bims-medebr 2022-07-31 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–07–31
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Fatty Acid-Binding Protein 5 Modulates Brain Endocannabinoid Tone and Retrograde Signaling in the Striatum.
Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease.
Early alterations in brain glucose metabolism and vascular function in a transgenic rat model of Alzheimer's disease.
Astrocyte energy and neurotransmitter metabolism in Alzheimer's disease: integration of the glutamate/GABA-glutamine cycle.
Changes in the Brain Metabolism Associated with Central Post-Stroke Pain in Hemorrhagic Pontine Stroke: An 18F-FDG-PET Study of the Brain.
α-glyceryl-phosphoryl-ethanolamine protects human hippocampal neurons from aging-induced cellular alterations.
Effects of Prolonged Intermittent Fasting Model on Energy Metabolism and Mitochondrial Functions in Neurons.
Mesenchymal stem cell-derived exosomes altered neuron cholesterol metabolism via Wnt5a-LRP1 axis and alleviated cognitive impairment in a progressive Parkinson's disease model.
Brain Region and Sex-specific Changes in Mitochondrial Biogenesis Induced by Acute Trimethyltin Exposure.
Erinacine A attenuates glutamate transporter 1 downregulation and protects against ischemic brain injury.
Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy.
Neurometabolism in focus.
Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?
Assessing potential correlation between T2 relaxation and diffusion of lactate in the mouse brain.
Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice.
Impacts of Formula Supplemented with Milk Fat Globule Membrane on the Neurolipidome of Brain Regions of Piglets.
Energy Metabolic Disorder of Astrocytes May Be an Inducer of Migraine Attack.
Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.
Effects of Sevoflurane Anesthesia on Cerebral Lipid Metabolism in the Aged Brain of Marmosets and Mice.
Investigating the Role of GABA in Neural Development and Disease Using Mice Lacking GAD67 or VGAT Genes.

Front Cell Neurosci. 2022 ;16 936939

Fatty Acid-Binding Protein 5 Modulates Brain Endocannabinoid Tone and Retrograde Signaling in the Striatum.

Mohammad Fauzan, Saida Oubraim, Mei Yu, Sherrye T Glaser, Martin Kaczocha, Samir Haj-Dahmane.

  The endocannabinoid (eCB) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are endogenous lipid neurotransmitters that regulate an array of physiological functions, including pain, stress homeostasis, and reward. Fatty acid-binding protein 5 (FABP5) is a key modulator of intracellular eCB transport and inactivation. Recent evidence suggests that FABP5 controls synaptic 2-AG signaling at excitatory synapses in the dorsal raphe nucleus. However, it is currently not known whether this function extends to other brain areas. To address this, we first profiled eCB levels across several brain areas in FABP5 knockout mice and wild-type controls and report that FABP5 deletion elevates AEA levels in the striatum, prefrontal cortex, midbrain, and thalamus, as well as midbrain 2-AG levels. The expression of eCB biosynthetic and catabolic enzymes was largely unaltered in these regions, although minor sex and region-specific changes in the expression of 2-AG catabolic enzymes were observed in female FABP5 KO mice. Robust FABP5 expression was observed in the striatum, a region where both AEA and 2-AG control synaptic transmission. Deletion of FABP5 impaired tonic 2-AG and AEA signaling at striatal GABA synapses of medium spiny neurons, and blunted phasic 2-AG mediated short-term synaptic plasticity without altering CB1R expression or function. Collectively, these results support the role of FABP5 as a key regulator of eCB signaling at excitatory and inhibitory synapses in the brain.

Keywords:  2-arachidonoylglycerol; FABP; GABA synapses; anandamide; endocannabinoid; fatty acid-binding protein; medium spiny neurons; striatum

DOI:  https://doi.org/10.3389/fncel.2022.936939
Mol Neurobiol. 2022 Jul 27.

Re-routing Metabolism by the Mitochondrial Pyruvate Carrier Inhibitor MSDC-0160 Attenuates Neurodegeneration in a Rat Model of Parkinson's Disease.

David Mallet, Raphael Goutaudier, Emmanuel L Barbier, Sebastien Carnicella, Jerry R Colca, Florence Fauvelle, Sabrina Boulet.

  A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson's disease (PD). Central regulators of energy production, mitochondria, are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. We investigated behavioral, cellular, and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrially related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. MSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation, and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation, and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. MSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

Keywords:  Energy metabolism; Mitochondrial pyruvate carrier; Neuroprotection; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-022-02962-9
Prog Neurobiol. 2022 Jul 20. pii: S0301-0082(22)00113-7. [Epub ahead of print] 102327

Early alterations in brain glucose metabolism and vascular function in a transgenic rat model of Alzheimer's disease.

Illsung L Joo, Wilfred W Lam, Wendy Oakden, Mary E Hill, Margaret M Koletar, Christopher D Morrone, Greg J Stanisz, JoAnne McLaurin, Bojana Stefanovic.

  Alteration in brain metabolism predates clinical onset of Alzheimer's Disease (AD). Realizing its potential as an early diagnostic marker, however, requires understanding how early AD metabolic dysregulation manifests on non-invasive brain imaging. We presently utilized magnetic resonance imaging and spectroscopy to map glucose and ketone metabolic profiles and image cerebrovascular function in a rat model of early stage AD - 9-month-old TgF344-AD (TgAD) rats - and their age-matched non-transgenic (nTg) littermates. Compared to the nTg rats, TgAD rats displayed attenuation in global cerebral and hippocampal vasoreactivity to hypercapnia, by 49±17% and 58±19%, respectively, while their functional hyperemia to somatosensory stimulation diminished by 69±5%. To assess brain glucose uptake, rats were fasted overnight and then challenged with an intravenous infusion of 2-deoxy-D-glucose (2DG). Compared to their non-transgenic littermates, TgAD rats exhibited 99±10% and 52±5% smaller glucose uptake in the entorhinal cortex and the hippocampus, respectively. Moreover, hippocampal glucose uptake reduction in male TgAD rats compared to the nTg was 54±36% greater than the reduction seen in female TgAD rats. TgAD rats also showed a 59±42% increase in total choline level in the hippocampus, suggesting increased membrane turnover. In combination with our earlier findings of impaired electrophysiological metrics at this early stage of AD pathology progression, our findings suggest that subtle neuronal function alterations that would be difficult to assess in a clinical population may be accompanied by MRI-detectable changes in brain glucose metabolism and cerebrovascular function.

Keywords:  Alzheimer’s disease; MRI; cerebral metabolism; early biomarker; vascular function

DOI:  https://doi.org/10.1016/j.pneurobio.2022.102327
Prog Neurobiol. 2022 Jul 21. pii: S0301-0082(22)00117-4. [Epub ahead of print] 102331

Astrocyte energy and neurotransmitter metabolism in Alzheimer's disease: integration of the glutamate/GABA-glutamine cycle.

Jens V Andersen, Arne Schousboe, Alexei Verkhratsky.

  Astrocytes contribute to the complex cellular pathology of Alzheimer's disease (AD). Neurons and astrocytes function in close collaboration through neurotransmitter recycling, collectively known as the glutamate/GABA-glutamine cycle, which is essential to sustain neurotransmission. Neurotransmitter recycling is intimately linked to astrocyte energy metabolism. In the course of AD, astrocytes undergo extensive metabolic remodeling, which may profoundly affect the glutamate/GABA-glutamine cycle. The consequences of altered astrocyte function and metabolism in relation to neurotransmitter recycling are yet to be comprehended. Metabolic alterations of astrocytes in AD deprive neurons of metabolic support, thereby contributing to synaptic dysfunction and neurodegeneration. In addition, several astrocyte-specific components of the glutamate/GABA-glutamine cycle, including glutamine synthesis and synaptic neurotransmitter uptake, are perturbed in AD. Integration of the complex astrocyte biology within the context of AD is essential for understanding the fundamental mechanisms of the disease, while restoring astrocyte metabolism may serve as an approach to arrest or even revert clinical progression of AD.

Keywords:  Neurotransmitter recycling; alternative substrates; astrogliosis; dementia; excitotoxicity; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1016/j.pneurobio.2022.102331
Brain Sci. 2022 Jun 27. pii: 837. [Epub ahead of print]12(7):

Changes in the Brain Metabolism Associated with Central Post-Stroke Pain in Hemorrhagic Pontine Stroke: An 18F-FDG-PET Study of the Brain.

Soo-Jin Choi, Na-Young Kim, Jun-Yup Kim, Young-Sil An, Yong-Wook Kim.

  Central post-stroke pain (CPSP) is an intractable neuropathic pain that can occur following central nervous system injuries. Spino-thalamo-cortical pathway damage contributes to CPSP development. However, brain regions involved in CPSP are unknown and previous studies were limited to supratentorial strokes with cortical lesion involvement. We analyzed the brain metabolism changes associated with CPSP following pontine hemorrhage. Thirty-two patients with isolated pontine hemorrhage were examined; 14 had CPSP, while 18 did not. Brain glucose metabolism was evaluated using 18F-fluorodeoxyglucose-positron emission tomography images. Additionally, regions revealing metabolic correlation with CPSP severity were analyzed. Patients with CPSP showed changes in the brain metabolism in the cerebral cortices and cerebellum. Compared with the control group, the CPSP group showed significant hypometabolism in the contralesional rostral anterior cingulum and ipsilesional primary motor cortex (Puncorrected < 0.001). However, increased brain metabolism was observed in the ipsilesional cerebellum (VI) and contralesional cerebellum (lobule VIIB) (Puncorrected < 0.001). Moreover, increased pain intensity correlated with decreased metabolism in the ipsilesional supplementary motor area and contralesional angular gyrus. This study emphasizes the role of the many different areas of the cortex that are involved in affective and cognitive processing in the development of CPSP.

Keywords:  cerebellum; cerebral cortex; cerebral hemorrhage; pain; pons; stroke

DOI:  https://doi.org/10.3390/brainsci12070837
Eur J Neurosci. 2022 Jul 28.

α-glyceryl-phosphoryl-ethanolamine protects human hippocampal neurons from aging-induced cellular alterations.

Elisa Zappelli, Simona Daniele, Lorenzo Ceccarelli, Matteo Vergassola, Lorella Ragni, Giorgina Mangano, Claudia Martini.

  Brain aging has been related to a decrease in cellular metabolism, to an accumulation of misfolded proteins and to an alteration of the lipid membrane composition. These alterations act as contributive aspects of age-related memory decline by reducing membrane excitability and neurotransmitter release. In this sense, precursors of phospholipids (PLs) can restore the physiological composition of cellular membranes and ameliorate the cellular defects associate with brain aging. In particular, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) have been shown to restore mitochondrial function, reduce the accumulation of amyloid beta (Aβ) and, at the same time, provide the amount of acetylcholine needed to reduce memory deficit. Among PL precursors, alpha-glycerylphosphorylethanolamine (GPE) has shown to protect astrocytes from Aβ injuries and to slow-down aging of human neural stem cells. GPE has been evaluated in aged human hippocampal neurons, which are implicated in learning and memory, and constitute a good in vitro model to investigate the beneficial properties of GPE. In order to mimic cellular aging, the cells have been maintained 21 DIV and challenged with GPE. Results of the present paper showed GPE ability to increase PE and PC content, glucose uptake and the activity of the chain respiratory complex I and of the GSK-3β pathway. Moreover, the nootropic compound showed an increase in the transcriptional/protein levels of neurotrophic and well-being related genes. Finally, GPE counteracted the accumulation of aging-related misfolded proteins (a-synuclein and tau). Overall, our data underline promising effects of GPE in counteracting cellular alterations related to brain aging and cognitive decline.

Keywords:  aging; neuronal metabolism; neuronal plasticity; phospholipid precursor; α-glycerylphosphorylethanolamine

DOI:  https://doi.org/10.1111/ejn.15783
Ann Neurosci. 2022 Jan;29(1): 21-31

Effects of Prolonged Intermittent Fasting Model on Energy Metabolism and Mitochondrial Functions in Neurons.

Meltem Pak, Süleyman Bozkurt, Arzu Pınarbaşı, Devrim Öz Arslan, Fehime Benli Aksungar.

   Background: Calorie restriction (CR) during daily nutrition has been shown to affect the prognosis of many chronic diseases such as metabolic syndrome, diabetes, and aging. As an alternative nutrition model, prolonged intermittent fasting (PF) in humans is defined by the absence of food for more than 12 h. In our previous human studies, CR and PF models were compared and it was concluded that the two models might have differences in signal transduction mechanisms. We have investigated the effects of these models on neurons at the molecular level in this study.
Methods: Neurons (SH-SY5Y) were incubated with normal medium (N), calorie-restricted medium (CR), fasting medium (PF), and glucose-free medium (G0) for 16 h. Simultaneously, ketone (beta-hydroxybutyrate; bOHB) was added to other experiment flasks containing the same media. Concentrations of lactate, lactate dehydrogenase (LDH), bOHB, and glucose were measured to demonstrate the changes in the energy metabolism together with the mitochondrial functions of cells. Citrate synthase activity and flow cytometric mitochondrial functions were investigated.
Results: At the end of incubations, lactate and LDH levels were decreased and mitochondrial activity was increased in all ketone-added groups (P < .01) regardless of the glucose concentration in the environment. In the fasting model, these differences were more prominent.
Conclusion: Our results demonstrated that neurons use ketones regardless of the amount of glucose, and bOHB-treated cells had positive changes in mitochondrial function. We conclude that the presence of bOHB might reverse neuron damage and that exogenous ketone treatment may be beneficial in the treatment of neurological diseases in the future.

Keywords:  Calorie restriction; Citrate synthase; Fasting; Ketone bodies; Mitochondrial function; Neuron cultures

DOI:  https://doi.org/10.1177/09727531211072303
Neurosci Lett. 2022 Jul 20. pii: S0304-3940(22)00371-8. [Epub ahead of print] 136810

Mesenchymal stem cell-derived exosomes altered neuron cholesterol metabolism via Wnt5a-LRP1 axis and alleviated cognitive impairment in a progressive Parkinson's disease model.

Xiaomin Xu, Zongshan Li, Huirong Zuo, Huimin Chen, Yaxing Gui.

  Parkinson's disease (PD) is associated with abnormal metabolism of brain cholesterol, and the metabolites of neuronal cholesterol may also affect neurodegenerative progression. In this study, we aim to explore the therapeutic effect of BMSC derived exosomes on motor and cognitive deficits in α-synuclein (α-Syn) A53T transgenic mice, a progressive PD animal model. Results revealed that rotating rod performance of α-Syn A53T TG mice decreased by 45.4%±8.6% at the age of 12 months compared with wide-type (WT) mice. Striatum injection of BMSC quiescent exosomes (BMSCquiescent-EXO) and BMSC induced exosomes (BMSCinduced-EXO) rescued the rotation behavior (BMSCquiescent-EXO: 92.3%±12.5% P=0.008; BMSCinduced-EXO: 102.3%±16.7%, P=0.006). Although there was no difference in the escape latency within 5 days of Morris water maze learning between groups in the 12-month old mice. The exploration latency was shorter (p<0.05) in BMSCquiescent-EXO and BMSCinduced-EXO groups, the number of explorations and novel object recognition index were significantly increased (p<0.05). More importantly, the total cholesterol level was increased (p<0.05), while the content of 24S-hydroxycholesterol significantly decreased (p<0.05) after intrastriatal injection BMSCquiescent-EXO and BMSCinduced-EXO in A53T group. Liquid chromatography-mass spectrometry (LC/MS) was performed to profile phospholipid metabolites in lipid raft of hippocampal neurons, demonstrating that BMSCquiescent-EXO injection caused the decreasing relative percentages of phosphatidylglycerol (PG) and phosphatidylethanolamine (PE) compared to those in A53T mice, while the relative percentages of phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidylcholine (PC) increased. The cholesterol content of lipid rafts was lower in BMSCquiescent-EXO and BMSCinduced-EXO groups than that in A53T group (P<0.05). In summary, exosomes isolated during BMSC dopaminergic neuron differentiation can significantly improve the motor, learning and memory ability of the progressive PD mice model, and its mechanism may be related to the change of altered phospholipid composition and cholesterol metabolism in hippocampal neurons.

Keywords:  Cholesterol; Exosomes; Lipid raft; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.neulet.2022.136810
Clin Psychopharmacol Neurosci. 2022 Aug 31. 20(3): 474-481

Brain Region and Sex-specific Changes in Mitochondrial Biogenesis Induced by Acute Trimethyltin Exposure.

Jung Ho Lee, Eun Hye Jang, Soon Ae Kim.

   Objective: In this study, we investigated sex- and region-specific effects of acute trimethyltin (TMT) exposure on mitochondrial biogenesis.
Methods: We treated TMT to primary neuronal cultures and 4-week-old male and female mice. We measured the mitochondrial DNA copy numbers using the quantitative polymerase chain reaction method. We also measured mitochondrial biogenesis related genes (sirtuin-1, estrogen-related receptor alpha, cytochrome C oxidase subunit IV) by western blotting.
Results: The mitochondrial DNA copy number increased in the primary hippocampal neuron; however, it decreased in the primary cortical neuron. The mitochondrial copy number increased in the hippocampus and decreased in the cortex in the TMT treated female mice, though the mitochondrial copy number increased in both cortex and hippocampus in the TMT treated male mice. TMT treatment increased sirtuin-1 expression in the male hippocampus but did not in the female brain. In the female brain, estrogen-related receptor alpha expression decreased in the cortex though there is no significant change in the male brain. The protein level of mitochondrial protein, cytochrome C oxidase subunit IV, increased in both cortex and hippocampus after TMT injection in male mice brain, but not in female mice brain.
Conclusion: Our data suggest that acute TMT exposure induces distinct sex-specific metabolic characteristics in the brain before significant sexual maturation.

Keywords:  Estrogens; Mitochondria; Sex characteristics; Trimethyltin

DOI:  https://doi.org/10.9758/cpn.2022.20.3.474
Life Sci. 2022 Jul 23. pii: S0024-3205(22)00533-1. [Epub ahead of print]306 120833

Erinacine A attenuates glutamate transporter 1 downregulation and protects against ischemic brain injury.

Pei-Chien Hsu, Yi-Jie Lan, Chin-Chu Chen, Li-Ya Lee, Wan-Ping Chen, Yun-Ching Wang, Yi-Hsuan Lee.

  Maintaining glutamate homeostasis through astrocyte-enriched glutamate transporter 1 (GLT-1) is critical for neuronal survival, but it is often disrupted after brain injury. Hericium erinaceus (HE), an edible mushroom, was reported to be anti-inflammatory and neuroprotective against brain ischemia, but its effect on glutamate homeostasis was unknown. Here we investigated the neuroprotective effect of erinacine A (EA), an active component of HE, with special focus on the GLT-1 function in the in vitro and in vivo cerebral ischemia mouse models. By using oxygen-glucose deprivation (OGD) to challenge mouse glia-neuron (GN) mixed culture as the in vitro model, we found that EA treatment significantly improved neuronal/astroglial survival and attenuated OGD-induced proinflammatory NFκB and AKT signaling activations. Notably, EA attenuated OGD-induced GLT-1 downregulation, and a selective GLT-1 inhibitor WAY-213613 reversed these EA-mediated neuroprotection. EA also ameliorated glutamate excitotoxicity effectively. In a transient hypoxia-ischemia (tHI) brain injury mouse model, we examined an EA treatment strategy by performing a pre-tHI daily oral gavage of EA (oEA) for 7 days followed by a post-tHI intranasal injection of EA (nEA) for 3 days, and found that this treatment significantly protected sensorimotor cortex and improved the post-tHI forepaw grip strength. Western blotting results further revealed that EA treatment also preserved astrocyte-enriched glutamate and aspartate transporter (GLAST) as well as a GLT-1 function-associated potassium channel Kir4.1 in the cerebral cortex and striatum after tHI. These results suggest that EA is effective for preserving GLT-1 and glutamate clearance machinery to protect against excitotoxicity after ischemic brain injury.

Keywords:  Astrocytes; Erinacine A; Excitotoxicity; Glutamate transporter 1; Ischemic stroke; Kir4.1

DOI:  https://doi.org/10.1016/j.lfs.2022.120833
Int J Mol Sci. 2022 Jul 15. pii: 7806. [Epub ahead of print]23(14):

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy.

Cristina Tringali, Paola Giussani.

  Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.

Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; ceramide; neurodegenerative disorders; sphingolipids; sphingosine-1-phosphate

DOI:  https://doi.org/10.3390/ijms23147806
Nat Metab. 2022 Jul;4(7): 793

Neurometabolism in focus.

DOI: https://doi.org/10.1038/s42255-022-00612-x
Nutrients. 2022 Jul 13. pii: 2880. [Epub ahead of print]14(14):

Fatty Acids: A Safe Tool for Improving Neurodevelopmental Alterations in Down Syndrome?

Carmen Martínez-Cué, Renata Bartesaghi.

  The triplication of chromosome 21 causes Down syndrome (DS), a genetic disorder that is characterized by intellectual disability (ID). The causes of ID start in utero, leading to impairments in neurogenesis, and continue into infancy, leading to impairments in dendritogenesis, spinogenesis, and connectivity. These defects are associated with alterations in mitochondrial and metabolic functions and precocious aging, leading to the early development of Alzheimer's disease. Intense efforts are currently underway, taking advantage of DS mouse models to discover pharmacotherapies for the neurodevelopmental and cognitive deficits of DS. Many treatments that proved effective in mouse models may raise safety concerns over human use, especially at early life stages. Accumulating evidence shows that fatty acids, which are nutrients present in normal diets, exert numerous positive effects on the brain. Here, we review (i) the knowledge obtained from animal models regarding the effects of fatty acids on the brain, by focusing on alterations that are particularly prominent in DS, and (ii) the progress recently made in a DS mouse model, suggesting that fatty acids may indeed represent a useful treatment for DS. This scenario should prompt the scientific community to further explore the potential benefit of fatty acids for people with DS.

Keywords:  cognition; down syndrome; fatty acids; intellectual disability; neurodevelopment; therapy

DOI:  https://doi.org/10.3390/nu14142880
Magn Reson Med. 2022 Jul 30.

Assessing potential correlation between T2 relaxation and diffusion of lactate in the mouse brain.

Eloïse Mougel, Sophie Malaquin, Julien Valette.

   PURPOSE: While diffusion and T2 relaxation are intertwined, little or no correlation exists between diffusion and T2 relaxation of intracellular metabolites in the rodent brain, as measured by diffusion-weighted MRS at different TEs. However, situation might be different for lactate, since it is present in both extracellular and intracellular spaces, which exhibit different diffusion properties and may also exhibit different T2 . Such a TE dependence would be crucial to account for when interpreting or modeling lactate diffusion. Here we propose to take advantage of a new diffusion sequence, where J-modulation of lactate is canceled even at long TE, thus retaining excellent signal, to assess potential T2 dependence on diffusion of lactate in the mouse brain.
METHODS: Using a frequency-selective diffusion-weighted spin-echo sequence that removes J-modulation at 1.3 ppm, thus preserving lactate signal even at long TE, we investigate the effect of TE between 50.9 and 110.9 ms (while keeping diffusion time constant) on apparent diffusivity and kurtosis in the mouse brain.
RESULTS: Regardless of the metabolites, no difference appears for the diffusion-weighted signal attenuation with increasing TE. For lactate, apparent diffusivity and kurtosis remain unchanged as TE increases.
CONCLUSION: No significant TE dependence of diffusivity and kurtosis is measured for lactate in the 50-110 ms TE range, confirming that potential T2 effects can be ignored when interpreting or modeling lactate diffusion.

Keywords:  DW-MRS; T2 relaxation; apparent diffusivity; apparent kurtosis; compartmentation; frequency-selective sequence; intracellular/extracellular; lactate

DOI:  https://doi.org/10.1002/mrm.29395
Int J Mol Sci. 2022 Jul 08. pii: 7580. [Epub ahead of print]23(14):

Neuroprotective Effects of Resveratrol by Modifying Cholesterol Metabolism and Aβ Processing in SAMP8 Mice.

Alejandro Sánchez-Melgar, Pedro J Izquierdo-Ramírez, Christian Griñán-Ferré, Mercè Pallàs, Mairena Martín, José Luis Albasanz.

  Cholesterol metabolism seems dysregulated and linked to amyloid-β (Aβ) formation in neurodegeneration, but the underlying mechanisms are poorly known. Resveratrol (RSV) is a polyphenol with antioxidant activity and neuroprotective properties. Here, we analyzed the effect of age and RSV supplementation on cholesterol metabolism in the brain and blood serum, and its potential link to Aβ processing, in SAMP8 mice-an animal model of aging and Alzheimer's disease. In the brain, our results revealed an age-related increase in ApoE and unesterified cholesterol in the plasma membrane whereas LDL receptor, HMG-CoA reductase, HMG-CoA-C1 synthase, and ABCA1 transporter remained unaltered. Furthermore, BACE-1 and APP gene expression was decreased. This dysregulation could be involved in the amyloidogenic processing pathway of APP towards Aβ formation. In turn, RSV exhibited an age-dependent effect. While levels of unesterified cholesterol in the plasma membrane were not affected by RSV, several participants in cholesterol uptake, release, and de novo synthesis differed, depending on age. Thus, RSV supplementation exhibited a different neuroprotective effect acting on Aβ processing or cholesterol metabolism in the brain at earlier or later ages, respectively. In blood serum, HDL lipoprotein and free cholesterol were increased by age, whereas VLDL and LDL lipoproteins remained unaltered. Again, the protective effect of RSV by decreasing the LDL or increasing the HDL levels also seems to depend on the intervention's moment. In conclusion, age is a prominent factor for cholesterol metabolism dysregulation in the brain of SAMP8 mice and influences the protective effects of RSV through cholesterol metabolism and Aβ processing.

Keywords:  Alzheimer’s disease; antioxidants; cell signaling; lipoproteins; receptors/seven transmembrane domain

DOI:  https://doi.org/10.3390/ijms23147580
Metabolites. 2022 Jul 26. pii: 689. [Epub ahead of print]12(8):

Impacts of Formula Supplemented with Milk Fat Globule Membrane on the Neurolipidome of Brain Regions of Piglets.

Karl Fraser, Leigh Ryan, Ryan N Dilger, Kelly Dunstan, Kelly Armstrong, Jason Peters, Hedley Stirrat, Neill Haggerty, Alastair K H MacGibbon, James Dekker, Wayne Young, Nicole C Roy.

  The milk fat globule membrane (MFGM) appears to play an important role in infant neurocognitive development; however, its mechanism(s) of action remains unclear. This study aimed to investigate the role of a dietary MFGM supplement on the lipid profiles of different neonatal brain regions. Ten-day-old male piglets (4-5 kg) were fed unsupplemented infant formula (control, n = 7) or an infant formula supplemented with low (4%) or high (8%) levels of MFGM (n = 8 each) daily for 21 days. Piglets were then euthanized, and brain tissues were sectioned. Untargeted liquid chromatography-mass spectrometry lipidomics was performed on the cerebellum, hippocampus, prefrontal cortex, and the rest of the brain. The analyses identified 271 and 171 lipids using positive and negative ionization modes, respectively, spanning 16 different lipid classes. MFGM consumption did not significantly alter the lipidome in most brain regions, regardless of dose, compared to the control infant formula. However, 16 triacylglyceride species were increased in the hippocampus (t-test, p-value < 0.05) of the high-supplemented piglets. Most lipids (262 (96.7%) and 160 (93.6%), respectively) differed significantly between different brain regions (ANOVA, false discovery rate corrected p-value < 0.05) independent of diet. Thus, this study highlighted that dietary MFGM altered lipid abundance in the hippocampus and detected large differences in lipid profiles between neonatal piglet brain regions.

Keywords:  brain; cerebellum; hippocampus; infant formula; lipidome; metabolomics; milk fat globule membrane; neonatal; piglets; prefrontal cortex

DOI:  https://doi.org/10.3390/metabo12080689
Brain Sci. 2022 Jun 28. pii: 844. [Epub ahead of print]12(7):

Energy Metabolic Disorder of Astrocytes May Be an Inducer of Migraine Attack.

Junhua Li, Xiaotong Ye, Yang Zhou, Shiqiao Peng, Peibing Zheng, Xiaoxiao Zhang, Jiajun Yang, Yanhong Xu.

  Migraine is a chronic headache disease, which ranks second in years lost due to disability. However, the mechanism of migraines is still not clear. In migraine patients, fasting can trigger headache attacks. We explored the probable mechanism of why fasting can induce headaches. Nitroglycerin (NTG) was used to induce acute migraine attacks in mice. Primary astrocytes were used to study the pathophysiological mechanism and a Seahorse analyzer was used to detect mitochondrial function. NTG induced more serious headaches in the fasting group. Both the head-scratching times and climbing-cage times in the fasting group were higher than those in normal-diet group. More ROS and inflammatory factors, such as IL-6 and IL-1β, were induced in low-glucose conditions. Seahorse showed that the basal oxygen consumption rate (OCR) and OCR for ATP production were lower in mice who had received NTG with low glucose levels than in other groups. The activity of AMPK was inhibited in this group, which may explain the Seahorse results. We concluded that in the low-glucose state, astrocytes produce more inflammatory factors, ROS, which may be a result of mitochondrial metabolism dysfunction. Improving mitochondrial function and supplying enough substrates may be an option for relieving migraine attacks.

Keywords:  fasting; inflammatory factor; migraine; mitochondrial dysfunction; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/brainsci12070844
JCI Insight. 2022 Jul 26. pii: e156346. [Epub ahead of print]

Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.

Manuela Lavorato, Eiko Nakamaru-Ogiso, Neal D Mathew, Elizabeth Herman, Nina K Shah, Suraiya Haroon, Rui Xiao, Christoph Seiler, Marni J Falk.

  Pathogenic variants in the human F Box and Leucine Rich Repeat Protein 4 (FBXL4) gene result in an autosomal recessive, multi-systemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain (RC) complex deficiencies with lactic acidemia. As no FDA-approved effective therapies exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a pyruvate dehydrogenase complex activator, dichloroacetate (DCA) in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts, which showed DCA efficacy in preventing brain damage, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1 (ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Further, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in human subjects with FBXL4-/- disease.

Keywords:  Drug therapy; Genetic diseases; Genetics; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.156346
Front Mol Neurosci. 2022 ;15 915570

Effects of Sevoflurane Anesthesia on Cerebral Lipid Metabolism in the Aged Brain of Marmosets and Mice.

Haoli Mao, Jiao Zhu, Yanyong Cheng, Lingling Shi, Xiao Chen, Ren Zhou, Zhenyu Xue, Siyu Liu, Zilong Qiu, Hong Jiang.

   Objective: In the lipid-rich brain, lipids performed signaling processes associated with the control system of the cell cycle, stress, and inflammatory reactions, as well as maintained brain and cellular homeostasis. The effects of general anesthesia on brain impairment in the elderly were controversial and complex. The study sought to evaluate the effect of lipid metabolism in the brain of aged marmosets and mice under long-term exposure to sevoflurane.
Methods: A total of 6 marmosets over 8-year-old and 10 mice aged 18 months were divided into the sevoflurane anesthesia and control groups, respectively. Marmosets in the sevoflurane anesthesia group were exposed to 1.5-2.5% sevoflurane and 100% O2 for 6 h. Mice anesthetized with sevoflurane were exposed to 3% sevoflurane and 60% O2 for 6 h. All prefrontal cortex tissues of marmosets and mice were harvested for the analysis of lipidomics.
Results: Compared to the control group, we found that phosphatidylethanolamine (PE) (18:0/22:5), PE (16:0/22:5), PE (18:2/22:5), PE (14:0/22:5), and PE (18:1/22:5) increased in the prefrontal cortex of marmosets in the sevoflurane group, while triglyceride (TAG)56:5-fatty acid (FA) 20:4, TAG58:10-FA22:6, and TAG60:10-FA22:6 decreased. For aged mice, we indicated that lipid components phosphatidic acid (PA) (18:1/20:2) and TAG52:5-FA20:4 in the sevoflurane group increased, but PE (14:0/22:4), diglyceride (DAG) (16:1/18:2), and lysophosphatidylcholine (LPC) (16:1) + AcO decreased. More deeply, sevoflurane anesthesia resulted in the presence of 70 specific lipids in mice and marmosets. The enriched lipid subclasses were mainly monoacylglycerophosphoethanolamines and five other subclasses.
Conclusion: Sevoflurane caused slight changes in lipid metabolism both in the aged brain of marmosets and mice. However, the pathways of lipid metabolism were not affected. The effects of sevoflurane on lipid metabolism in aged brains may differ among species.

Keywords:  brain; general anesthesia; lipid metabolism; marmosets; mice; sevoflurane

DOI:  https://doi.org/10.3389/fnmol.2022.915570
Int J Mol Sci. 2022 Jul 19. pii: 7965. [Epub ahead of print]23(14):

Investigating the Role of GABA in Neural Development and Disease Using Mice Lacking GAD67 or VGAT Genes.

Erika Bolneo, Pak Yan S Chau, Peter G Noakes, Mark C Bellingham.

  Normal development and function of the central nervous system involves a balance between excitatory and inhibitory neurotransmission. Activity of both excitatory and inhibitory neurons is modulated by inhibitory signalling of the GABAergic and glycinergic systems. Mechanisms that regulate formation, maturation, refinement, and maintenance of inhibitory synapses are established in early life. Deviations from ideal excitatory and inhibitory balance, such as down-regulated inhibition, are linked with many neurological diseases, including epilepsy, schizophrenia, anxiety, and autism spectrum disorders. In the mammalian forebrain, GABA is the primary inhibitory neurotransmitter, binding to GABA receptors, opening chloride channels and hyperpolarizing the cell. We review the involvement of down-regulated inhibitory signalling in neurological disorders, possible mechanisms for disease progression, and targets for therapeutic intervention. We conclude that transgenic models of disrupted inhibitory signalling-in GAD67+/- and VGAT-/- mice-are useful for investigating the effects of down-regulated inhibitory signalling in a range of neurological diseases.

Keywords:  GABA; GABA-receptors; GABAergic transmission; GAD65; GAD67; VGAT; glutamatergic transmission; neural development

DOI:  https://doi.org/10.3390/ijms23147965