bims-medebr 2023-11-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–11–12
twenty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.
Brain cholesterol homeostasis and its association with neurodegenerative diseases.
The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.
Humanin ameliorates TBI-related cognitive impairment by attenuating mitochondrial dysfunction and inflammation.
3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.
Dihydropteridine Reductase Deficiency - A Rare and Potentially Treatable Cause Mimicking Cerebral Palsy.
Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.
Repeated sleep deprivation decreases the flux into hexosamine biosynthetic pathway/O-GlcNAc cycling and aggravates Alzheimer's disease neuropathology in adult zebrafish.
Decreased long-chain acylcarnitine content increases mitochondrial coupling efficiency and prevents ischemia-induced brain damage in rats.
Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission.
Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.
Long-term lifestyle intervention is superior to transient modification for neuroprotection in D-galactose-induced aging rats.
Lack of HCAR1, the lactate GPCR, signaling promotes autistic-like behavior.
Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) deficiency: a rare case with bicytopenia and coagulopathy.
Neurovascular unit disruption and blood-brain barrier leakage in MCT8 deficiency.
Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families.
The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation.
Reactive Matrices for MALDI-MS of Cholesterol.
MITOCHONDRIAL BIOENERGETICS AND CYTOMETRIC CHARACTERIZATION OF A SYNAPTOSOMAL PREPARATION FROM MOUSE BRAIN CORTEX.
Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment.
Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex.
Associations of the Mediterranean-DASH Intervention for Neurodegenerative Delay diet with brain structural markers and their changes.
Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis.
Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes.
Erythropoietin regulates developmental myelination in the brain stimulating postnatal oligodendrocyte maturation.

Nat Metab. 2023 Nov 06.

Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila.

Yasmine Rabah, Raquel Francés, Julia Minatchy, Laura Guédon, Coraline Desnous, Pierre-Yves Plaçais, Thomas Preat.

Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.

DOI: https://doi.org/10.1038/s42255-023-00910-y
Neurochem Int. 2023 Nov 08. pii: S0197-0186(23)00163-8. [Epub ahead of print] 105635

Brain cholesterol homeostasis and its association with neurodegenerative diseases.

Yi Gao, Shiying Ye, Yuehong Tang, Wenjuan Tong, Shaowei Sun.

  The brain is the most cholesterol-rich organ in mammals. However, cholesterol metabolism in the brain is completely independent of other tissues due to the presence of the blood-brain barrier (BBB). Neurons, astrocytes and oligodendrocytes are the main cells responsible for cholesterol synthesis in the brain. The cholesterol content in the brain is maintained at a relatively constant level under strict regulation of synthesis, transport, and turnover, that is, brain cholesterol homeostasis. Once this balance is disrupted, neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) ensue. This review summarizes the processes controlling cholesterol homeostasis with respect to the synthesis, transport and turnover of cholesterol in the brain. We further focus on how cholesterol imbalance contributes to neurodegenerative diseases to explore the possibilities to modulate the key steps involved, which will provide clues for the development of therapies for the treatment of central nervous system (CNS) diseases.

Keywords:  Central nervous system; Cholesterol homeostasis; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.neuint.2023.105635
J Neurochem. 2023 Nov 06.

The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.

Elisa M York, Anne Miller, Sylwia A Stopka, Juan Ramón Martínez-François, Md Amin Hossain, Gerard Baquer, Michael S Regan, Nathalie Y R Agar, Gary Yellen.

  The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition.

Keywords:  brain metabolism; glucose metabolism; ketone body metabolism; lactate metabolism; mass spectrometry imaging; stable isotope tracing

DOI:  https://doi.org/10.1111/jnc.16004
Cells. 2023 Nov 02. pii: 2564. [Epub ahead of print]12(21):

Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition.

Kyle J Connolly, Juliette Margaria, Erika Di Biase, Oliver Cooper, Penelope J Hallett, Ole Isacson.

  Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson's disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads.

Keywords:  APOE; Alzheimer’s disease; GBA1; Lewy body dementia; Parkinson’s disease; cholesterol; glia; inflammation; lipids; lysosomes

DOI:  https://doi.org/10.3390/cells12212564
Biochim Biophys Acta Mol Basis Dis. 2023 Nov 03. pii: S0925-4439(23)00303-4. [Epub ahead of print] 166937

Humanin ameliorates TBI-related cognitive impairment by attenuating mitochondrial dysfunction and inflammation.

Pavan Thapak, Zhe Ying, Victoria Palafox-Sanchez, Guanglin Zhang, Xia Yang, Fernando Gomez-Pinilla.

  Traumatic brain injury (TBI) often results in a reduction of the capacity of cells to sustain energy demands, thus, compromising neuronal function and plasticity. Here we show that the mitochondrial activator humanin (HN) counteracts a TBI-related reduction in mitochondrial bioenergetics, including oxygen consumption rate. HN normalized the disruptive action of TBI on memory function, and restored levels of synaptic proteins (synapsin 1 and p-CREB). HN also counteracted TBI-related elevations of pro-inflammatory cytokines in plasma (TNF-α, INF-y, IL 17, IL 5, MCP 5, GCSF, RANNETS, sTNFRI) as well as in the hippocampus (gp-130 and p-STAT3). Gp-130 is an integral part of cytokine receptor impinging on STAT3 (Tyr-705) signaling. Furthermore, HN reduced astrocyte proliferation in TBI. The overall evidence suggests that HN plays an integral role in normalizing fundamental aspects of TBI pathology which are central to energy balance, brain function, and plasticity.

Keywords:  Astrogliosis; Inflammation; Mitochondrial bioenergetics; Synaptic plasticity; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.bbadis.2023.166937
Clin Chim Acta. 2023 Nov 05. pii: S0009-8981(23)00431-X. [Epub ahead of print]551 117629

3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.

Elizabeth A Jennings, Zane H Abi-Rached, Dylan E Jones, Robert O Ryan.

  The acylcarnitines comprise a wide range of acyl groups linked via an ester bond to the hydroxyl group of L-carnitine. Mass spectrometry methods are capable of measuring the relative abundance of hundreds of acylcarnitines in a single drop of blood. As such, acylcarnitines can serve as sensitive biomarkers of disease. For certain acylcarnitines, however, their biochemical origin, and biomedical significance, remain unclear. One such example is 3-methylglutaryl (3MG) carnitine (C5-3M-DC). Whereas 3MG carnitine levels are normally very low, elevated levels are detected in discrete inborn errors of metabolism (IEM) as well as different forms of heart disease. Moreover, acute injury, including γ radiation exposure, paraquat poisoning, and traumatic brain injury manifest elevated levels of 3MG carnitine in blood and/or urine. Recent evidence indicates that two distinct biosynthetic routes to 3MG carnitine exist. The first, caused by an inherited deficiency in the leucine catabolism pathway enzyme, 3-hydroxy-3-methylglutaryl (HMG) CoA lyase, leads to a buildup of trans-3-methylglutaconyl (3MGC) CoA. Reduction of the double bond in trans-3MGC CoA generates 3MG CoA, which is then converted to 3MG carnitine by carnitine acyltransferase. This route, however, cannot explain why 3MG carnitine levels increase in IEMs that do not affect leucine metabolism or various chronic and acute disease states. In these cases, disease-related defects in aerobic energy metabolism result in diversion of acetyl CoA to trans-3MGC CoA. Once formed, trans-3MGC CoA is reduced to 3MG CoA and esterified to form 3MG carnitine. Thus, 3MG carnitine, represents a potential biomarker of disease processes associated with compromised mitochondrial energy metabolism.

Keywords:  3-methylglutaryl; Acylcarnitine; Biomarker; Heart disease; Mitochondria

DOI:  https://doi.org/10.1016/j.cca.2023.117629
Endocr Metab Immune Disord Drug Targets. 2023 Nov 08.

Dihydropteridine Reductase Deficiency - A Rare and Potentially Treatable Cause Mimicking Cerebral Palsy.

Marta Ribeiro, Mafalda Rebelo, Andreia Pereira, Diana Antunes, Ana Cristina Ferreira, Sandra Jacinto.

   INTRODUCTION: Dihydropteridine reductase deficiency (DHPRD) is a rare genetic disorder of tetrahydrobiopterin (BH4) regeneration, a cofactor for several enzymes, including phenylalanine hydroxylase. Due to hyperphenylalaninemia (HPA), patients can be detected by the newborn metabolic screening, when available. The most common symptoms of DHPRD may mimic cerebral palsy: developmental/cognitive impairment, hypotonia, peripheral hypertonia, dystonia, feeding difficulties, epilepsy, and microcephaly. The long-term neurodevelopmental outcome is strongly influenced by the early initiation of effective treatment.
CASE REPORT: A 2-year-old boy, born in Guinea, was evaluated in our center with the diagnosis of "cerebral palsy". He was born after a prolonged labor, and had feeding difficulties and severe developmental delay. Examination revealed microcephaly, axial hypotonia, and dyskinetic movements without hypertension. No seizures or oculogyric crisis were reported. Brain MRI showed slight brain atrophy and hyperintensity T2/FLAIR in basal ganglia. The diagnosis of cerebral palsy was questioned, and further investigation was carried out. HPA raised the possibility of BH4 deficiency, supported by increased biopterin in urine, decreased neurotransmitters in CSF, and low DHPR enzyme activity. A variant (128_130del (p.(Val43del)) in apparent homozygosity was later detected in the QPDR gene. At 4 years old, he started L-dopa/carbidopa, oxitriptan, and a phenylalanine-restrictive diet with moderate clinical improvement.
CONCLUSION: When the diagnosis of "cerebral palsy" is questionable, other etiologies should be investigated, particularly disorders that have specific disease-modifying treatment. In our patient, the atypical constellation of neurological signs, brain MRI findings, and the nonexistence of newborn metabolic screening in the country of origin supported additional investigation. The presence of HPA-associated dystonia was crucial to the investigation and was later confirmed as DHPRD. Unfortunately, at this stage, the reversibility of the neurological damage in response to treatment is doubtful.

Keywords:  Cerebral Palsy; Dihydropteridine reductase deficiency; Dystonia; Hyperphenylalaninemia; Metabolic Screening; QPDR gene

DOI:  https://doi.org/10.2174/0118715303279209231026044120
iScience. 2023 Nov 17. 26(11): 108196

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice.

Nicole K H Yiew, Stanislaw Deja, Daniel Ferguson, Kevin Cho, Chaowapong Jarasvaraparn, Miriam Jacome-Sosa, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck.

  The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.

Keywords:  Cellular physiology; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2023.108196
J Neuroinflammation. 2023 Nov 09. 20(1): 257

Repeated sleep deprivation decreases the flux into hexosamine biosynthetic pathway/O-GlcNAc cycling and aggravates Alzheimer's disease neuropathology in adult zebrafish.

Jiwon Park, Dong Yeol Kim, Geum-Sook Hwang, Inn-Oc Han.

  This study investigated chronic and repeated sleep deprivation (RSD)-induced neuronal changes in hexosamine biosynthetic pathway/O-linked N-acetylglucosamine (HBP/O-GlcNAc) cycling of glucose metabolism and further explored the role of altered O-GlcNAc cycling in promoting neurodegeneration using an adult zebrafish model. RSD-triggered degenerative changes in the brain led to impairment of memory, neuroinflammation and amyloid beta (Aβ) accumulation. Metabolite profiling of RSD zebrafish brain revealed a significant decrease in glucose, indicating a potential association between RSD-induced neurodegeneration and dysregulated glucose metabolism. While RSD had no impact on overall O-GlcNAcylation levels in the hippocampus region, changes were observed in two O-GlcNAcylation-regulating enzymes, specifically, a decrease in O-GlcNAc transferase (OGT) and an increase in O-GlcNAcase (OGA). Glucosamine (GlcN) treatment induced an increase in O-GlcNAcylation and recovery of the OGT level that was decreased in the RSD group. In addition, GlcN reversed cognitive impairment by RSD. GlcN reduced neuroinflammation and attenuated Aβ accumulation induced by RSD. Repeated treatment of zebrafish with diazo-5-oxo-l-norleucine (DON), an inhibitor of HBP metabolism, resulted in cognitive dysfunction, neuroinflammation and Aβ accumulation, similar to the effects of RSD. The pathological changes induced by DON were restored to normal upon treatment with GlcN. Both the SD and DON-treated groups exhibited a common decrease in glutamate and γ-aminobutyric acid compared to the control group. Overexpression of OGT in zebrafish brain rescued RSD-induced neuronal dysfunction and neurodegeneration. RSD induced a decrease in O-GlcNAcylation of amyloid precursor protein and increase in β-secretase activity, which were reversed by GlcN treatment. Based on the collective findings, we propose that dysregulation of HBP and O-GlcNAc cycling in brain plays a crucial role in RSD-mediated progression of neurodegeneration and Alzheimer's disease pathogenesis. Targeting of this pathway may, therefore, offer an effective regulatory approach for treatment of sleep-associated neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Hexosamine; Sleep; Zebrafish

DOI:  https://doi.org/10.1186/s12974-023-02944-1
Biomed Pharmacother. 2023 Nov 02. pii: S0753-3322(23)01601-3. [Epub ahead of print]168 115803

Decreased long-chain acylcarnitine content increases mitochondrial coupling efficiency and prevents ischemia-induced brain damage in rats.

Liga Zvejniece, Baiba Svalbe, Edijs Vavers, Melita Ozola, Solveiga Grinberga, Baiba Gukalova, Eduards Sevostjanovs, Edgars Liepinsh, Maija Dambrova.

  Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether lowering LCAC levels with the anti-ischemia compound 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB) protects brain mitochondrial function and improves neurological outcomes after transient middle cerebral artery occlusion (MCAO). The effects of 14 days of pretreatment with methyl-GBB (5 mg/kg, p.o.) on brain acylcarnitine (short-, long- and medium-chain) concentrations and brain mitochondrial function were evaluated in Wistar rats. Additionally, the mitochondrial respiration and reactive oxygen species (ROS) production rates were determined using ex vivo high-resolution fluorespirometry under normal conditions, in models of ischemia-reperfusion injury (reverse electron transfer and anoxia-reoxygenation) and 24 h after MCAO. MCAO model rats underwent vibrissae-evoked forelimb-placing and limb-placing tests to assess neurological function. The infarct volume was measured on day 7 after MCAO using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with methyl-GBB significantly reduced the LCAC content in brain tissue, which decreased the ROS production rate without affecting the respiration rate, indicating an increase in mitochondrial coupling. Furthermore, methyl-GBB treatment protected brain mitochondria against anoxia-reoxygenation injury. In addition, treatment with methyl-GBB significantly reduced the infarct size and improved neurological outcomes after MCAO. Increased mitochondrial coupling efficiency may be the basis for the neuroprotective effects of methyl-GBB. This study provides evidence that maintaining brain energy metabolism by lowering the levels of LCACs protects against ischemia-induced brain damage in experimental stroke models.

Keywords:  Ischemic stroke; Long-chain acylcarnitines; MCAO; Methyl-GBB; ROS

DOI:  https://doi.org/10.1016/j.biopha.2023.115803
J Inherit Metab Dis. 2023 Nov 06.

Metabolic characterization of neurogenetic disorders involving glutamatergic neurotransmission.

Sofía Illescas, Yaiza Diaz-Osorio, Anna Serradell, Lucía Toro-Soria, Uliana Musokhranvoa, Natalia Juliá-Palacios, Juliana Ribeiro-Constante, Xavier Altafaj, Mireia Olivella, Mar O'Callaghan, Alejandra Darling, Judith Armstrong, Rafael Artuch, Àngels García-Cazorla, Alfonso Oyarzábal.

  The study of inborn errors of neurotransmission has been mostly focused on monoamine disorders, GABAergic and glycinergic defects. The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives. We have performed a semi-targeted metabolomic analysis on CSF samples from 25 patients with neurogenetic disorders with an important expression in the glutamatergic synapse and 5 controls. Samples from patients diagnosed with MECP2, CDKL5, GRINpathies and STXBP1 related encephalopathies were included. We have performed univariate (UVA) and multivariate statistical analysis (MVA), using Wilcoxon rank-sum test, principal component analysis (PCA), and oPLS-DA. By using the results of both analyses, we have identified the metabolites that were significantly altered and that were important in clustering the respective groups. On these, we performed pathway- and network-based analyses to define which metabolic pathways were possibly altered in each pathology. We have observed alterations in the tryptophan and branched-chain amino acid metabolism pathways, which interestingly converge on LAT1 transporter-dependency to cross the blood-brain barrier (BBB). Analysis of the expression of LAT1 transporter in brain samples from a mouse model of Rett syndrome (MECP2) revealed a decrease in the transporter expression, that was already noticeable at pre-symptomatic stages. The study of the glutamatergic synapse from this perspective advances the understanding of their pathophysiology, shining light on an under-studied feature as is their metabolic signature. This article is protected by copyright. All rights reserved.

Keywords:  Neurodevelopmental diseases; Rett syndrome; SLC7A5; metabolomics; tryptophan

DOI:  https://doi.org/10.1002/jimd.12689
Nat Metab. 2023 Nov 09.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.

Arkadiusz Liskiewicz, Ahmed Khalil, Daniela Liskiewicz, Aaron Novikoff, Gerald Grandl, Gandhari Maity-Kumar, Robert M Gutgesell, Mostafa Bakhti, Aimée Bastidas-Ponce, Oliver Czarnecki, Konstantinos Makris, Heiko Lickert, Annette Feuchtinger, Monica Tost, Callum Coupland, Lisa Ständer, Seun Akindehin, Sneha Prakash, Faiyaz Abrar, Russell L Castelino, Yantao He, Patrick J Knerr, Bin Yang, Wouter F J Hogendorf, Shiqi Zhang, Susanna M Hofmann, Brian Finan, Richard D DiMarchi, Matthias H Tschöp, Jonathan D Douros, Timo D Müller.

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6-8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR-GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.

DOI: https://doi.org/10.1038/s42255-023-00931-7
Life Sci. 2023 Nov 06. pii: S0024-3205(23)00883-4. [Epub ahead of print]334 122248

Long-term lifestyle intervention is superior to transient modification for neuroprotection in D-galactose-induced aging rats.

Patcharapong Pantiya, Chanisa Thonusin, Titikorn Chunchai, Hiranya Pintana, Benjamin Ongnok, Wichwara Nawara, Busarin Arunsak, Aphisek Kongkaew, Nipon Chattipakorn, Siriporn C Chattipakorn.

   AIMS: To investigate whether transient dietary restriction or aerobic exercise in young adulthood exert long-lasting protection against brain aging later in life.
MAIN METHODS: Seven-week-old male Wistar rats were divided into 2 groups and given either normal saline as a vehicle (n = 8) or 150 mg/kg/day of D-galactose (n = 40) for 28 weeks, the D-galactose being used to induce aging. At week 13 of the experiment, D-galactose-treated rats were further divided into 5 groups, 1) no intervention, 2) transient dietary restriction for 6 weeks (week 13-18), 3) transient exercise for 6 weeks (week 13-18), 4) long-term dietary restriction for 16 weeks (week 13-28), and 5) long-term exercise for 16 weeks (week 13-28). At the end of week 28, cognitive function was examined, followed by molecular studies in the hippocampus.
KEY FINDINGS: Our results showed that either long-term dietary restriction or aerobic exercise effectively attenuated cognitive function in D-galactose-treated rats via the attenuation of oxidative stress, cellular senescence, Alzheimer's-like pathology, neuroinflammation, and improvements in mitochondria, brain metabolism, adult neurogenesis, and synaptic integrity. Although transient interventions provided benefits in some brain parameters in D-galactose-treated rats, an improvement in cognitive function was not observed.
SIGNIFICANCE: Our findings suggested that transient lifestyle interventions failed to exert a long-lasting protective effect against brain aging. Hence, novel drugs mimicking the neuroprotective effect of long-term dietary restriction or exercise and the combination of the two since young age appear to be more appropriate treatments for the elderly who are unable to engage in long-term dietary restriction or exercise.

Keywords:  Aerobic exercise; Aging; Cognitive impairment; D-galactose; Dietary restriction

DOI:  https://doi.org/10.1016/j.lfs.2023.122248
Cell Commun Signal. 2023 Nov 09. 21(1): 196

Lack of HCAR1, the lactate GPCR, signaling promotes autistic-like behavior.

Mohammad Ali Mohammad Nezhady, Gael Cagnone, Jean-Sébastien Joyal, Sylvain Chemtob.

  The GPCR HCAR1 is known to be the sole receptor for lactate, which modulates its metabolic effects. Despite its significant role in many processes, mice deficient in HCAR1 exhibit no visible phenotype and are healthy and fertile. We performed transcriptomic analysis on HCAR1 deficient cells, in combination with lactate, to explore pathophysiologically altered processes. Processes such as immune regulation, various cancers, and neurodegenerative diseases were significantly enriched for HCAR1 transcriptomic signature. However, the most affected process of all was autism spectrum disorder. We performed behavioral tests on HCAR1 KO mice and observed that these mice manifest autistic-like behavior. Our data opens new avenues for research on HCAR1 and lactate effect at a pathological level. Video Abstract.

Keywords:  Anxiety; Autism spectrum disorder; Autistic-like behavior; GPCR; HCAR1; Lactate; Signaling

DOI:  https://doi.org/10.1186/s12964-023-01188-z
BMJ Case Rep. 2023 Nov 06. pii: e257011. [Epub ahead of print]16(11):

Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) deficiency: a rare case with bicytopenia and coagulopathy.

Dalia El-Sayed, Hanaa El-Karaksy, Yasser Wali, Ilham Youssry.

  Mitochondrial 3-hydroxymethylglutaryl-CoA synthase-2 (HMGCS2) is the main enzyme involved in ketogenesis. It is an essential enzyme for the catalysis of β-oxidation-derived-acetyl-CoA and acetoacetyl Co-A to produce β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) and free coenzyme A.The deficiency of this enzyme (3-hydoxy-3-methylglutaryl-CoA synthase) is a very rare metabolic disorder with limited cases described in the literature. The manifestations of this disease include hypoketotic hypoglycaemia, metabolic acidosis, lethargy, hepatomegaly with fatty liver and encephalopathy.We report a middle childhood male who presented with hepatosplenomegaly, lymphadenopathy and bicytopenia. The case was diagnosed by the whole exome sequencing which revealed a homozygous missense variant of uncertain significance in HMGCS2 gene.

Keywords:  Haematology (incl blood transfusion); Metabolic disorders

DOI:  https://doi.org/10.1136/bcr-2023-257011
Fluids Barriers CNS. 2023 Nov 03. 20(1): 79

Neurovascular unit disruption and blood-brain barrier leakage in MCT8 deficiency.

Marina Guillén-Yunta, Víctor Valcárcel-Hernández, Ángel García-Aldea, Guadalupe Soria, José Manuel García-Verdugo, Ana Montero-Pedrazuela, Ana Guadaño-Ferraz.

   BACKGROUND: The monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease.
METHODS: Neurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls.
RESULTS: Ultrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density.
CONCLUSIONS: These findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease.

Keywords:  Blood–brain barrier; MCT8 deficiency; Neurovascular unit; Rare disease; Thyroid hormone transporters; Thyroid hormones

DOI:  https://doi.org/10.1186/s12987-023-00481-w
Orphanet J Rare Dis. 2023 Nov 03. 18(1): 344

Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families.

Marwa Al Busaidi, Feda E Mohamed, Eiman Al-Ajmi, Nadia Al Hashmi, Khalid Al-Thihli, Amna Al Futaisi, Watfa Al Mamari, Fathiya Al-Murshedi, Fatma Al-Jasmi.

   BACKGROUND: In metabolic stress, the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) enzyme is involved in energy production through the gluconeogenesis pathway. PEPCK-C deficiency is a rare childhood-onset autosomal recessive metabolic disease caused by PCK1 genetic defects. Previous studies showed a broad clinical spectrum ranging from asymptomatic to recurrent hypoglycemia with/without lactic acidosis, encephalopathy, seizures, and liver failure.
RESULTS: In this article, we discuss the occurrence of PEPCK-C deficiency in four families from the United Arab Emirates and Oman. All patients presented with unexplained hypoglycemia as a common feature. Two out of the seven patients presented with episodes of encephalopathy that resulted in seizures and neuroregression leading to global developmental delay and one patient had a neonatal presentation. Observed biochemical abnormalities include elevated lactate, transaminases, and tricarboxylic acid cycle metabolites in most patients. Elevated creatine kinase was documented in two patients. Whole exome sequencing revealed two novel (c.574T > C, and c.1268 C > T) and a previously reported splice site (c.961 + 1G > A) PCK1 variant in the affected families.
CONCLUSION: Patients become vulnerable during intercurrent illness; thus, prevention and prompt reversal of a catabolic state are crucial to avoid irreversible brain damage. This report will help to expand the clinical understanding of this rare disease and recommends screening for PEPCK-C deficiency in unexplained hypoglycemia.

Keywords:  Encephalopathy; Hypoglycemia; PCK1; Phosphoenolpyruvate Carboxykinase

DOI:  https://doi.org/10.1186/s13023-023-02946-5
Acta Pharmacol Sin. 2023 Nov 07.

The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation.

Shi-Hao Cui, Na Suo, Ying Yang, Xuan Wu, Shi-Meng Guo, Xin Xie.

  Oligodendrocytes (OLs) are glial cells that ensheath neuronal axons and form myelin in the central nervous system (CNS). OLs are differentiated from oligodendrocyte precursor cells (OPCs) during development and myelin repair, which is often insufficient in the latter case in demyelinating diseases such as multiple sclerosis (MS). Many factors have been reported to regulate OPC-to-OL differentiation, including a number of G protein-coupled receptors (GPCRs). In an effort to search pathways downstream of GPCRs that might be involved in OPC differentiation, we discover that U73122, a phosphoinositide specific phospholipase C (PI-PLC) inhibitor, dramatically promotes OPC-to-OL differentiation and myelin regeneration in experimental autoimmune encephalomyelitis model. Unexpectedly, U73343, a close analog of U73122 which lacks PI-PLC inhibitory activity also promotes OL differentiation, while another reported PI-PLC inhibitor edelfosine does not have such effect, suggesting that U73122 and U73343 enhance OPC differentiation independent of PLC. Although the structures of U73122 and U73343 closely resemble 17β-estradiol, and both compounds do activate estrogen receptors Erα and Erβ with low efficacy and potency, further study indicates that these compounds do not act through Erα and/or Erβ to promote OPC differentiation. RNA-Seq and bioinformatic analysis indicate that U73122 and U73343 may regulate cholesterol biosynthesis. Further study shows both compounds increase 14-dehydrozymostenol, a steroid reported to promote OPC differentiation, in OPC culture. In conclusion, the aminosteroids U73122 and U73343 promote OPC-to-OL generation and myelin formation by regulating cholesterol biosynthesis pathway.

Keywords:  U73122; differentiation; oligodendrocyte; oligodendrocyte progenitor cell; remyelination

DOI:  https://doi.org/10.1038/s41401-023-01183-7
Anal Chem. 2023 Nov 10.

Reactive Matrices for MALDI-MS of Cholesterol.

Zhiyi Yang, Zong Chang, Ka Deng, Junjie Gu, Yihao Wu, Qinchao Sun, Qian Luo.

Cholesterol is a critical molecule whose dysregulation in certain brain regions is related to multiple neurological disorders. It is of pathological importance to map the distribution of cholesterol in brain. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been widely used in the molecular imaging of metabolites at a high spatial resolution. However, it is challenging to analyze cholesterol by MALDI-MS due to its difficulty in ionization. Herein, we present for the first time a type of reactive matrix for MALDI-MS of cholesterol. Methylpyridinium carboxaldehydes react with cholesterol and other hydroxyl-containing sterols, which greatly enhanced both desorption and ionization and improved the limits of detection to the low μg/mL range. Compared with previous methods, our reactive matrix requires only one step of chemical derivatization and avoids time-consuming enzymatic reaction, which simplified the sample pretreatment. The reactive matrix was successfully used in mapping the distribution of cholesterol in brain tissue sections using MALDI-MS imaging. In summary, this work has provided a sensitive and simple method for the MALDI-MS analysis of cholesterol, has proposed a novel solution to visualize the distribution of sterol metabolites, and has great potential for applications in neurological and pathological studies.

DOI: https://doi.org/10.1021/acs.analchem.3c04127
Mitochondrion. 2023 Nov 07. pii: S1567-7249(23)00085-5. [Epub ahead of print]

MITOCHONDRIAL BIOENERGETICS AND CYTOMETRIC CHARACTERIZATION OF A SYNAPTOSOMAL PREPARATION FROM MOUSE BRAIN CORTEX.

Paulina Lombardi, Analía G Karadayian, Juan I Guerra, Juanita Bustamante, Georgina Rodríguez de Lores Arnaiz, Silvia Lores-Arnaiz.

  Mitochondrial function at synapses can be assessed in isolated nerve terminals. Synaptosomes are structures obtained in vitro by detaching the nerve endings from neuronal bodies under controlled homogenization conditions. Several protocols have been described for the preparation of intact synaptosomal fractions. Herein a fast and economical method to obtain synaptosomes with optimal intrasynaptic mitochondria functionality was described. Synaptosomal fractions were obtained from mouse brain cortex by differential centrifugation followed by centrifugation in a Ficoll gradient. The characteristics of the subcellular particles obtained were analyzed by flow cytometry employing specific tools. Integrity and specificity of the obtained organelles were evaluated by calcein and SNAP-25 probes. The proportion of positive events of the synaptosomal preparation was 75 ± 2 % and 48 ± 7% for calcein and Synaptosomal-Associated Protein of 25 kDa (SNAP-25), respectively. Mitochondrial integrity was evaluated by flow cytometric analysis of cardiolipin content, which indicated that 73 ± 1% of the total events were 10 N-nonylacridine orange (NAO)-positive. Oxygen consumption, ATP production and mitochondrial membrane potential determinations showed that mitochondria inside synaptosomes remained functional after the isolation procedure. Mitochondrial and synaptosomal enrichment were determined by measuring synaptosomes/ homogenate ratio of specific markers. Functionality of synaptosomes was verified by nitric oxide detection after glutamate addition. As compared with other methods, the present protocol can be performed briefly, does not imply high economic costs, and provides an useful tool for the isolation of a synaptosomal preparation with high mitochondrial respiratory capacity and an adequate integrity and function of intraterminal mitochondria.

Keywords:  brain cortex; flow cytometry; intrasynaptic mitochondria; mitochondrial function; synaptosomes

DOI:  https://doi.org/10.1016/j.mito.2023.10.002
Nat Commun. 2023 Nov 03. 14(1): 7060

Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment.

Jacob M Stillman, Francisco Mendes Lopes, Jing-Ping Lin, Kevin Hu, Daniel S Reich, Dorothy P Schafer.

Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF) likely due to lipofuscin (lipo-AF) and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipo-AF signal accumulates first within microglia and it occurs earliest in white versus gray matter. Importantly, in gray matter, lipo-AF signal can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. We further show that there is an age-dependent accumulation of lipo-AF inside and outside of microglia, which is not affected by amyloid plaques. We finally implement a robust and cost-effective strategy to quench AF in mouse, marmoset, and human brain tissue.

DOI: https://doi.org/10.1038/s41467-023-42809-y
Commun Biol. 2023 11 08. 6(1): 1133

Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex.

Lyvin Tat, Noemi Cannizzaro, Zachary Schaaf, Shailaja Racherla, Teodoro Bottiglieri, Ralph Green, Konstantinos S Zarbalis.

Previous reports have provided evidence that insufficient or excessive maternal folic acid (FA) intake during pregnancy can alter neurodevelopment of the offspring by modulating prenatal neurogenesis. Furthermore, our earlier work in a mouse model confirmed long-term structural changes at the cellular level of either deficient or excessive FA supply by comparably reducing dendritic arborization of cortical projection neurons. Here, we report that excessive amounts of FA decrease arborization of deep layer projection neurons, but not upper layer neurons and that reduced complexity of deep layer neurons is not observed when folic acid is replaced by folinic acid, a stable reduced form of folate. In addition, deficiency of B12, a vitamin that critically regulates folate metabolism, causes even more marked decreases in neuronal arborization in both deep and upper layer neurons and particularly in combination with FA excess. Furthermore, both FA excess and B12 deficiency affect synaptic density and morphology. Our findings point to neurodevelopmental risks associated with insufficient amounts of prenatal B12, particularly in association with high levels of FA intake, suggesting that the neurodevelopmental program is sensitive to an imbalance in the status of these interacting micronutrients.

DOI: https://doi.org/10.1038/s42003-023-05492-9
Alzheimers Dement. 2023 Nov 06.

Associations of the Mediterranean-DASH Intervention for Neurodegenerative Delay diet with brain structural markers and their changes.

Hui Chen, Michelle M Dunk, Binghan Wang, Mengjia Zhao, Jie Shen, Geng Zong, Yuesong Pan, Lusha Tong, Weili Xu, Changzheng Yuan.

   INTRODUCTION: The associations of the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet with brain structural changes are unclear.
METHODS: Among 26,466 UK Biobank participants, a 15-point MIND score was calculated from 24-hour diet recalls from 2009 to 2012. We assessed its associations with 17 magnetic-resonance-derived brain volumetric markers and their longitudinal changes and explored whether genetic factors modify the associations.
RESULTS: Higher MIND adherence was associated with larger volumes of thalamus, putamen, pallidum, hippocampus, and accumbens (beta per 3-unit increment ranging from 0.024 to 0.033) and lower white matter hyperintensities (P-trends < 0.05), regardless of genetic predispositions of Alzheimer's disease. MIND score was not associated with their longitudinal changes (P > 0.05) over a median of 2.2 years among participants with repeated imaging assessments (N = 2963), but was associated with slower atrophy in putamen (beta: 0.026, P-trend = 0.044) and pallidum (beta: 0.030, P-trend = 0.033) among APOE ε4 non-carriers (N = 654).
DISCUSSION: The MIND diet showed beneficial associations with certain brain imaging markers, and its associations with long-term brain structural changes warrants future investigation.
HIGHLIGHTS: Adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet was significantly associated with higher volumes and larger gray matter volumes in certain brain regions in UK adults, and the associations were not modified by genetic factors. No significant associations were observed between MIND diet and longitudinal changes in the investigated brain structural markers over a median of 2.2 years. Higher MIND score was significantly associated with slower atrophy in the putamen and pallidum among APOE ε4 non-carriers.

Keywords:  aging; brain structure; cohort study; diet; genetic factors; nutrition

DOI:  https://doi.org/10.1002/alz.13521
Cell Rep Med. 2023 Nov 02. pii: S2666-3791(23)00472-X. [Epub ahead of print] 101278

Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis.

Afroditi Tsitsou-Kampeli, Stefano Suzzi, Mor Kenigsbuch, Akisawa Satomi, Romano Strobelt, Oded Singer, Ester Feldmesser, Maitreyee Purnapatre, Sarah Phoebeluc Colaiuta, Eyal David, Liora Cahalon, Oliver Hahn, Tony Wyss-Coray, Yosef Shaul, Ido Amit, Michal Schwartz.

  The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

Keywords:  24-OH; Alzheimer’s disease; COVID-19; CYP46A1; TNF-α; blood-CSF barrier; inflammation; neurodegeneration aging

DOI:  https://doi.org/10.1016/j.xcrm.2023.101278
Cell Death Dis. 2023 11 07. 14(11): 722

Pyruvate dehydrogenase kinase 1 protects against neuronal injury and memory loss in mouse models of diabetes.

Yuan Yao, Jiaming Shi, Chunlai Zhang, Wei Gao, Ning Huang, Yaobei Liu, Weiwen Yan, Yingguang Han, Wenjuan Zhou, Liang Kong.

Hyperglycemia-induced aberrant glucose metabolism is a causative factor of neurodegeneration and cognitive impairment in diabetes mellitus (DM) patients. The pyruvate dehydrogenase kinase (PDK)-lactic acid axis is regarded as a critical link between metabolic reprogramming and the pathogenic process of neurological disorders. However, its role in diabetic neuropathy remains unclear. Here, we found that PDK1 and phosphorylation of pyruvate dehydrogenase (PDH) were obviously increased in high glucose (HG)-stimulated primary neurons and Neuro-2a cell line. Acetyl-coA, a central metabolic intermediate, might enhance PDK1 expression via histone H3K9 acetylation modification in HG condition. The epigenetic regulation of PDK1 expression provided an available negative feedback pattern in response to HG environment-triggered mitochondrial metabolic overload. However, neuronal PDK1 was decreased in the hippocampus of streptozotocin (STZ)-induced diabetic mice. Our data showed that the expression of PDK1 also depended on the hypoxia-inducible factor-1 (HIF-1) transcriptional activation under the HG condition. However, HIF-1 was significantly reduced in the hippocampus of diabetic mice, which might explain the opposite expression of PDK1 in vivo. Importantly, overexpression of PDK1 reduced HG-induced reactive oxygen species (ROS) generation and neuronal apoptosis. Enhancing PDK1 expression in the hippocampus ameliorated STZ-induced cognitive impairment and neuronal degeneration in mice. Together, our study demonstrated that both acetyl-coA-induced histone acetylation and HIF-1 are necessary to direct PDK1 expression, and enhancing PDK1 may have a protective effect on cognitive recovery in diabetic mice. Schematic representation of the protective effect of PDK1 on hyperglycemia-induced neuronal injury and memory loss. High glucose enhanced the expression of PDK1 in an acetyl-coA-dependent histone acetylation modification to avoid mitochondrial metabolic overload and ROS release. However, the decrease of HIF-1 may impair the upregulation of PDK1 under hyperglycemia condition. Overexpression of PDK1 prevented hyperglycemia-induced hippocampal neuronal injury and memory loss in diabetic mice.

DOI: https://doi.org/10.1038/s41419-023-06249-2
Sci Rep. 2023 Nov 09. 13(1): 19522

Erythropoietin regulates developmental myelination in the brain stimulating postnatal oligodendrocyte maturation.

Paola Muttathukunnel, Michael Wälti, Mostafa A Aboouf, Christina Köster-Hegmann, Tatjana Haenggi, Max Gassmann, Patrizia Pannzanelli, Jean-Marc Fritschy, Edith M Schneider Gasser.

Myelination is a process tightly regulated by a variety of neurotrophic factors. Here, we show-by analyzing two transgenic mouse lines, one overexpressing EPO selectively in the brain Tg21(PDGFB-rhEPO) and another with targeted removal of EPO receptors (EPORs) from oligodendrocyte progenitor cells (OPC)s (Sox10-cre;EpoRfx/fx mice)-a key function for EPO in regulating developmental brain myelination. Overexpression of EPO resulted in faster postnatal brain growth and myelination, an increased number of myelinating oligodendrocytes, faster axonal myelin ensheathment, and improved motor coordination. Conversely, targeted ablation of EPORs from OPCs reduced the number of mature oligodendrocytes and impaired motor coordination during the second postnatal week. Furthermore, we found that EPORs are transiently expressed in the subventricular zone (SVZ) during the second postnatal week and EPO increases the postnatal expression of essential oligodendrocyte pro-differentiation and pro-maturation (Nkx6.2 and Myrf) transcripts, and the Nfatc2/calcineurin pathway. In contrast, ablation of EPORs from OPCs inactivated the Erk1/2 pathway and reduced the postnatal expression of the transcripts. Our results reveal developmental time windows in which EPO therapies could be highly effective for stimulating oligodendrocyte maturation and myelination.

DOI: https://doi.org/10.1038/s41598-023-46783-9