bims-medebr 2023-11-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒11‒05
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study.
Cholesterol is required for activity-dependent synaptic growth.
In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury.
Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.
Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease.
Mitochondrial transport in neurons and evidence for its involvement in acute neurological disorders.
Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function.
Neuronal aerobic glycolysis exacerbates synapse loss in aging mice.
Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75NTR signaling in the p75exonIII-KO mice.
Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.
Regulation of microglial responses after pediatric traumatic brain injury: exploring the role of SHIP-1.
Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2- 13 C]Pyruvate MR Spectroscopy.
Semiquantitative analysis of cerebral [18F]FDG-PET uptake in pediatric patients.
Delivery of mitochondria-containing extracellular vesicles to the BBB for ischemic stroke therapy.
Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.
Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models.
Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.
Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition.
The AMPK activator metformin improves recovery from demyelination by shifting oligodendrocyte bioenergetics and accelerating OPC differentiation.
[Mitochondrial pyruvate carrier deficiency: 3 cases report and literature review].
[18F]-FDG uptake in brain slices prepared from an aged mouse model of Alzheimer's disease using a dynamic autoradiography technique.

EBioMedicine. 2023 Oct 26. pii: S2352-3964(23)00415-2. [Epub ahead of print]97 104849

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study.

Antonella Tramutola, Hannah S Bakels, Federica Perrone, Michela Di Nottia, Tommaso Mazza, Maria Pia Abruzzese, Martina Zoccola, Sara Pagnotta, Rosalba Carrozzo, Susanne T de Bot, Marzia Perluigi, Willeke M C van Roon-Mom, Ferdinando Squitieri.

  BACKGROUND: Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD.METHODS: We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression.
FINDINGS: GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p < 0.0001, 95% [CI 0.91, 1.09]; p = 0.046, 95% [CI 0.93, 1.07]). In the frontal cortex, this occurred without evidence of extensive neuronal degeneration. Patients with HE-PHD had deregulated mitochondrial complex expression, particularly complexes II-III, levels of which were lower in frontal cortex versus controls (p = 0.027, 95% [CI 17.1, 17.6]; p = 0.002, 95% CI [16.6, 16.9]) and patients with AOHD (p = 0.052, 95% [CI 17.0, 17.6]; p = 0.002, 95% [CI 16.6, 16.7]). Hexokinase-II expression was also lower in HE-PHD frontal cortex and striatum versus controls (p = 0.010, 95% [CI 17.8, 18.2]; p = 0.045, 95% [CI 18.6, 18.7]) and in frontal cortex versus patients with AOHD (p = 0.013, 95% [CI 17.7, 18.1]). Expression JOHD levels were consistently different to those of HE-PHD but similar to those of AOHD.
INTERPRETATION: Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains.
FUNDING: '5 × 1000' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.

Keywords:  Brain dysfunction; Fibroblasts; Frontal cortex; Glucose metabolism; Glucose transporters; Paediatric-onset Huntington disease

DOI:  https://doi.org/10.1016/j.ebiom.2023.104849
J Cell Sci. 2023 Oct 30. pii: jcs.261563. [Epub ahead of print]

Cholesterol is required for activity-dependent synaptic growth.

Amber Shaheen, Claire L Richter Gorey, Adam Sghaier, Jeffrey S Dason.

  Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates cholesterol levels in neuronal membranes and whether these changes affect neuronal development and function. We generated transgenic flies that express the cholesterol binding D4H domain of Perfringolysin O toxin and found increased levels of cholesterol in presynaptic terminals of Drosophila larval neuromuscular junctions following increased synaptic activity. Reduced cholesterol impaired synaptic growth and largely prevented activity-dependent synaptic growth. Presynaptic knockdown of adenylyl cyclase phenocopied the impaired synaptic growth caused by reducing cholesterol. Furthermore, the effects of knocking down adenylyl cyclase and reducing cholesterol were not additive, suggesting that they function in the same pathway. Increasing cAMP levels using a dunce mutant with reduced phosphodiesterase activity failed to rescue this impaired synaptic growth, suggesting that cholesterol functions downstream of cAMP. We used a PKA sensor to show that reducing cholesterol levels reduced presynaptic PKA activity. Collectively, our results demonstrate that enhanced synaptic activity increased cholesterol levels in presynaptic terminals and that these changes likely activate the cAMP-PKA pathway during activity-dependent growth.

Keywords:   Drosophila ; CAMP; Cholesterol; Lipids; PKA; Presynaptic; Synaptic

DOI:  https://doi.org/10.1242/jcs.261563
Mol Neurobiol. 2023 Nov 01.

In Vivo Intracerebral Administration of α-Ketoisocaproic Acid to Neonate Rats Disrupts Brain Redox Homeostasis and Promotes Neuronal Death, Glial Reactivity, and Myelination Injury.

Ângela Beatris Zemniaçak, Rafael Teixeira Ribeiro, Camila Vieira Pinheiro, Sâmela de Azevedo Cunha, Tailine Quevedo Tavares, Ediandra Tissot Castro, Guilhian Leipnitz, Moacir Wajner, Alexandre Umpierrez Amaral.

  Maple syrup urine disease (MSUD) is caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, resulting in tissue accumulation of branched-chain α-keto acids and amino acids, particularly α-ketoisocaproic acid (KIC) and leucine. Affected patients regularly manifest with acute episodes of encephalopathy including seizures, coma, and potentially fatal brain edema during the newborn period. The present work investigated the ex vivo effects of a single intracerebroventricular injection of KIC to neonate rats on redox homeostasis and neurochemical markers of neuronal viability (neuronal nuclear protein (NeuN)), astrogliosis (glial fibrillary acidic protein (GFAP)), and myelination (myelin basic protein (MBP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase)) in the cerebral cortex and striatum. KIC significantly disturbed redox homeostasis in these brain structures 6 h after injection, as observed by increased 2',7'-dichlorofluorescein oxidation (reactive oxygen species generation), malondialdehyde levels (lipid oxidative damage), and carbonyl formation (protein oxidative damage), besides impairing the antioxidant defenses (diminished levels of reduced glutathione and altered glutathione peroxidase, glutathione reductase, and superoxide dismutase activities) in both cerebral structures. Noteworthy, the antioxidants N-acetylcysteine and melatonin attenuated or normalized most of the KIC-induced effects on redox homeostasis. Furthermore, a reduction of NeuN, MBP, and CNPase, and an increase of GFAP levels were observed at postnatal day 15, suggesting neuronal loss, myelination injury, and astrocyte reactivity, respectively. Our data indicate that disruption of redox homeostasis, associated with neural damage caused by acute intracerebral accumulation of KIC in the neonatal period may contribute to the neuropathology characteristic of MSUD patients.

Keywords:  Cerebral cortex; Maple syrup urine disease; Neurochemical markers; Redox homeostasis; Striatum; α-Ketoisocaproic acid

DOI:  https://doi.org/10.1007/s12035-023-03718-9
Transl Neurodegener. 2023 Oct 31. 12(1): 48

Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics.

Izabela Lepiarz-Raba, Ismail Gbadamosi, Roberta Florea, Rosa Chiara Paolicelli, Ali Jawaid.

  Microglia, the resident immune cells of the brain, are increasingly implicated in the regulation of brain health and disease. Microglia perform multiple functions in the central nervous system, including surveillance, phagocytosis and release of a variety of soluble factors. Importantly, a majority of their functions are closely related to changes in their metabolism. This natural inter-dependency between core microglial properties and metabolism offers a unique opportunity to modulate microglial activities via nutritional or metabolic interventions. In this review, we examine the existing scientific literature to synthesize the hypothesis that microglial phagocytosis of amyloid beta (Aβ) aggregates in Alzheimer's disease (AD) can be selectively enhanced via metabolic interventions. We first review the basics of microglial metabolism and the effects of common metabolites, such as glucose, lipids, ketone bodies, glutamine, pyruvate and lactate, on microglial inflammatory and phagocytic properties. Next, we examine the evidence for dysregulation of microglial metabolism in AD. This is followed by a review of in vivo studies on metabolic manipulation of microglial functions to ascertain their therapeutic potential in AD. Finally, we discuss the effects of metabolic factors on microglial phagocytosis of healthy synapses, a pathological process that also contributes to the progression of AD. We conclude by enlisting the current challenges that need to be addressed before strategies to harness microglial phagocytosis to clear pathological protein deposits in AD and other neurodegenerative disorders can be widely adopted.

Keywords:  Alzheimer's disease; Inflammation; Metabolism; Microglia; Neurodegeneration; Phagocytosis

DOI:  https://doi.org/10.1186/s40035-023-00382-w
J Extracell Vesicles. 2023 11;12(11): e12340

Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease.

Bhumsoo Kim, Yoon-Tae Kang, Faye E Mendelson, John M Hayes, Masha G Savelieff, Sunitha Nagrath, Eva L Feldman.

  The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate- and glucose-induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate-treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance.

Keywords:  Alzheimer's disease; amyloid precursor protein; diabetes; extracellular vesicles; insulin resistance; metabolic syndrome; obesity; tau

DOI:  https://doi.org/10.1002/jev2.12340
Front Neurosci. 2023 ;17 1268883

Mitochondrial transport in neurons and evidence for its involvement in acute neurological disorders.

Dengfeng Lu, Yun Feng, Guangjie Liu, Yayi Yang, Yubo Ren, Zhouqing Chen, Xiaoou Sun, Yixiang Guan, Zhong Wang.

  Ensuring mitochondrial quality is essential for maintaining neuronal homeostasis, and mitochondrial transport plays a vital role in mitochondrial quality control. In this review, we first provide an overview of neuronal mitochondrial transport, followed by a detailed description of the various motors and adaptors associated with the anterograde and retrograde transport of mitochondria. Subsequently, we review the modest evidence involving mitochondrial transport mechanisms that has surfaced in acute neurological disorders, including traumatic brain injury, spinal cord injury, spontaneous intracerebral hemorrhage, and ischemic stroke. An in-depth study of this area will help deepen our understanding of the mechanisms underlying the development of various acute neurological disorders and ultimately improve therapeutic options.

Keywords:  TRAK; acute neurological disorders; dynein; kinesin; miro; myosin

DOI:  https://doi.org/10.3389/fnins.2023.1268883
Brain Behav Immun. 2023 Oct 30. pii: S0889-1591(23)00317-3. [Epub ahead of print]

Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function.

Jing Wen, Senthil Kumaran Satyanarayanan, Ang Li, Lingli Yan, Ziai Zhao, Qiuju Yuan, Kuan-Pin Su, Huanxing Su.

  Alzheimer's disease (AD) and other forms of dementia represent major public health challenges but effective therapeutic options are limited. Pathological brain aging is associated with microvascular changes and impaired clearance systems. The application of omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) is one of the most promising nutritional interventions in neurodegenerative disorders from epidemiological data, clinical and pre-clinical studies. As essential components of neuronal membranes, n-3 PUFAs have shown neuroprotection and anti-inflammatory effects, as well as modulatory effects through microvascular pathophysiology, amyloid-beta (Aβ) clearance and glymphatic pathways. This review meticulously explores these underlying mechanisms that contribute to the beneficial effects of n-3 PUFAs against AD and dementia, synthesizing evidence from both animal and interventional studies.

Keywords:  Alzheimer’s disease; Brain clearance; Dementia; Glymphatic system; Omega-3 polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.bbi.2023.10.018
Exp Neurol. 2023 Oct 29. pii: S0014-4886(23)00275-3. [Epub ahead of print]371 114590

Neuronal aerobic glycolysis exacerbates synapse loss in aging mice.

Wenhui Zhou, Xingyue Yang, Huixia Wang, Wenjuan Yao, Dandan Chu, Feng Wu.

  Brain consumes nearly 20% supply of energy from glucose metabolism by oxidative phosphorylation and aerobic glycolysis. Less active state of glycolytic enzymes results in a limited capacity of glycolysis in the neurons of adult brain. Here we identified that Warburg effect is enhanced in hippocampal neurons during aging. As hippocampal neurons age, lactate levels progressively increase. Notably, we observed upregulated protein levels of PFKFB3 in the hippocampus of 20-month-old mice compared to young mice, and this higher PFKFB3 expression correlated with declining memory performance in aging mice. Remarkably, in aging mice, knocking down Pfkfb3 in hippocampal neurons rescued cognitive decline and synapse loss. Conversely, Pfkfb3 overexpression in hippocampal neurons led to cognitive impairment and synapse elimination, associated with heightened glycolysis. In vitro experiments with cultured primary neurons confirmed that Pfkfb3 overexpression increased glycolysis and that glycolytic inhibition could prevent apoptotic competency in neurons. These findings underscore that glycolysis in hippocampal neurons could potentially be targeted as a therapeutic avenue to mitigate cognitive decline and preserve synaptic integrity during aging.

Keywords:  Aerobic glycolysis; Aging; Cognitive decline; PFKFB3; Synapse loss

DOI:  https://doi.org/10.1016/j.expneurol.2023.114590
Front Mol Neurosci. 2023 ;16 1237458

Cholinergic neurodegeneration and cholesterol metabolism dysregulation by constitutive p75NTR signaling in the p75exonIII-KO mice.

Raquel Comaposada-Baró, Andrea Benito-Martínez, Juan Julian Escribano-Saiz, María Luisa Franco, Lorenzo Ceccarelli, Isabel Calatayud-Baselga, Helena Mira, Marçal Vilar.

  Degeneration of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer's disease (AD). However, few mouse models of AD recapitulate the neurodegeneration of the cholinergic system. The p75 neurotrophin receptor, p75NTR, has been associated with the degeneration of BFCNs in AD. The senescence-accelerated mouse prone number 8 (SAMP8) is a well-accepted model of accelerated and pathological aging. To gain a better understanding of the role of p75NTR in the basal forebrain during aging, we generated a new mouse line, the SAMP8-p75exonIII-/-. Deletion of p75NTR in the SAMP8 background induces an increase in the number of BFCNs at birth, followed by a rapid decline during aging compared to the C57/BL6 background. This decrease in the number of BFCNs correlates with a worsening in the Y-maze memory test at 6 months in the SAMP8-p75exonIII-/-. We found that SAMP8-p75exonIII-/- and C57/BL6-p75exonIII-/- mice expressed constitutively a short isoform of p75NTR that correlates with an upregulation of the protein levels of SREBP2 and its targets, HMGCR and LDLR, in the BF of both SAMP8-p75exonIII-/- and C57/BL6-p75exonIII-/- mice. As the neurodegeneration of the cholinergic system and the dysregulation of cholesterol metabolism are implicated in AD, we postulate that the generated SAMP8-p75exonIII-/- mouse strain might constitute a good model to study long-term cholinergic neurodegeneration in the CNS. In addition, our results support the role of p75NTR signaling in cholesterol biosynthesis regulation.

Keywords:  NGF (nerve growth factor); TrkA (tropomyosin receptor kinase); aging; cholesterol; cholinergic neurodegeneration; p75 neurotrophin receptor

DOI:  https://doi.org/10.3389/fnmol.2023.1237458
Mol Genet Metab. 2023 Oct 20. pii: S1096-7192(23)00340-2. [Epub ahead of print] 107710

Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.

Parith Wongkittichote, Cassandra Pantano, Emily Bogush, Cesar Augusto P Alves, Xinying Hong, Miao He, Matthew M Demczko, Rebecca D Ganetzky, Amy Goldstein.

  Iron‑sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.

Keywords:  IBA57; Iron‑sulfur clusters; Lysine metabolism; Mitochondrial disorder; Rhabdomyolysis

DOI:  https://doi.org/10.1016/j.ymgme.2023.107710
Front Neurosci. 2023 ;17 1276495

Regulation of microglial responses after pediatric traumatic brain injury: exploring the role of SHIP-1.

Erskine Chu, Richelle Mychasiuk, Tabitha R F Green, Akram Zamani, Larissa K Dill, Rishabh Sharma, April L Raftery, Evelyn Tsantikos, Margaret L Hibbs, Bridgette D Semple.

  Introduction: Severe traumatic brain injury (TBI) is the world's leading cause of permanent neurological disability in children. TBI-induced neurological deficits may be driven by neuroinflammation post-injury. Abnormal activity of SH2 domain-containing inositol 5' phosphatase-1 (SHIP-1) has been associated with dysregulated immunological responses, but the role of SHIP-1 in the brain remains unclear. The current study investigated the immunoregulatory role of SHIP-1 in a mouse model of moderate-severe pediatric TBI.Methods: SHIP-1+/- and SHIP-1-/- mice underwent experimental TBI or sham surgery at post-natal day 21. Brain gene expression was examined across a time course, and immunofluorescence staining was evaluated to determine cellular immune responses, alongside peripheral serum cytokine levels by immunoassays. Brain tissue volume loss was measured using volumetric analysis, and behavior changes both acutely and chronically post-injury.
Results: Acutely, inflammatory gene expression was elevated in the injured cortex alongside increased IBA-1 expression and altered microglial morphology; but to a similar extent in SHIP-1-/- mice and littermate SHIP-1+/- control mice. Similarly, the infiltration and activation of CD68-positive macrophages, and reactivity of GFAP-positive astrocytes, was increased after TBI but comparable between genotypes. TBI increased anxiety-like behavior acutely, whereas SHIP-1 deficiency alone reduced general locomotor activity. Chronically, at 12-weeks post-TBI, SHIP-1-/- mice exhibited reduced body weight and increased circulating cytokines. Pro-inflammatory gene expression in the injured hippocampus was also elevated in SHIP-1-/- mice; however, GFAP immunoreactivity at the injury site in TBI mice was lower. TBI induced a comparable loss of cortical and hippocampal tissue in both genotypes, while SHIP-1-/- mice showed reduced general activity and impaired working memory, independent of TBI.
Conclusion: Together, evidence does not support SHIP-1 as an essential regulator of brain microglial morphology, brain immune responses, or the extent of tissue damage after moderate-severe pediatric TBI in mice. However, our data suggest that reduced SHIP-1 activity induces a greater inflammatory response in the hippocampus chronically post-TBI, warranting further investigation.

Keywords:  PI3K; immune responses; immune signaling; inflammation; neurotrauma

DOI:  https://doi.org/10.3389/fnins.2023.1276495
medRxiv. 2023 Oct 19. pii: 2023.10.16.23297053. [Epub ahead of print]

Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2- 13 C]Pyruvate MR Spectroscopy.

Hsin-Yu Chen, Jeremy W Gordon, Nicholas Dwork, Brian T Chung, Andrew Riselli, Sanjay Sivalokanathan, Robert A Bok, James B Slater, Daniel B Vigneron, M Roselle Abraham, Peder E Z Larson.

Introduction: The normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2- 13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2- 13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility.Methods: Good Manufacturing Practice [2- 13 C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner.
Results: The study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2- 13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2- 13 C]lactate, TCA-associated metabolite [5- 13 C]glutamate, and [1- 13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation).
Conclusions: HP [2- 13 C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1- 13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

DOI: https://doi.org/10.1101/2023.10.16.23297053
Pediatr Radiol. 2023 Nov 01.

Semiquantitative analysis of cerebral [18F]FDG-PET uptake in pediatric patients.

Álvaro Cruz-Cortes, Arturo Avendaño-Estrada, Sarael Alcauter, Juan Carlos Núñez-Enríquez, Belen Rivera-Bravo, Miguel Ángel Olarte-Casas, Miguel Ángel Ávila-Rodríguez.

  BACKGROUND: Glycolytic metabolism in the brain of pediatric patients, imaged with [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET) is incompletely characterized.OBJECTIVE: The purpose of the current study was to characterize [18F]FDG-PET brain uptake in a large sample of pediatric patients with non-central nervous system diseases as an alternative to healthy subjects to evaluate changes at different pediatric ages.
MATERIALS AND METHODS: Seven hundred ninety-five [18F]FDG-PET examinations from children < 18 years of age without central nervous system diseases were included. Each brain image was spatially normalized, and the standardized uptake value (SUV) was obtained. The SUV and the SUV relative to different pseudo-references were explored as a function of age.
RESULTS: At all evaluated ages, the occipital lobe showed the highest [18F]FDG uptake (0.27 ± 0.04 SUV/year), while the parietal lobe and brainstem had the lowest uptake (0.17 ± 0.02 SUV/year, for both regions). An increase [18F]FDG uptake was found for all brain regions until 12 years old, while no significant uptake differences were found between ages 13 (SUV = 5.39) to 17 years old (SUV = 5.52) (P < 0.0001 for the whole brain). A sex dependence was found in the SUVmean for the whole brain during adolescence (SUV 5.04-5.25 for males, 5.68-5.74 for females, P = 0.0264). Asymmetries in [18F]FDG uptake were found in the temporal and central regions during infancy.
CONCLUSIONS: Brain glycolytic metabolism of [18F]FDG, measured through the SUVmean, increased with age until early adolescence (< 13 years old), showing differences across brain regions. Age, sex, and brain region influence [18F]FDG uptake, with significant hemispheric asymmetries for temporal and central regions.

Keywords:  Brain metabolism; Children brain; Development; Neuroimaging; SUV; [18F]FDG-PET

DOI:  https://doi.org/10.1007/s00247-023-05794-4
Expert Opin Drug Deliv. 2023 Nov 03.

Delivery of mitochondria-containing extracellular vesicles to the BBB for ischemic stroke therapy.

Kandarp M Dave, Donna B Stolz, Devika S Manickam.

  INTRODUCTION: Ischemic stroke-induced mitochondrial dysfunction in brain endothelial cells (BECs) leads to breakdown of the blood-brain barrier (BBB) causing long-term neurological dysfunction. Restoration of mitochondrial function in injured BECs is a promising therapeutic strategy to alleviate stroke-induced damage. Mounting evidence demonstrate that selected subsets of cell-derived extracellular vehicles (EVs), such as exosomes (EXOs) and microvesicles (MVs), contain functional mitochondrial components. Therefore, development of BEC-derived mitochondria-containing EVs for delivery to the BBB will (1) alleviate mitochondrial dysfunction and limit long-term neurological dysfunction in ischemic stroke and (2) provide an alternative therapeutic option for treating numerous other diseases associated with mitochondrial dysfunction.AREA COVERED: This review will discuss (1) how EV subsets package different types of mitochondrial components during their biogenesis, (2) mechanisms of EV internalization and functional mitochondrial responses in the recipient cells, and (3) EV biodistribution and pharmacokinetics - key factors involved in the development of mitochondria-containing EVs as a novel BBB-targeted stroke therapy.
EXPERT OPINION: Mitochondria-containing MVs have demonstrated therapeutic benefits in ischemic stroke and other pathologies associated with mitochondrial dysfunction. Delivery of MV mitochondria to the BBB is expected to protect the BBB integrity and neurovascular unit post-stroke. MV mitochondria quality control, characterization, mechanistic understanding of its effects in vivo, safety and efficacy in different preclinical models, large-scale production, and establishment of regulatory guidelines are foreseeable milestones to harness the clinical potential of MV mitochondria delivery.

Keywords:  BBB; Exosomes; Microvesicles; Mitochondria; extracellular vesicles; stroke

DOI:  https://doi.org/10.1080/17425247.2023.2279115
Brain Imaging Behav. 2023 Nov 02.

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

Hideaki Tani, Iska Moxon-Emre, Natalie J Forde, Nicholas H Neufeld, Kathleen S Bingham, Ellen M Whyte, Barnett S Meyers, George S Alexopoulos, Matthew J Hoptman, Anthony J Rothschild, Hiroyuki Uchida, Alastair J Flint, Benoit H Mulsant, Aristotle N Voineskos.

  BACKGROUND: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites.METHODS: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups.
RESULTS: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate.
CONCLUSIONS: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

Keywords:  Antipsychotics; Brain metabolites; Magnetic resonance spectroscopy; Placebo; Randomized controlled trial

DOI:  https://doi.org/10.1007/s11682-023-00807-0
Mol Psychiatry. 2023 Nov 01.

Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models.

Luana Naia, Makoto Shimozawa, Erika Bereczki, Xidan Li, Jianping Liu, Richeng Jiang, Romain Giraud, Nuno Santos Leal, Catarina Moreira Pinho, Erik Berger, Victoria Lim Falk, Giacomo Dentoni, Maria Ankarcrona, Per Nilsson.

Accumulation of amyloid β-peptide (Aβ) is a driver of Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation of downstream effects of Aβ accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in AppNL-F and AppNL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both AppNL-F and AppNL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca2+-overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aβ-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD.

DOI: https://doi.org/10.1038/s41380-023-02289-4
PLoS One. 2023 ;18(11): e0286660

Real-time resolution studies of the regulation of pyruvate-dependent lactate metabolism by hexokinases in single cells.

Scott John, Guillaume Calmettes, Shili Xu, Bernard Ribalet.

Lactate is a mitochondrial substrate for many tissues including neuron, muscle, skeletal and cardiac, as well as many cancer cells, however little is known about the processes that regulate its utilization in mitochondria. Based on the close association of Hexokinases (HK) with mitochondria, and the known cardio-protective role of HK in cardiac muscle, we have investigated the regulation of lactate and pyruvate metabolism by hexokinases (HKs), utilizing wild-type HEK293 cells and HEK293 cells in which the endogenous HKI and/or HKII have been knocked down to enable overexpression of wild type and mutant HKs. To assess the real-time changes in intracellular lactate levels the cells were transfected with a lactate specific FRET probe. In the HKI/HKII double knockdown cells, addition of extracellular pyruvate caused a large and sustained decrease in lactate. This decrease was rapidly reversed upon inhibition of the malate aspartate shuttle by aminooxyacetate, or inhibition of mitochondrial oxidative respiration by NaCN. These results suggest that in the absence of HKs, pyruvate-dependent activation of the TCA cycle together with the malate aspartate shuttle facilitates lactate transformation into pyruvate and its utilization by mitochondria. With replacement by overexpression of HKI or HKII the cellular response to pyruvate and NaCN was modified. With either hexokinase present, both the decrease in lactate due to the addition of pyruvate and the increase following addition of NaCN were either transient or suppressed altogether. Blockage of the pentose phosphate pathway with the inhibitor 6-aminonicotinamide (6-AN), abolished the effects of HK replacement. These results suggest that blocking of the malate aspartate shuttle by HK may involve activation of the pentose phosphate pathway and increased NADPH production.

DOI: https://doi.org/10.1371/journal.pone.0286660
Diabetes Metab J. 2023 Aug 23.

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition.

Ho Gyun Lee, Il Hyeon Jung, Byong Seo Park, Hye Rim Yang, Kwang Kon Kim, Thai Hien Tu, Jung-Yong Yeh, Sewon Lee, Sunggu Yang, Byung Ju Lee, Jae Geun Kim, Il Seong Nam-Goong.

  Background: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors.Methods: Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice.
Results: Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus.
Conclusion: This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment.

Keywords:  Appetite; Dapagliflozin; Energy metabolism; Hypothalamus; Obesity

DOI:  https://doi.org/10.4093/dmj.2022.0261
Front Cell Neurosci. 2023 ;17 1254303

The AMPK activator metformin improves recovery from demyelination by shifting oligodendrocyte bioenergetics and accelerating OPC differentiation.

Mohanlall Narine, Maryam A Azmi, Martin Umali, Ashley Volz, Holly Colognato.

  Multiple Sclerosis (MS) is a chronic disease characterized by immune-mediated destruction of myelinating oligodendroglia in the central nervous system. Loss of myelin leads to neurological dysfunction and, if myelin repair fails, neurodegeneration of the denuded axons. Virtually all treatments for MS act by suppressing immune function, but do not alter myelin repair outcomes or long-term disability. Excitingly, the diabetes drug metformin, a potent activator of the cellular "energy sensor" AMPK complex, has recently been reported to enhance recovery from demyelination. In aged mice, metformin can restore responsiveness of oligodendrocyte progenitor cells (OPCs) to pro-differentiation cues, enhancing their ability to differentiate and thus repair myelin. However, metformin's influence on young oligodendroglia remains poorly understood. Here we investigated metformin's effect on the temporal dynamics of differentiation and metabolism in young, healthy oligodendroglia and in oligodendroglia following myelin damage in young adult mice. Our findings reveal that metformin accelerates early stages of myelin repair following cuprizone-induced myelin damage. Metformin treatment of both isolated OPCs and oligodendrocytes altered cellular bioenergetics, but in distinct ways, suppressing oxidative phosphorylation and enhancing glycolysis in OPCs, but enhancing oxidative phosphorylation and glycolysis in both immature and mature oligodendrocytes. In addition, metformin accelerated the differentiation of OPCs to oligodendrocytes in an AMPK-dependent manner that was also dependent on metformin's ability to modulate cell metabolism. In summary, metformin dramatically alters metabolism and accelerates oligodendroglial differentiation both in health and following myelin damage. This finding broadens our knowledge of metformin's potential to promote myelin repair in MS and in other diseases with myelin loss or altered myelination dynamics.

Keywords:  cuprizone; metabolism; metformin; multiple sclerosis; myelin repair; oligodendrocyte

DOI:  https://doi.org/10.3389/fncel.2023.1254303
Zhonghua Er Ke Za Zhi. 2023 Nov 02. 61(11): 995-1000

[Mitochondrial pyruvate carrier deficiency: 3 cases report and literature review].

H F Jiang, F Fang, Z M Liu, C L Xu, P Q Zhao, X L Fu.

Objective: To analyze the clinical and genetic features of patients with mitochondrial pyruvate carrier deficiency (MPYCD). Methods: This was a case series research. The clinical data, genetic characteristics, and glutamine treatment efficacy of 3 patients diagnosed with MPYCD at the Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, Guizhou Provincial People's Hospital, from August 2019 to June 2023 were retrospectively collected. A literature search with "MPC1 gene" "MPC2 gene and" "mitochondrial pyruvate carrier deficiency" as keywords was conducted at the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI) and PubMed (up to June 2023). Clinical and genetic characteristics of patients with MPYCD were summarized. Results: Case 1 was a 3 years and 11 months old boy, while case 2 was a 4 years and 10 months old boy and case 3 was an 8 years and 9 months old girl. Case 2 and case 3 were siblings from one consanguineous family. All 3 patients presented with general developmental delay, growth failure and elevated serum lactate. Cranial magnetic resonance imaging (MRI) showed subtle bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus in case 1, but normal in case 2 and 3. Trio-WES revealed case 1 harboring compound heterozygous missense variants c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1 gene, while case 2 and 3 revealed a homozygous variant c.290G>A (p.Arg97Gln) in the same gene. All 3 cases were diagnosecl as MPYCD. Clinical symptoms including motor ability, cognition and activity endurance were improved in these 3 patients after taking glutamine for 2 years. A total of 5 articles published in English were reviewed, and no Chinese literature was found. Including these 3 cases, 15 cases were enrolled for analysis. Eleven patients carried MPC1 gene variants and 4 cases carried MPC2 gene variants. Except for 3 cases died during prenatal period, 9 of 12 enrolled born cases were onset before 6 months old. The most common clinical symptoms were mental and motor general developmental delay, microcephaly, growth failure and hypotonia. All patients had elevated blood lactate and pyruvate, but the ratio of lactate/pyruvate was normal. Seven patients performed cranial MRI, 3 exhibited non-specific changes, 2 showed bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus, and 3 were normal. A total of 5 MPC1 gene missense variants and 2 MPC2 gene variants were identified in 15 cases. Conclusions: Onset age of patients with MPYCD is usually within 6 months. The main clinical characteristics are developmental delay, microcephaly and growth failure, accompanied by increased serum lactate and pyruvate. Glutamine supplement could lead to clinical improvements.

DOI: https://doi.org/10.3760/cma.j.cn112140-20230803-00074
Ann Nucl Med. 2023 Nov 03.

[18F]-FDG uptake in brain slices prepared from an aged mouse model of Alzheimer's disease using a dynamic autoradiography technique.

Hiroko Maruyama, Misaki Gomi, Thet-Thet Lwin, Akio Yoneyama, Toru Sasaki.

  OBJECTIVE: 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography ([18F]-FDG-PET) is a imaging modality that has been used to measure of glucose metabolism in the brain in Alzheimer's disease (AD). Clinically, decreased glucose uptake has been reported in the brain of AD, although the precise underlying mechanisms have not yet been elucidated. To elucidate the mechanisms of decreased [18F]-FDG uptake in the AD by PET, [18F]-FDG uptake in the brain of aged model mouse of AD was investigated using a dynamic autoradiography technique "bioradiography". A X-ray phase-contrast imaging (X-PCI) and a histopathological evaluation were also investigated to elucidate the mechanisms underlying the relationships between decreased [18F]-FDG uptake and the pathological changes in the brain of AD mouse.METHODS: In this study, AD model mouse (5XFAD, APP+/PS1+) were used. [18F]-FDG-bioradiography was conducted in fresh slices of brain tissue under the condition of resting (slices immersed in 5 mM K+ solution) and metabolically active (in 50 mM K+ solution). Amyloid β42 (Aβ42) deposition in the brain of AD mouse was confirmed by X-PCI. In addition, the positive cells of phosphated tau protein (P-tau) and deposition of Aβ42 were also examined by immunohistochemical staining.
RESULTS: No significant differences were observed between the two groups in the resting condition. In the activate condition of the brain, [18F]-FDG uptake was significantly decreased in AD mice compared to WT mice. In X-PCI showed Aβ deposition in the AD mouse, but not in the WT. The AD mouse also showed increased P-tau, accumulation of Aβ42, increase in neuronal apoptosis, and decrease in the number of neurons than that of the WT mouse.
CONCLUSION: Neuronal damage, and induction of neuronal apoptosis, decreased [18F]-FDG uptake, increased Aβ accumulation and P-tau induced neurofibrillary degeneration are observed in AD mouse. In clinical diagnosis, reduction of [18F]-FDG uptake by PET is one of the means of diagnosing the onset of AD. Our results suggest that decreased uptake of [18F]-FDG in the brains of AD may be associated with neuronal dysfunction and cell death in the brain.

Keywords:  Alzheimer’s disease; Amyloid-β42; Bioradiography; Tau protein; X-ray phase-contrast imaging; [18F]-FDG-PET

DOI:  https://doi.org/10.1007/s12149-023-01879-0