenotypes, which are generally more severe in the double KO. We observed transcriptional activation markers of the mitochondrial integrated stress response (mt-ISR) in the double chchd10 -/- and chchd2 -/- KO model, suggesting that this pathway is involved in the restoration of Complex I assembly in our double KO model. The data presented here, demonstrates that the Complex I assembly defect in our single KO models arises independently of the mt-ISR. Furthermore, this study provides evidence that both proteins are required for normal vertebrate development. This article is protected by copyright. All rights reserved.

Keywords:  CHCHD10; CHCHD2; amyotrophic lateral sclerosis; mitochondria; zebrafish

DOI:  https://doi.org/10.1002/dneu.22909
Aging (Albany NY). 2023 Feb 13. 15

The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging.

Trisha A Staab, Grace McIntyre, Lu Wang, Joycelyn Radeny, Lisa Bettcher, Melissa Guillen, Margaret P Peck, Azia P Kalil, Samantha P Bromley, Daniel Raftery, Jason P Chan.

  Lipid metabolism affects cell and physiological functions that mediate animal healthspan and lifespan. Lipidomics approaches in model organisms have allowed us to better understand changes in lipid composition related to age and lifespan. Here, using the model C. elegans, we examine the lipidomes of mutants lacking enzymes critical for sphingolipid metabolism; specifically, we examine acid sphingomyelinase (asm-3), which breaks down sphingomyelin to ceramide, and ceramide synthase (hyl-2), which synthesizes ceramide from sphingosine. Worm asm-3 and hyl-2 mutants have been previously found to be long- and short-lived, respectively. We analyzed longitudinal lipid changes in wild type animals compared to mutants at 1-, 5-, and 10-days of age. We detected over 700 different lipids in several lipid classes. Results indicate that wildtype animals exhibit increased triacylglycerols (TAG) at 10-days compared to 1-day, and decreased lysophoshatidylcholines (LPC). We find that 10-day hyl-2 mutants have elevated total polyunsaturated fatty acids (PUFA) and increased LPCs compared to 10-day wildtype animals. These changes mirror another short-lived model, the daf-16/FOXO transcription factor that is downstream of the insulin-like signaling pathway. In addition, we find that hyl-2 mutants have poor oxidative stress response, supporting a model where mutants with elevated PUFAs may accumulate more oxidative damage. On the other hand, 10-day asm-3 mutants have fewer TAGs. Intriguingly, asm-3 mutants have a similar lipid composition as the long-lived, caloric restriction model eat-2/mAChR mutant. Together, these analyses highlight the utility of lipidomic analyses to characterize metabolic changes during aging in C. elegans.

Keywords:  C. elegans; aging; fatty acid metabolism; lipidomics; sphingolipid metabolism

DOI:  https://doi.org/10.18632/aging.204515
Cannabis Cannabinoid Res. 2023 Feb 17.

Chronic Administration of Δ9-Tetrahydrocannabinol Alters Brain Glucose Uptake and Improves Waiting Impulsivity in the Rat.

Isabelle Miederer, Ulrich Schmitt, Nicole Bausbacher, Jörg Röhrich, Philipp Mildenberger, Beat Lutz, Oliver Tüscher, Mathias Schreckenberger.

  Introduction: Δ9-Tetrahydrocannabinol (THC) acts as an agonist at cannabinoid receptors. Its chronic intake affects many behaviors, including cognitive processes. The aims of this study in rats are to assess the chronic effects of THC on impulsivity and on regional brain glucose uptake. Materials and Methods: For the determination of "waiting impulsivity," a total of 20 male Lister Hooded rats were trained to perform a reaction time task, followed by a baseline test of impulsivity and baseline glucose uptake measurements with [18F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Then, 10 rats each received 3 mg/kg THC or vehicle injected intraperitoneally daily for 21 days. Subsequently, a second behavioral test and PET measurements were performed, and blood THC concentrations were determined. Analyses of variance of brain regions of the impulsivity network with the parameter "standardized uptake value" regarding glucose uptake and correlation analyses of the collected parameters were carried out. Discussion: After chronic THC treatment, decreased glucose uptake (p-values <0.05) was found in cingulate cortex, hippocampus, amygdala, thalamus, and cerebellar cortex, as compared with vehicle-treated rats. The number of correct no-go responses (increased waiting time) significantly increased (p<0.05) in THC-treated rats. Furthermore, correct no-go responses correlated positively and strongly with the THC blood concentrations (Spearman's ρ=0.79, p<0.01). Conclusion: These findings reflect a specific reduction in impulsive behavior after chronic THC treatment, showing a functionally relevant influence of THC on "waiting impulsivity" with reduced selective glucose uptake at the same time.

Keywords:  PET imaging; THC; [18F]FDG; impulsivity; rat

DOI:  https://doi.org/10.1089/can.2022.0268
Front Oncol. 2023 ;13 976945

Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment.

Lisa R Decotret, Rocky Shi, Kiersten N Thomas, Manchi Hsu, Catherine J Pallen, Kevin L Bennewith.

  Organotypic cultures of murine brain slices are well-established tools in neuroscience research, including electrophysiology studies, modeling neurodegeneration, and cancer research. Here, we present an optimized ex vivo brain slice invasion assay that models glioblastoma multiforme (GBM) cell invasion into organotypic brain slices. Using this model, human GBM spheroids can be implanted with precision onto murine brain slices and cultured ex vivo to allow tumour cell invasion into the brain tissue. Traditional top-down confocal microscopy allows for imaging of GBM cell migration along the top of the brain slice, but there is limited resolution of tumour cell invasion into the slice. Our novel imaging and quantification technique involves embedding stained brain slices into an agar block, re-sectioning the slice in the Z-direction onto slides, and then using confocal microscopy to image cellular invasion into the brain tissue. This imaging technique allows for the visualization of invasive structures beneath the spheroid that would otherwise go undetected using traditional microscopy approaches. Our ImageJ macro (BraInZ) allows for the quantification of GBM brain slice invasion in the Z-direction. Importantly, we note striking differences in the modes of motility observed when GBM cells invade into Matrigel in vitro versus into brain tissue ex vivo highlighting the importance of incorporating the brain microenvironment when studying GBM invasion. In summary, our version of the ex vivo brain slice invasion assay improves upon previously published models by more clearly differentiating between migration along the top of the brain slice versus invasion into the slice.

Keywords:  brain microenvironment; confocal microscopy; glioblastoma multiforme; invasion; metastasis; organotypic brain slice culture

DOI:  https://doi.org/10.3389/fonc.2023.976945
Aging Pathobiol Ther. 2022 ;4(4): 129-131

Targeting IGF1R signaling for brain aging and Alzheimer's disease.

Joo Young Park, Martin Darvas, Warren Ladiges.

  The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1RR407H) variant enriched in centenarians with a reduction in IGF1R protein activity. Middle-aged mice show improved cognitive performance thus possibly modeling IGF1R signaling in the aging brain, similar to what was reported in the aging heart. Because Alzheimer's disease (AD) is an age-related disease, specific IGF1RR407H pathways could be therapeutic targets in mice with AAV vector-based AD as well as for overall brain aging.

Keywords:  Alzheimer’s disease; IGF1R signaling; IGF1RR407H variant; brain aging; cognition

DOI:  https://doi.org/10.31491/apt.2022.12.103
FASEB J. 2023 03;37(3): e22805

Netrin-1 attenuates cerebral ischemia/reperfusion injury by limiting mitochondrial ROS and Ca2+ levels via activation of AKT phosphorylation and mitochondrial m-AAA protease AFG3L2.

Xiaosheng Yang, Yang Liu, Weijie Zhong, Yi Li, Wenchuan Zhang.

  Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.

Keywords:  AFG3L2; Ca2+ levels; Netrin-1; ischemia-reperfusion injury; mitochondrial ROS; phosphorylated AKT

DOI:  https://doi.org/10.1096/fj.202201739R
Epilepsia. 2023 Feb 12.

Metabolomic, Proteomic, and Transcriptomic Changes in Adults with Epilepsy on Modified Atkins Diet.

Dominique F Leitner, Yik Siu, Aryeh Korman, Ziyan Lin, Evgeny Kanshin, Daniel Friedman, Sasha Devore, Beatrix Ueberheide, Aristotelis Tsirigos, Drew R Jones, Thomas Wisniewski, Orrin Devinsky.

   OBJECTIVE: High fat and low carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible Modified Atkins Diet (MAD) that is more palatable, mimicking fasting and inducing high ketone body levels. Low carbohydrate diets may shift brain energy production, particularly impacting neuron and astrocyte linked metabolism.
METHODS: We evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to Control participants consuming a non-modified higher carbohydrate diet (n = 6 MAD, mean age 43.7 years, range 21-53, diet average 10 days; n = 10 Control, mean age 41.9 years, range 28-64).
RESULTS: By metabolomics, there were 13 increased metabolites in plasma (n = 15 participants with available specimens) that included 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex (n = 16), and 11 decreased metabolites in hippocampus (n = 6) that had top associations with mitochondrial functions. Cortex and plasma 3-hydroxybutyric acid levels had a positive correlation (p = 0.0088, R2 = 0.48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p < 0.01, FDR > 5%) in hippocampal NADH related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling).
SIGNIFICANCE: Short-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to Control participants, in combination with trending expression changes observed in hippocampal NADH related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables.

Keywords:  metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.1111/epi.17540
Front Neurosci. 2023 ;17 1104886

Severity-dependent functional connectome and the association with glucose metabolism in the sensorimotor cortex of Parkinson's disease.

Zhenxiang Zang, Tianbin Song, Jiping Li, Binbin Nie, Shanshan Mei, Yuqing Zhang, Jie Lu.

  Functional MRI studies have achieved promising outcomes in revealing abnormal functional connectivity in Parkinson's disease (PD). The primary sensorimotor area (PSMA) received a large amount of attention because it closely correlates with motor deficits. While functional connectivity represents signaling between PSMA and other brain regions, the metabolic mechanism behind PSMA connectivity has rarely been well established. By introducing hybrid PET/MRI scanning, the current study enrolled 33 advanced PD patients during medication-off condition and 25 age-and-sex-matched healthy controls (HCs), aiming to not only identify the abnormal functional connectome pattern of the PSMA, but also to simultaneously investigate how PSMA functional connectome correlates with glucose metabolism. We calculated degree centrality (DC) and the ratio of standard uptake value (SUVr) using resting state fMRI and 18F-FDG-PET data. A two-sample t-test revealed significantly decreased PSMA DC (PFWE < 0.014) in PD patients. The PSMA DC also correlated negatively with H-Y stage (P = 0.031). We found a widespread reduction of H-Y stage associated (P-values < 0.041) functional connectivity between PSMA and the visual network, attention network, somatomotor network, limbic network, frontoparietal network as well as the default mode network. The PSMA DC correlated positively with FDG-uptake in the HCs (P = 0.039) but not in the PD patients (P > 0.44). In summary, we identified disease severity-dependent PSMA functional connectome which in addition uncoupled with glucose metabolism in PD patients. The current study highlighted the critical role of simultaneous PET/fMRI in revealing the functional-metabolic mechanism in the PSMA of PD patients.

Keywords:  Parkinson's disease; functional connectome; glucose metabolism; hybrid PET/MRI; sensorimotor cortex

DOI:  https://doi.org/10.3389/fnins.2023.1104886
Neurosci Biobehav Rev. 2023 Feb 10. pii: S0149-7634(23)00051-9. [Epub ahead of print] 105082

Long-lasting effects of very preterm birth on brain structure in adulthood: a systematic review and meta-analysis.

Claire E Kelly, Michelle Shaul, Deanne K Thompson, Rheanna M Mainzer, Joseph Ym Yang, Thijs Dhollander, Jeanie Ly Cheong, Terrie E Inder, Lex W Doyle, Peter J Anderson.

  Early life experiences, such as very preterm (VP) birth, can affect brain and cognitive development. Several prior studies investigated brain structure in adults born VP; synthesising these studies may help to provide a clearer understanding of long-term effects of VP birth on the brain. We systematically searched Medline and Embase for articles that investigated brain structure using MRI in adulthood in individuals born VP (<32 weeks' gestation) or with very low birth weight (VLBW; <1500g), and controls born at term or with normal birth weight. In total, 77 studies met the review inclusion criteria, of which 28 studies were eligible for meta-analyses, including data from up to 797 VP/VLBW participants and 518 controls, aged 18-33 years. VP/VLBW adults exhibited volumetric, morphologic and microstructural alterations in subcortical and temporal cortical regions compared with controls, with pooled standardised mean differences up to -1.0 (95% confidence interval: -1.2, -0.8). This study suggests there is a persisting neurological impact of VP birth, which may provide developmental neurobiological insights for adult cognition in high-risk populations.

Keywords:  Preterm birth; brain imaging; diffusion imaging; magnetic resonance imaging; neurodevelopment; neuroscience

DOI:  https://doi.org/10.1016/j.neubiorev.2023.105082