bims-medebr 2022-08-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–08–07
twelve papers selected by
Regina F. Fernández, Johns Hopkins University

Differential role of neuronal glucose and PFKFB3 in memory formation during development.
The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule.
Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review.
The Cholesteryl Ester Transfer Protein (CETP) raises Cholesterol Levels in the Brain.
Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.
Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.
Free Radical Chain Reactions and Polyunsaturated Fatty Acids in Brain Lipids.
α-linolenic acid interconversion is sufficient as a source of longer chain ω-3 polyunsaturated fatty acids in humans: An opinion.
Sphingolipids and DHA Improve Cognitive Deficits in Aged Beagle Dogs.
Life-long dietary restrictions have negligible or damaging effects on late-life cognitive performance: A key role for genetics in outcomes.
The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field.
The uses of transcriptomics and lipidomics indicated that direct contact with graphene oxide altered lipid homeostasis through ER stress in 3D human brain organoids.

Glia. 2022 Aug 02.

Differential role of neuronal glucose and PFKFB3 in memory formation during development.

Emmanuel Cruz, Benjamin Bessières, Pierre Magistretti, Cristina M Alberini.

  The consumption of glucose in the brain peaks during late childhood; yet, whether and how glucose metabolism is differentially regulated in the brain during childhood compared to adulthood remains to be understood. In particular, it remains to be determined how glucose metabolism is involved in behavioral activations such as learning. Here we show that, compared to adult, the juvenile rat hippocampus has significantly higher mRNA levels of several glucose metabolism enzymes belonging to all glucose metabolism pathways, as well as higher levels of the monocarboxylate transporters MCT1 and MCT4 and the glucose transporters endothelial-GLUT1 and GLUT3 proteins. Furthermore, relative to adults, long-term episodic memory formation in juvenile animals requires significantly higher rates of aerobic glycolysis and astrocytic-neuronal lactate coupling in the hippocampus. Only juvenile but not adult long-term memory formation recruits GLUT3, neuronal 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and more efficiently engages glucose in the hippocampus. Hence, compared to adult, the juvenile hippocampus distinctively regulates glucose metabolism pathways, and formation of long-term memory in juveniles involves differential neuronal glucose metabolism mechanisms.

Keywords:  GLUT3; PFKFB3; development; glucose; hippocampus; lactate; memory

DOI:  https://doi.org/10.1002/glia.24248
Nutr Metab (Lond). 2022 Jul 30. 19(1): 52

The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule.

Xiangli Xue, Beibei Liu, Jingyun Hu, Xuepeng Bian, Shujie Lou.

  Lactate has previously been considered a metabolic waste and is mainly involved in exercise-induced fatigue. However, recent studies have found that lactate may be a mediator of the beneficial effects of exercise on brain health. Lactate plays a dual role as an energy supply substrate and a signaling molecule in this process. On the one hand, astrocytes can uptake circulating glucose or degrade glycogen for glycolysis to produce lactate, which is released into the extracellular space. Neurons can uptake extracellular lactate as an important supplement to their energy metabolism substrates, to meet the demand for large amounts of energy when synaptic activity is enhanced. Thus, synaptic activity and energy transfer show tight metabolic coupling. On the other hand, lactate acts as a signaling molecule to activate downstream signaling transduction pathways by specific receptors, inducing the expression of immediate early genes and cerebral angiogenesis. Moderate to high-intensity exercise not only increases lactate production and accumulation in muscle and blood but also promotes the uptake of skeletal muscle-derived lactate by the brain and enhances aerobic glycolysis to increase brain-derived lactate production. Furthermore, exercise regulates the expression or activity of transporters and enzymes involved in the astrocyte-neuron lactate shuttle to maintain the efficiency of this process; exercise also activates lactate receptor HCAR1, thus affecting brain plasticity. Rethinking the role of lactate in cognitive function and the regulatory effect of exercise is the main focus and highlights of the review. This may enrich the theoretical basis of lactate-related to promote brain health during exercise, and provide new perspectives for promoting a healthy aging strategy.

Keywords:  Astrocyte-neuron metabolic coupling; Cognitive function; Exercise intervention; Lactate receptor HCAR1/GPR81; Lactate shuttle

DOI:  https://doi.org/10.1186/s12986-022-00687-z
Front Nutr. 2022 ;9 934497

Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review.

Ksenia Shcherbakova, Alexander Schwarz, Sergey Apryatin, Marina Karpenko, Alexander Trofimov.

  It is now widely accepted that ketosis (a physiological state characterized by elevated plasma ketone body levels) possesses a wide range of neuroprotective effects. There is a growing interest in the use of ketogenic supplements, including medium-chain triglycerides (MCT), to achieve intermittent ketosis without adhering to a strict ketogenic diet. MCT supplementation is an inexpensive and simple ketogenic intervention, proven to benefit both individuals with normal cognition and those suffering from mild cognitive impairment, Alzheimer's disease, and other cognitive disorders. The commonly accepted paradigm underlying MCT supplementation trials is that the benefits stem from ketogenesis and that MCT supplementation is safe. However, medium-chain fatty acids (MCFAs) may also exert effects in the brain directly. Moreover, MCFAs, long-chain fatty acids, and glucose participate in mutually intertwined metabolic pathways. Therefore, the metabolic effects must be considered if the desired procognitive effects require administering MCT in doses larger than 1 g/kg. This review summarizes currently available research on the procognitive effects of using MCTs as a supplement to regular feed/diet without concomitant reduction of carbohydrate intake and focuses on the revealed mechanisms linked to particular MCT metabolites (ketone bodies, MCFAs), highlighting open questions and potential considerations.

Keywords:  capric acid (C10); caprylic acid (C8); cardiometabolic health; ketosis; medium-chain fatty acids; medium-chain triglycerides; neuroprotection; procognitive activity

DOI:  https://doi.org/10.3389/fnut.2022.934497
J Lipid Res. 2022 Jul 31. pii: S0022-2275(22)00093-1. [Epub ahead of print] 100260

The Cholesteryl Ester Transfer Protein (CETP) raises Cholesterol Levels in the Brain.

Felix Oestereich, Noosha Yousefpour, Ethan Yang, Jasmine Phénix, Zari Saadati Nezhad, Albert Nitu, Antonio Vázquez Cobá, Alfredo Ribeiro-da-Silva, Pierre Chaurand, Lisa Marie Munter.

  The cholesteryl ester transfer protein (CETP) is a lipid transfer protein responsible for the exchange of cholesteryl esters and triglycerides between lipoproteins. Decreased CETP activity is associated with longevity, cardiovascular health, and maintenance of good cognitive performance. Interestingly, mice lack the CETP-encoding gene and have very low levels of low-density lipoprotein (LDL) particles compared to humans. Currently, the molecular mechanisms induced due to CETP activity are not clear. To understand how CETP activity affects the brain, we utilized CETP transgenic (CETPtg) mice that show elevated LDL levels upon induction of CETP expression through a high cholesterol diet. CETPtg mice on a high cholesterol diet showed up to 22% higher cholesterol levels in the brain. Using a microarray on mostly astrocyte-derived mRNA, we found that this cholesterol increase is likely not due to elevated de novo synthesis of cholesterol. However, cholesterol efflux is decreased in CETPtg mice along with an upregulation of the complement factor C1Q, which plays a role in neuronal cholesterol clearance. Our data suggest that CETP activity affects brain health through modulating cholesterol distribution and clearance. Therefore, we propose that CETPtg mice constitute a valuable research tool to investigate the impact of cholesterol metabolism on brain function.

Keywords:  24S-hydroxycholesterol; Alzheimer’s disease; C1Q; CETP transgenic mice; TREM2; brain lipids; complement system; low-density lipoprotein; mass spectrometry; microarray

DOI:  https://doi.org/10.1016/j.jlr.2022.100260
CNS Neurosci Ther. 2022 Aug 06.

Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.

Claudia Fuchs, Livia Cosentino, Chiara Urbinati, Maria Cristina Talamo, Giorgio Medici, Maria Cristina Quattrini, Nicola Mottolese, Donatella Pietraforte, Andrea Fuso, Elisabetta Ciani, Bianca De Filippis.

   INTRODUCTION: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.
METHODS: The effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48 h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het).
RESULTS: The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by Cdkl5-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212).
CONCLUSIONS: Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD.

Keywords:  CDKL5 deficiency disorder; animal model; behavior; cytoskeleton; therapeutic approach; transfection

DOI:  https://doi.org/10.1111/cns.13907
Nat Neurosci. 2022 Aug;25(8): 1020-1033

Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.

Chia-Chen Liu, Jing Zhao, Yuan Fu, Yasuteru Inoue, Yingxue Ren, Yuanxin Chen, Sydney V Doss, Francis Shue, Suren Jeevaratnam, Ligia Bastea, Na Wang, Yuka A Martens, Wenhui Qiao, Minghui Wang, Na Zhao, Lin Jia, Yu Yamazaki, Akari Yamazaki, Cassandra L Rosenberg, Zhen Wang, Dehui Kong, Zonghua Li, Lindsey A Kuchenbecker, Zachary A Trottier, Lindsey Felton, Justin Rogers, Zachary S Quicksall, Cynthia Linares, Joshua Knight, Yixing Chen, Aishe Kurti, Takahisa Kanekiyo, John D Fryer, Yan W Asmann, Peter Storz, Xusheng Wang, Junmin Peng, Bin Zhang, Betty Y S Kim, Guojun Bu.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

DOI: https://doi.org/10.1038/s41593-022-01127-0
ACS Omega. 2022 Jul 26. 7(29): 25337-25345

Free Radical Chain Reactions and Polyunsaturated Fatty Acids in Brain Lipids.

Sharon C W Ng, Ran Furman, Paul H Axelsen, Mikhail S Shchepinov.

Polyunsaturated fatty acyl chains (PUFAs) concentrate in the brain and give rise to numerous oxidative chemical degradation products. It is widely assumed that these products are the result of free radical chain reactions, and reactions of this type have been demonstrated in preparations where a single PUFA substrate species predominates. However, it is unclear whether such reactions can occur in the biologically complex milieu of lipid membranes where PUFA substrates are a minority species, and where diverse free radical scavengers or other quenching mechanisms are present. It is of particular interest to know whether they occur in brain, where PUFAs are concentrated and where PUFA oxidation products have been implicated in the pathogenesis of neurodegenerative disorders. To ascertain whether free radical chain reactions can occur in a complex brain lipid mixture, mouse brain lipids were extracted, formed into vesicles, and treated with a fixed number of hydroxyl radicals under conditions wherein the concentrations and types of PUFA-containing phospholipids were varied. Specific phospholipid species in the mixture were assayed by tandem mass spectrometry to quantify the oxidative losses of endogenous PUFA-containing phospholipids. Results reveal crosstalk between the oxidative degradation of ω3 and ω6 PUFAs that can only be explained by the occurrence of free radical chain reactions. These results demonstrate that PUFAs in a complex brain lipid mixture can participate in free radical chain reactions wherein the extent of oxidative degradation is not limited by the number of reactive oxygen species available to initiate such reactions. These reactions may help explain otherwise puzzling in vivo interactions between ω3 and ω6 PUFAs in mouse brain.

DOI: https://doi.org/10.1021/acsomega.2c02285
Lipids. 2022 Jul 31.

α-linolenic acid interconversion is sufficient as a source of longer chain ω-3 polyunsaturated fatty acids in humans: An opinion.

Graham C Burdge.

  α-linolenic acid (αLNA) conversion into the functionally important ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), has been regarded as inadequate for meeting nutritional requirements for these PUFA. This view is based on findings of small αLNA supplementation trials and stable isotope tracer studies that have been interpreted as indicating human capacity for EPA and, in particular, DHA synthesis is limited. The purpose of this review is to re-evaluate this interpretation. Markedly differing study designs, inconsistent findings and lack of trial replication preclude robust consensus regarding the nutritional adequacy of αLNA as a source of EPC and DHA. The conclusion that αLNA conversion in humans is constrained is inaccurate because it presupposes the existence of an unspecified, higher level of metabolic activity. Since capacity for EPA and DHA synthesis is the product of evolution it may be argued that the levels of EPA and DHA it maintains are nutritionally appropriate. Dietary and supra-dietary EPA plus DHA intakes confer health benefits. Paradoxically, such health benefits are also found amongst vegetarians who do not consume EPA and DHA, and for whom αLNA conversion is the primary source of ω-3 PUFA. Since there are no reported adverse effects on health or cognitive development of diets that exclude EPA and DHA, their synthesis from αLNA appears to be nutritionally adequate. This is consistent with the dietary essentiality of αLNA and has implications for developing sustainable nutritional recommendations for ω-3 PUFA.

Keywords:  docosahexaenoic acid; eicosapentaenoic acid; omega-3; polyunsaturated fatty acids; vegetarian; α-linolenic acid

DOI:  https://doi.org/10.1002/lipd.12355
Front Vet Sci. 2022 ;9 646451

Sphingolipids and DHA Improve Cognitive Deficits in Aged Beagle Dogs.

Joseph A Araujo, Sergi Segarra, Jessica Mendes, Andrea Paradis, Melissa Brooks, Sandy Thevarkunnel, Norton W Milgram.

  Canine cognitive dysfunction syndrome (CDS) is a disorder found in senior dogs that is typically defined by the development of specific behavioral signs which are attributed to pathological brain aging and no other medical causes. One way of objectively characterizing CDS is with the use of validated neuropsychological test batteries in aged Beagle dogs, which are a natural model of this condition. This study used a series of neuropsychological tests to evaluate the effectiveness of supplementation with a novel lipid extract containing porcine brain-derived sphingolipids (Biosfeen®) and docosahexaenoic acid (DHA) for attenuating cognitive deficits in aged Beagles. Two groups (n = 12), balanced for baseline cognitive test performance, received a daily oral dose of either test supplement, or placebo over a 6-month treatment phase. Cognitive function was evaluated using the following tasks: delayed non-matching to position (DNMP), selective attention, discrimination learning retention, discrimination reversal learning, and spatial discrimination acquisition and reversal learning. The effect of the supplement on brain metabolism using magnetic resonance spectroscopy (MRS) was also examined. A significant decline (p = 0.02) in DNMP performance was seen in placebo-treated dogs, but not in dogs receiving the supplement, suggesting attenuation of working memory performance decline. Compared to placebo, the supplemented group also demonstrated significantly improved (p = 0.01) performance on the most difficult pattern of the spatial discrimination task and on reversal learning of the same pattern (p = 0.01), potentially reflecting improved spatial recognition and executive function, respectively. MRS revealed a significant increase (p = 0.048) in frontal lobe glutamate and glutamine in the treatment group compared to placebo, indicating a physiological change which may be attributed to the supplement. Decreased levels of glutamate and glutamine have been correlated with cognitive decline, suggesting the observed increase in these metabolites might be linked to the positive cognitive effects found in the present study. Results of this study suggest the novel lipid extract may be beneficial for counteracting age-dependent deficits in Beagle dogs and supports further investigation into its use for treatment of CDS. Additionally, due to parallels between canine and human aging, these results might also have applicability for the use of the supplement in human cognitive health.

Keywords:  aging; canine; cognition; cognitive dysfunction syndrome; executive function; neurodegeneration

DOI:  https://doi.org/10.3389/fvets.2022.646451
Neurobiol Aging. 2022 Jul 11. pii: S0197-4580(22)00155-5. [Epub ahead of print]118 108-116

Life-long dietary restrictions have negligible or damaging effects on late-life cognitive performance: A key role for genetics in outcomes.

Andrew R Ouellette, Niran Hadad, Andrew Deighan, Laura Robinson, Kristen O'Connell, Adam Freund, Gary A Churchill, Catherine C Kaczorowski.

  Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls on Y-maze working memory (WM) and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging to recall of CFM. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with CFM outcomes in aged mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with the neuronal monocarboxylate transporter MCT2 encoded by Slc16a7 highlighted as novel target.

Keywords:  Caloric restriction; Cognition; Genetic diversity; Intermittent fasting; Metabolism

DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.07.004
Biol Pharm Bull. 2022 ;45(8): 1008-1021

The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field.

Yugo Takagi, Shun Nishikado, Jumpei Omi, Junken Aoki.

  Lysophospholipids are phospholipids with only one fatty acid. During the past two decades, it has become apparent that lysophospholipids are not merely degradation products but have various physiological and pathological functions in vivo via G protein-coupled receptor (GPCR)-type receptors. These include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylinositol/lysophosphatidylglucose (LPI/LPtdGlc), and lysophosphatidylserine (LysoPS). This review focuses on identifying the functions of the receptors, enzymes, transporters, and carrier proteins required for these four lysophospholipids to function as lipid mediators. We also note that many of advances in this field have been made by Japanese pharmaceutical scientists.

Keywords:  G protein-coupled receptor; lysophosphatidic acid; lysophosphatidylinositol; lysophosphatidylserine; lysophospholipid mediator; sphingosine 1-phosphate

DOI:  https://doi.org/10.1248/bpb.b22-00304
Sci Total Environ. 2022 Aug 02. pii: S0048-9697(22)04914-2. [Epub ahead of print] 157815

The uses of transcriptomics and lipidomics indicated that direct contact with graphene oxide altered lipid homeostasis through ER stress in 3D human brain organoids.

Xudong Liu, Chao Yang, P Chen, Lei Zhang, Yi Cao.

  The potential uses of graphene-based nanomaterials (NMs) in various fields lead to the concern about their neurotoxicity, considering that graphene-based NMs are capable to cross blood brain barrier (BBB) and enter central nervous system (CNS). Although previous studies reported the possibility of graphene-based NM exposure to alter lipid homeostasis in animals or cultured neurons, recent studies suggested the need to use 3D human brain organoids for mechanism-based toxicological studies as this model might better recapitulate the complex human brains. Herein, we used multi-omics techniques to investigate the mechanisms of graphene oxide (GO) on lipid homeostasis in a novel 3D brain organoid model. We found that 50 μg/mL GO induced cytotoxicity but not superoxide. RNA-sequencing data showed that 50 μg/mL GO significantly up-regulated and down-regulated 80 and 121 genes, respectively. Furthermore, we found that GO exposure altered biological molecule metabolism pathways including lipid metabolism. Consistently, lipidomics data supported dose-dependent alteration of lipid profiles by GO in 3D brain organoids. Interestingly, co-exposure to GO and endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid (4-PBA) decreased most of the lipid classes compared with the exposure of GO only. We further verified that exposure to GO promoted ER stress marker GRP78 proteins, which in turn activated IRE1α/XBP-1 axis, and these changes were partially or completely inhibited by 4-PBA. These results proved that direct contact with GO disrupted lipid homeostasis through the activation of ER stress. As 3D brain organoids resemble human brains, these data might be better extrapolated to humans.

Keywords:  3D brain organoids; Endoplasmic reticulum (ER) stress; Graphene oxide (GO); Lipidomics; Transcriptomics

DOI:  https://doi.org/10.1016/j.scitotenv.2022.157815