bims-medebr 2022-05-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–05–22
thirty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Creatine supplementation reduces the cerebral oxidative and metabolic stress responses to acute in utero hypoxia in the late-gestation fetal sheep.
Emerging evidence for compromised axonal bioenergetics and axoglial metabolic coupling as drivers of neurodegeneration.
What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?
Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape.
Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule.
Cognitive disorder and dementia in type 2 diabetes mellitus.
Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain α-keto acids.
Glial-neuron crosstalk in health and disease: A focus on metabolism, obesity, and cognitive impairment.
Hippocampal Mitochondrial Abnormalities Induced the Dendritic Complexity Reduction and Cognitive Decline in a Rat Model of Spinal Cord Injury.
Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.
Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids.
Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia.
Females Exhibit Better Cerebral Pressure Autoregulation, Less Mitochondrial Dysfunction, and Reduced Excitotoxicity following Severe Traumatic Brain Injury.
Targeting Mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases.
Downregulation of mitochondrial pyruvate carrier 2 aggravates neuronal injury in the cortex following cerebral ischemia in rat.
Endosulfan causes oxidative stress in the liver and brain that involves inhibition of NADH dehydrogenase and altered antioxidant enzyme status in rat.
Gut-based manipulations spur hippocampal mitochondrial bioenergetics in a model of pediatric epilepsy.
The Role of Mitochondrial Dynamin in Stroke.
Biological aging processes underlying cognitive decline and neurodegenerative disease.
Effects of high-fat diet on nutrient metabolism and cognitive functions in young APPKINL-G-F/NL-G-F mice.
Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.
UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases.
Small-molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria-related diseases.
Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.
Neuron-astrocyte transmitophagy is altered in Alzheimer's disease.
Long Term Survivals in Aggressive Primary Brain Malignancies Treated With an Adjuvant Ketogenic Diet.
Oxidative stress-induced damage to the developing hippocampus is mediated by GSK3beta.
The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL-G-F Model of Alzheimer's Disease.
Age-Dependent Alterations of Cognition, Mitochondrial Function, and Beta-Amyloid Deposition in a Murine Model of Alzheimer's Disease-A Longitudinal Study.
Demonstration of Ameliorating Effect of Vardenafil Through Its Anti-Inflammatory and Neuroprotective Properties in Autism Spectrum Disorder Induced by Propionic Acid on Rat Model.
PC Splice-Site Variant c.1825+5G>A Caused Intron Retention in a Patient With Pyruvate Carboxylase Deficiency: A Case Report.
AGING-ASSOCIATED COGNITIVE DECLINE IS REVERSED BY D-SERINE SUPPLEMENTATION.
High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.
Glucose metabolism patterns: A potential index to characterize brain ageing and predict high conversion risk into cognitive impairment.
Altered Mitochondrial Protein Homeostasis and Proteinopathies.
Midlife omega-3 fatty acid intake predicts later life white matter microstructure in an age- and APOE-dependent manner.

J Physiol. 2022 May 19.

Creatine supplementation reduces the cerebral oxidative and metabolic stress responses to acute in utero hypoxia in the late-gestation fetal sheep.

Nhi Thao Tran, Greg M Kowalski, Anna M Muccini, Ilias Nitsos, Nadia Hale, Rod J Snow, David W Walker, Stacey J Ellery.

   KEY POINTS: Fetal hypoxia can cause persistent metabolic and oxidative stress responses that disturbs energy homeostasis in the brain. Creatine in its phosphorylated form is an endogenous phosphagen; therefore, supplementation is a proposed prophylactic treatment for fetal hypoxia. Fetal sheep instrumented with a cerebral microdialysis probe were continuously infused with or without creatine-monohydrate for 10 days before induction of 10 min umbilical cord occlusion (UCO; 131 days gestation). Cerebral interstitial fluid was collected up to 72 hours following UCO. Prior to UCO, fetal creatine supplementation reduced interstitial cerebral pyruvate and glycerol concentrations. Fetal creatine supplementation reduced cerebral hydroxyl radical efflux up to 24 hours post-UCO. Fetuses with higher arterial creatine concentrations before UCO and reduced levels of systemic hypoxaemia during UCO were associated with reduced cerebral interstitial pyruvate, lactate, and • OH following UCO. Creatine supplementation leads to some improvements in cerebral bioenergetics following in utero acute hypoxia.
ABSTRACT: Prophylactic creatine treatment may reduce hypoxic brain injury due to its ability to sustain intracellular ATP levels thereby reducing oxidative and metabolic stress responses during oxygen deprivation. Using microdialysis, we investigated the real-time in vivo effects of fetal creatine supplementation on cerebral metabolism following acute in utero hypoxia caused by umbilical cord occlusion (UCO). Fetal sheep (118 days gestation [dGA]) were implanted with an inflatable silastic cuff around the umbilical cord and a microdialysis probe inserted into the right cerebral hemisphere for interstitial fluid sampling. Creatine (6 mg.kg-1 .h-1 ) or saline was continuously infused intravenously from 122 dGA. At 131 dGA, a 10 min UCO was induced. Hourly microdialysis samples were obtained from -24 to 72 h post-UCO and analysed for percentage change of hydroxyl radicals (• OH) and interstitial metabolites (lactate, pyruvate, glutamate, glycerol, glycine). Histochemical markers of protein and lipid oxidation were assessed at post-mortem 72 h post-UCO. Prior to UCO, creatine treatment reduced pyruvate and glycerol concentrations in the microdialysate outflow. Creatine treatment reduced interstitial cerebral • OH outflow 0-24 h post-UCO. Fetuses with higher arterial creatine concentrations before UCO presented with reduced levels of hypoxaemia (pO2 and sO2 ) during UCO which were associated with reduced interstitial cerebral pyruvate, lactate and • OH accumulation. No effects of creatine treatment on immunohistochemical markers of oxidative stress were found. In conclusion, fetal creatine treatment decreased cerebral outflow of • OH and was associated with an improvement in cerebral bioenergetics following acute hypoxia. Abstract figure legend Prophylactic fetal creatine supplementation is a proposed treatment strategy for acute transient asphyxia such as umbilical cord occlusion (UCO). Fetal sheep with higher circulating arterial creatine (Cr) concentrations before UCO and reduced levels of systemic hypoxaemia during UCO were associated with reduced accumulation of cerebral interstitial pyruvate (Pyr), lactate (Lac), and reactive oxygen species (specifically • OH) following UCO as measured by microdialysis. There are three proposed mechanisms which include maintaining ATP turnover during hypoxia therefore reducing the need for aerobic metabolism as well as anaerobic processes, and active reactive oxygen species scavenging. This article is protected by copyright. All rights reserved.

Keywords:  cerebral metabolism; creatine; hypoxia-ischaemia; microdialysis; oxidative stress

DOI:  https://doi.org/10.1113/JP282840
Neurobiol Dis. 2022 May 12. pii: S0969-9961(22)00143-7. [Epub ahead of print] 105751

Emerging evidence for compromised axonal bioenergetics and axoglial metabolic coupling as drivers of neurodegeneration.

Bogdan Beirowski.

  Impaired bioenergetic capacity of the nervous system is thought to contribute to the pathogenesis of many neurodegenerative diseases (NDD). Since neuronal synapses are believed to be the major energy consumers in the nervous system, synaptic derangements resulting from energy deficits have been suggested to play a central role for the development of many of these disorders. However, long axons constitute the largest compartment of the neuronal network, require large amounts of energy, are metabolically and structurally highly vulnerable, and undergo early injurious stresses in many NDD. These stresses likely impose additional energy demands for continuous adaptations and repair processes, and may eventually overwhelm axonal maintenance mechanisms. Indeed, pathological axon degeneration (pAxD) is now recognized as an etiological focus in a wide array of NDD associated with bioenergetic abnormalities. In this paper I first discuss the recognition that a simple experimental model for pAxD is regulated by an auto-destruction program that exhausts distressed axons energetically. Provision of the energy substrate pyruvate robustly counteracts this axonal breakdown. Importantly, energy decline in axons is not only a consequence but also an initiator of this program. This opens the intriguing possibility that axon dysfunction and pAxD can be suppressed by preemptively energizing distressed axons. Second, I focus on the emerging concept that axons communicate energetically with their flanking glia. This axoglial metabolic coupling can help offset the axonal energy decline that activates the pAxD program but also jeopardize axon integrity as a result of perturbed glial metabolism. Third, I present compelling evidence that abnormal axonal energetics and compromised axoglial metabolic coupling accompany the activation of the pAxD auto-destruction pathway in models of glaucoma, a widespread neurodegenerative condition with pathogenic overlap to other common NDD. In conclusion, I propose a novel conceptual framework suggesting that therapeutic interventions focused on bioenergetics support of the nervous system should also address axons and their metabolic interactions with glia.

Keywords:  Axonal degeneration; Bioenergetics; Metabolism; Oligodendrocyte; Schwann cell

DOI:  https://doi.org/10.1016/j.nbd.2022.105751
Neurology. 2022 May 17. 98(20): 836-840

What Is the Role of Mitochondrial Dysfunction in Programmed Axon Death?

Eduardo Benarroch.

DOI: https://doi.org/10.1212/WNL.0000000000200691
Front Cell Neurosci. 2022 ;16 892968

Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape.

Mohanlall Narine, Holly Colognato.

  Once believed to be part of the nervenkitt or "nerve glue" network in the central nervous system (CNS), oligodendroglial cells now have established roles in key neurological functions such as myelination, neuroprotection, and motor learning. More recently, oligodendroglia has become the subject of intense investigations aimed at understanding the contributions of its energetics to CNS physiology and pathology. In this review, we discuss the current understanding of oligodendroglial metabolism in regulating key stages of oligodendroglial development and health, its role in providing energy to neighboring cells such as neurons, as well as how alterations in oligodendroglial bioenergetics contribute to disease states. Importantly, we highlight how certain inputs can regulate oligodendroglial metabolism, including extrinsic and intrinsic mediators of cellular signaling, pharmacological compounds, and even dietary interventions. Lastly, we discuss emerging studies aimed at discovering the therapeutic potential of targeting components within oligodendroglial bioenergetic pathways.

Keywords:  glycolysis; lactate; metabolism; myelin; oligodendrocyte; oligodendrocyte progenitor cell (OPC); remyelination

DOI:  https://doi.org/10.3389/fncel.2022.892968
Front Nutr. 2022 ;9 800901

Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule.

Ming Cai, Hongbiao Wang, Haihan Song, Ruoyu Yang, Liyan Wang, Xiangli Xue, Wanju Sun, Jingyun Hu.

  Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.

Keywords:  brain diseases; brain function; energy substrates; lactate; signal molecule

DOI:  https://doi.org/10.3389/fnut.2022.800901
World J Diabetes. 2022 Apr 15. 13(4): 319-337

Cognitive disorder and dementia in type 2 diabetes mellitus.

Genaro G Ortiz, Miguel Huerta, Héctor A González-Usigli, Erandis D Torres-Sánchez, Daniela Lc Delgado-Lara, Fermín P Pacheco-Moisés, Mario A Mireles-Ramírez, Blanca Mg Torres-Mendoza, Roxana I Moreno-Cih, Irma E Velázquez-Brizuela.

  Insulin, a key pleiotropic hormone, regulates metabolism through several signaling pathways in target tissues including skeletal muscle, liver, and brain. In the brain, insulin modulates learning and memory, and impaired insulin signaling is associated with metabolic dysregulation and neurodegenerative diseases. At the receptor level, in aging and Alzheimer's disease (AD) models, the amount of insulin receptors and their functions are decreased. Clinical and animal model studies suggest that memory improvements are due to changes in insulin levels. Furthermore, diabetes mellitus (DM) and insulin resistance are associated with age-related cognitive decline, increased levels of β-amyloid peptide, phosphorylation of tau protein; oxidative stress, pro-inflammatory cytokine production, and dyslipidemia. Recent evidence shows that deleting brain insulin receptors leads to mild obesity and insulin resistance without influencing brain size and apoptosis development. Conversely, deleting insulin-like growth factor 1 receptor (IGF-1R) affects brain size and development, and contributes to behavior changes. Insulin is synthesized locally in the brain and is released from the neurons. Here, we reviewed proposed pathophysiological hypotheses to explain increased risk of dementia in the presence of DM. Regardless of the exact sequence of events leading to neurodegeneration, there is strong evidence that mitochondrial dysfunction plays a key role in AD and DM. A triple transgenic mouse model of AD showed mitochondrial dysfunction, oxidative stress, and loss of synaptic integrity. These alterations are comparable to those induced in wild-type mice treated with sucrose, which is consistent with the proposal that mitochondrial alterations are associated with DM and contribute to AD development. Alterations in insulin/IGF-1 signaling in DM could lead to mitochondrial dysfunction and low antioxidant capacity of the cell. Thus, insulin/IGF-1 signaling is important for increased neural processing and systemic metabolism, and could be a specific target for therapeutic strategies to decrease alterations associated with age-related cognitive decline.

Keywords:  Alzheimer´s disease; Cognitive decline; Diabetes mellitus; Insulin; Vascular dementia

DOI:  https://doi.org/10.4239/wjd.v13.i4.319
Neurochem Int. 2022 May 13. pii: S0197-0186(22)00085-7. [Epub ahead of print]157 105360

Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain α-keto acids.

Alexandre Umpierrez Amaral, Moacir Wajner.

  Maple syrup urine disease (MSUD) is an autosomal recessive neurometabolic disorder caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, which catalyzes the oxidative decarboxylation of the branched-chain α-keto acids (BCKA). The metabolic blockage results in tissue accumulation and high urinary excretion of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as alloisoleucine, and their respective BCKA α-ketoisocaproic (α-KIC), α-ketoisovaleric and α-keto-β-methylvaleric acids. Affected patients usually manifest acute episodes of encephalopathy associated with seizures, coma and life-threatening cerebral edema in the first weeks of life, which is followed by progressive neurological deterioration with motor delay, ataxia, intellectual disability and psychiatric symptoms. The pathophysiology of the brain damage in MSUD has been mainly focused on brain amino acid imbalance leading to deficient cerebral protein and neurotransmitter synthesis. However, the acute episodes of severe neurological symptoms accompanied by large increases of BCKA/BCAA levels suggest neurotoxic actions of these compounds. In this particular, mounting evidence from humans and animal models support an important role of particularly leucine and α-KIC on the pathogenesis of the brain injury in MSUD. In this review we will present the current knowledge of the major mechanisms presumably involved in MSUD neuropathology and highlight the neurotoxic properties of the BCAA and BCKA, disturbing brain bioenergetics and redox homeostasis, besides inducing neuroinflammation. We suggest that these pathomechanisms may contribute to the neurological sequelae of MSUD patients and hopefully allow the design of novel therapeutic strategies, including antioxidant and bioenergetics stimulating drugs targeting the mitochondria.

Keywords:  Bioenergetics; Branched-chain amino acids; Branched-chain α-keto acids; Maple syrup urine disease; Neuroinflammation; Redox homeostasis

DOI:  https://doi.org/10.1016/j.neuint.2022.105360
Neurobiol Dis. 2022 May 15. pii: S0969-9961(22)00158-9. [Epub ahead of print] 105766

Glial-neuron crosstalk in health and disease: A focus on metabolism, obesity, and cognitive impairment.

Rosemary E Henn, Mohamed H Noureldein, Sarah E Elzinga, Bhumsoo Kim, Masha G Savelieff, Eva L Feldman.

  Dementia is a complex set of disorders affecting normal cognitive function. Recently, several clinical studies have shown that diabetes, obesity, and components of the metabolic syndrome (MetS) are associated with cognitive impairment, including dementias such as Alzheimer's disease. Maintaining normal cognitive function is an intricate process involving coordination of neuron function with multiple brain glia. Well-orchestrated bioenergetics is a central requirement of neurons, which need large amounts of energy but lack significant energy storage capacity. Thus, one of the most important glial functions is to provide metabolic support and ensure an adequate energy supply for neurons. Obesity and metabolic disease dysregulate glial function, leading to a failure to respond to neuron energy demands, which results in neuronal damage. In this review, we outline evidence for links between diabetes, obesity, and MetS components to cognitive impairment. Next, we focus on the metabolic crosstalk between the three major glial cell types, oligodendrocytes, astrocytes, and microglia, with neurons under physiological conditions. Finally, we outline how diabetes, obesity, and MetS components can disrupt glial function, and how this disruption might impair glia-neuron metabolic crosstalk and ultimately promote cognitive impairment.

Keywords:  Astrocyte; Axon; Cognitive impairment; Dementia; Diabetes; Metabolic syndrome; Metabolism; Microglia; Neuron; Obesity; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.nbd.2022.105766
Oxid Med Cell Longev. 2022 ;2022 9253916

Hippocampal Mitochondrial Abnormalities Induced the Dendritic Complexity Reduction and Cognitive Decline in a Rat Model of Spinal Cord Injury.

Xvlei Hu, Liang Wu, Yujun Wen, Juan Liu, Hailiang Li, Yifan Zhang, Zhihua Wang, Jiangwei Ding, Zhong Zeng, Hechun Xia.

Spinal cord injury (SCI) is a progressive neurodegenerative disease in addition to a traumatic event. Cognitive dysfunction following SCI has been widely reported in patients and animal models. However, the neuroanatomical changes affecting cognitive function after SCI, as well as the mechanisms behind these changes, have so far remained elusive. Herein, we found that SCI accelerates oxidative stress damage of hippocampal neuronal mitochondria. Then, for the first time, we presented a three-dimensional morphological atlas of rat hippocampal neurons generated using a fluorescence Micro-Optical Sectioning Tomography system, a method that accurately identifies the spatial localization of neurons and trace neurites. We showed that the number of dendritic branches and dendritic length was decreased in late stage of SCI. Western blot and transmission electron microscopy analyses also showed a decrease in synaptic communication. In addition, a battery of behavioral tests in these animals revealed hippocampal based cognitive dysfunction, which could be attributed to changes in the dendritic complexity of hippocampal neurons. Taken together, these results suggested that mitochondrial abnormalities in hippocampal neurons induced the dendritic complexity reduction and cognitive decline following SCI. Our study highlights the neuroanatomical basis and importance of mitochondria in brain degeneration following SCI, which might contribute to propose new therapeutic strategies.

DOI: https://doi.org/10.1155/2022/9253916
Appl Biochem Biotechnol. 2022 May 19.

Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.

Twinkle Dhillon, Amit Kumar, Vijay Kumar.

  Monocrotophos (MCP) is systemic organophosphate insecticide used against crop pests. It is reported to cause mammalian toxicity through both acute and chronic exposure. In the present study, we have shown the protective role of N-acetylcysteine (NAC) against MCP-induced oxidative stress in frontal cortex, corpus striatum and hippocampus brain regions of rats. Male Albino Wistar rats were divided into control, NAC-treated, MCP and NAC + MCP-treated groups. An oral dose of MCP (0.9 mg/kg b.wt) and NAC (200 mg/kg b.wt) was administered for 28 days. Results showed an increase in lipid peroxidation (LPO) and protein oxidation followed by decreased antioxidant enzymes after 28 days of MCP exposure. Histopathological analysis showed that monocrotophos exposure caused neurodegenerative changes as evident by neurons with dystrophic changes in the form of shrunken hyperchromatic nuclei in all the regions of the rat brain. N-acetylcysteine supplementation to MCP-treated rats showed a reduction in oxidative stress and ameliorated cellular alterations in all of the three regions. The results of the study indicate that N-acetylcysteine offers neuroprotection by improving antioxidant response and decreasing oxidative stress in different regions of the rat brain.

Keywords:  Antioxidants; Brain regions; Monocrotophos; N-acetylcysteine; Oxidative stress

DOI:  https://doi.org/10.1007/s12010-022-03967-9
Front Mol Neurosci. 2022 ;15 840265

Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids.

Alejandra I Romero-Morales, Vivian Gama.

  Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.

Keywords:  brain organoids; glycolysis; mitochondria; neural precursor cells; neural rosettes; oxidative phosphorylation; stem cells

DOI:  https://doi.org/10.3389/fnmol.2022.840265
Neurochem Res. 2022 May 21.

Therapeutic implications of glucose transporters (GLUT) in cerebral ischemia.

Veerta Sharma, Thakur Gurjeet Singh, Ashi Mannan.

  Cerebral ischemia is a leading cause of death in the globe, with a large societal cost. Deprivation of blood flow, together with consequent glucose and oxygen shortage, activates a variety of pathways that result in permanent brain damage. As a result, ischemia raises energy demand, which is linked to significant alterations in brain energy metabolism. Even at the low glucose levels reported in plasma during ischemia, glucose transport activity may adjust to assure the supply of glucose to maintain normal cellular function. Glucose transporters in the brain are divided into two groups: sodium-independent glucose transporters (GLUTs) and sodium-dependent glucose cotransporters (SGLTs).This review assess the GLUT structure, expression, regulation, pathobiology of GLUT in cerebral ischemia and regulators of GLUT and it also provides the synopsis of the literature exploring the relationship between GLUT and the various downstream signalling pathways for e.g., AMP-activated protein kinase (AMPK), CREB (cAMP response element-binding protein), Hypoxia-inducible factor 1 (HIF)-1, Phosphatidylinositol 3-kinase (PI3-K), Mitogen-activated protein kinase (MAPK) and adenylate-uridylate-rich elements (AREs). Therefore, the aim of the present review was to elaborate the therapeutic implications of GLUT in the cerebral ischemia.

Keywords:  Cerebral ischemia; GLUT-1 deficiency syndrome; Glucose transporters; Hypoxia-inducible factor 1; Neurodegeneration

DOI:  https://doi.org/10.1007/s11064-022-03620-1
J Neurotrauma. 2022 May 19.

Females Exhibit Better Cerebral Pressure Autoregulation, Less Mitochondrial Dysfunction, and Reduced Excitotoxicity following Severe Traumatic Brain Injury.

Teodor Mikael Svedung Wettervik, Anders Hånell, Timothy Howells, Per Enblad, Anders Lewén.

  The aim of the study was to investigate sex-related differences in intracranial pressure (ICP) dynamics, cerebral pressure autoregulation (PRx55-15), cerebral energy metabolism, and clinical outcome after severe traumatic brain injury (TBI). One-hundred sixty-nine adult TBI patients, treated at the neurointensive care (NIC) unit, at Uppsala University Hospital, 2008-2020, with ICP and cerebral microdialysis (MD) monitoring, were included. Of the 169 TBI patients, 131 (78%) were male and 38 (22%) female. Male patients were more often injured by motor vehicle accidents and less often by bicycle accidents (p < 0.05). There were otherwise no difference in age, neurological status at admission, and types of intracranial hemorrhages between the sexes. The percent of monitoring time with ICP above 20 mmHg and CPP below 60 mmHg were similar for both sexes. Males exhibited more disturbed cerebral pressure autoregulation (PRx55-15 (mean ± SD); 0.28 ± 0.18 vs. 0.17 ± 0.23, p < 0.05) day 1, worse cerebral energy metabolism (MD-lactate-/pyruvate-ratio (median (IQR)); 25 (19-31) vs. 20 (17-25), p < 0.01) and mitochondrial dysfunction (higher burden of MD-LPR > 25 and MD-pyruvate > 120 µM (median (IQR)); 13 (0-58) % vs. 3 (0-17) %, p < 0.05) day 2 to 5, increased excitotoxicity (MD-glutamate median (IQR); 9 (4-32) µM vs. 5 (3-10) µM, p < 0.05) day 2 to 5, and higher biomarker levels of cellular injury (MD-glycerol median (IQR); 103 (66-193) µM vs. 68 (49-106) µM, p < 0.01) most pronounced day 6 to 10. There was no difference in mortality or the degree of favorable outcome between the sexes. Altogether, females exhibited more favorable cerebral physiology post-TBI, particularly better mitochondrial function and reduced excitotoxicity, but this did not translate into better clinical outcome compared to males. Future studies needs to further explore potential sex differences in secondary injury mechanisms in TBI.

Keywords:  CBF autoregulation; HEAD TRAUMA; HUMAN STUDIES; MICRODIALYSIS; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2022.0097
Biomed J. 2022 May 11. pii: S2319-4170(22)00074-9. [Epub ahead of print]

Targeting Mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases.

Gurjit Kaur Bhatti, Anshika Gupta, Paras Pahwa, Naina Khullar, Satwinder Singh, Umashanker Navik, Shashank Kumar, Sarabjit Singh Mastana, Arubala P Reddy, P Hemachandra Reddy, Jasvinder Singh Bhatti.

  Mitochondria are the organelles that generate energy for the cells and act as biosynthetic and bioenergetic factories, vital for normal cell functioning and human health. Mitochondrial bioenergetics is considered an important measure to assess the pathogenesis of various diseases. Dysfunctional mitochondria affect or cause several conditions involving the most energy-intensive organs, including the brain, muscles, heart, and liver. This dysfunction may be attributed to an alteration in mitochondrial enzymes, increased oxidative stress, impairment of electron transport chain and oxidative phosphorylation, or mutations in mitochondrial DNA that leads to the pathophysiology of various pathological conditions, including neurological and metabolic disorders. The drugs or compounds targeting mitochondria are considered more effective and safer for treating these diseases. In this review, we make an effort to concise the available literature on mitochondrial bioenergetics in various conditions and the therapeutic potential of various drugs/compounds targeting mitochondrial bioenergetics in metabolic and neurodegenerative diseases.

Keywords:  Antioxidants; Bioenergetics; Electron transport chain; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/j.bj.2022.05.002
Brain Res Bull. 2022 May 14. pii: S0361-9230(22)00122-8. [Epub ahead of print]

Downregulation of mitochondrial pyruvate carrier 2 aggravates neuronal injury in the cortex following cerebral ischemia in rat.

Yue Wang, Yue Liu, Yuan Yuan, Ying Zhang, Yanlin Luo, Song Han, Yi Yan, Zhaohui Wang, Xiao Liu, Li Zhao.

  Cerebral ischemia is one of the most common disabling and lethal diseases worldwide, but its underlying mechanisms remain unclear. Mitochondrial pyruvate carrier 2 (MPC2), a subunit of MPC complex, plays pivotal roles in coordinating glycolytic and mitochondrial activities. In the present study, the expression of MPC2 was significantly reduced in the ischemic cerebral cortex of rats at 24h after bilateral internal carotid artery occlusion (BICAO), and in the cortical neurons after 1h oxygen-glucose deprivation (OGD)/24h reoxygenation treatment. After MPC2 gene knockdown, the number and expression of neurons were remarkably decreased in the ischemic cerebral cortex of BICAO rats and OGD-treated neurons. UK5099 significantly reduced the number, expression and viability of OGD-treated neurons, and resulted in a significant decrease in length of neurite. Using RNA-sequencing (RNA-seq) technique, we further identified MPC2-related differential genes in the ischemic cerebral cortex of BICAO rats. In conclusion, our results suggested that the decrease in MPC2 expression aggravated ischemic injury, and MPC2-related genes might be a novel therapeutic target for cerebral ischemia.

Keywords:  Bilateral internal carotid artery occlusion (BICAO); Mitochondrial pyruvate carrier 2 (MPC2); Neuron; RNA-sequencing (RNA-seq) technique

DOI:  https://doi.org/10.1016/j.brainresbull.2022.05.007
Ecotoxicol Environ Saf. 2022 May 11. pii: S0147-6513(22)00433-X. [Epub ahead of print]239 113593

Endosulfan causes oxidative stress in the liver and brain that involves inhibition of NADH dehydrogenase and altered antioxidant enzyme status in rat.

Megha Murali, T Shivanandappa.

  Endosulfan, a neurotoxic, highly persistent organochlorine insecticide, is known for its acute and chronic toxicity. We have shown that a single sublethal dose of endosulfan caused high induction of oxidative stress in the liver and brain by altering the antioxidant status, as shown by reduction in the antioxidant enzymes SOD, GPx, GST, GR along with increased ROS and lipid peroxidation. The cerebral region in the brain showed a higher level of oxidative stress than the cerebellum, revealing differential sensitivity of the brain regions to endosulfan. Depletion of natural antioxidants causes the imbalance of redox status in cells, and the role of mitochondrial distress causally related to the cellular oxidative stress in vivo is not well understood. We have shown that reduction in the mitochondrial NADH dehydrogenase activity in the brain is associated with the induction of ROS in endosulfan-treated rats. Although oxidative stress is induced in both the liver and brain, the oxidative damage to the brain has implications for the toxic outcome in view of the brain's lower antioxidant defenses and high oxygen consumption.

Keywords:  Antioxidant enzymes; Endosulfan; Glutathione; Lipid peroxidation; Mitochondrial NADH dehydrogenase; Oxidative stress

DOI:  https://doi.org/10.1016/j.ecoenv.2022.113593
Biochim Biophys Acta Mol Basis Dis. 2022 May 16. pii: S0925-4439(22)00116-8. [Epub ahead of print] 166446

Gut-based manipulations spur hippocampal mitochondrial bioenergetics in a model of pediatric epilepsy.

Chunlong Mu, Thomas A Tompkins, Jong M Rho, Morris H Scantlebury, Jane Shearer.

  A growing body of evidence supports a role of the gut microbiota in regulating diverse physiological processes, including neural function and metabolism via the gut-brain axis. Infantile spasms syndrome is an early-onset epileptic encephalopathy associated with perturbed brain mitochondrial bioenergetics. Employing a neonatal rat model of infantile spasms, mitochondria respirometry and biochemical analyses, the present study reveals that gut microbiota manipulation by diet, antibiotics and probiotics have the potential to enhance hippocampal mitochondrial bioenergetics. Although preliminary in nature, our data reveal that microbial manipulation that regulates brain mitochondrial function may be a novel strategy for the treatment of epileptic disorders.

Keywords:  Epilepsy; Ketogenic diet; Microbiota manipulation; Mitochondria bioenergetics; Probiotics

DOI:  https://doi.org/10.1016/j.bbadis.2022.166446
Oxid Med Cell Longev. 2022 ;2022 2504798

The Role of Mitochondrial Dynamin in Stroke.

Chenchen Li, Chunli Chen, Haiyun Qin, Chuncao Ao, Jinlun Chen, Jieqiong Tan, Liuwang Zeng.

Stroke is one of the leading causes of death and disability in the world. However, the pathophysiological process of stroke is still not fully clarified. Mitochondria play an important role in promoting nerve survival and are an important drug target for the treatment of stroke. Mitochondrial dysfunction is one of the hallmarks of stroke. Mitochondria are in a state of continuous fission and fusion, which are termed as mitochondrial dynamics. Mitochondrial dynamics are very important for maintaining various functions of mitochondria. In this review, we will introduce the structure and functions of mitochondrial fission and fusion related proteins and discuss their role in the pathophysiologic process of stroke. A better understanding of mitochondrial dynamin in stroke will pave way for the development of new therapeutic options.

DOI: https://doi.org/10.1155/2022/2504798
J Clin Invest. 2022 05 16. pii: e158453. [Epub ahead of print]132(10):

Biological aging processes underlying cognitive decline and neurodegenerative disease.

Mitzi M Gonzales, Valentina R Garbarino, Erin Pollet, Juan P Palavicini, Dean L Kellogg, Ellen Kraig, Miranda E Orr.

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

DOI: https://doi.org/10.1172/JCI158453
Neuropsychopharmacol Rep. 2022 May 18.

Effects of high-fat diet on nutrient metabolism and cognitive functions in young APPKINL-G-F/NL-G-F mice.

Wei Wang, Daisuke Tanokashira, Yudai Shibayama, Ryuhei Tsuji, Megumi Maruyama, Chiemi Kuroiwa, Takashi Saito, Takaomi C Saido, Akiko Taguchi.

   AIM: Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer's disease (AD); however, the relationship between the 2 conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aβ accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life has an impact on nutrient metabolism and neurological phenotypes in young AD mouse models is not known. In the present study, we examined the effects of HFD on young APPKINL-G-F/NL-G-F mice, one of the novel KI-AD mouse models.
METHODS: The mice were categorized by diet into 2 experimental groups, normal diet (ND) and HFD. Four-week-old wild-type (WT) and APPKINL-G-F/NL-G-F mice were fed ND or HFD for 9 weeks. Both types of mice on ND and HFD were examined during young adulthood.
RESULTS: HFD caused T2DM-related metabolic disturbances in both young WT and APPKINL-G-F/NL-G-F mice, whereas impaired thermoregulation and shortage of alternative energy sources specifically occurred in young APPKINL-G-F/NL-G-F mice. However, HFD had no impact on the cognitive function, Aβ levels, and phosphorylation of hippocampal insulin receptor substrate 1 (IRS1) at all the 3 Ser sites in both types of mice.
CONCLUSION: HFD is effective in causing metabolic disturbances in young WT and APPKINL-G-F/NL-G-F mice but is ineffective in inducing neurological disorders in both types of mice, suggesting that the aging effects, along with long-term HFD, facilitate neurological alterations.

Keywords:  Alzheimer’s disease; cognitive function; high-fat diet; hippocampus; insulin receptor substrate 1; knock-in mouse model; nutrient metabolism; type 2 diabetes mellitus

DOI:  https://doi.org/10.1002/npr2.12257
PLoS Biol. 2022 May 20. 20(5): e3001655

Diet-responsive transcriptional regulation of insulin in a single neuron controls systemic metabolism.

Ava Handley, Qiuli Wu, Tessa Sherry, Rebecca Cornell, Roger Pocock.

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.

DOI: https://doi.org/10.1371/journal.pbio.3001655
Orphanet J Rare Dis. 2022 May 17. 17(1): 204

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases.

Juan M Suárez-Rivero, Carmen J Pastor-Maldonado, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Perez, José A Sánchez-Alcázar.

   BACKGROUND: Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed.
RESULTS: In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression.
CONCLUSIONS: Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.

Keywords:  GFM1; Mitochondria; Tetracycline; UPRmt

DOI:  https://doi.org/10.1186/s13023-022-02331-8
Med Res Rev. 2022 May 16.

Small-molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria-related diseases.

Annamaria Haleckova, Ondrej Benek, Lucie Zemanová, Rafael Dolezal, Kamil Musilek.

  Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia-reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small-molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.

Keywords:  cyclophilin D; drug discovery; enzyme inhibition; mitochondria; mitochondrial permeability transition pore

DOI:  https://doi.org/10.1002/med.21892
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac045

Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.

Shaobo Li, Xiaowu Gai, Swe Swe Myint, Katti Arroyo, Libby Morimoto, Catherine Metayer, Adam J de Smith, Kyle M Walsh, Joseph L Wiemels.

   Background: Childhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.
Methods: We conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2789 controls to identify enrichment of mitochondrial variant associated with GBM risk. We also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed.
Results: We identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25-163.4, P-value 9.5 X 10-4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88-4.75, P-value = 3.42 X 10-6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99-6.40, P-value = 1.41 X 10-6) populations in ethnicity-stratified analyses.
Conclusion: We report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.

Keywords:  mitochondrial genome; pediatric glioblastoma; risk factor; variant

DOI:  https://doi.org/10.1093/noajnl/vdac045
Neurobiol Dis. 2022 May 13. pii: S0969-9961(22)00145-0. [Epub ahead of print]170 105753

Neuron-astrocyte transmitophagy is altered in Alzheimer's disease.

Riikka Lampinen, Irina Belaya, Liudmila Saveleva, Jeffrey R Liddell, Dzhessi Rait, Mikko T Huuskonen, Raisa Giniatullina, Annika Sorvari, Liisi Soppela, Nikita Mikhailov, Isabella Boccuni, Rashid Giniatullin, Marcela Cruz-Haces, Julia Konovalova, Marja Koskuvi, Andrii Domanskyi, Riikka H Hämäläinen, Gundars Goldsteins, Jari Koistinaho, Tarja Malm, Sweelin Chew, Kirsi Rilla, Anthony R White, Nicholas Marsh-Armstrong, Katja M Kanninen.

  Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization of neuronal mitochondria is significantly increased in astrocytes isolated from AD mouse brains. We also demonstrate that the degradation of neuronal mitochondria by astrocytes is increased in AD mice at the age of 6 months onwards. Furthermore, we demonstrate for the first time a similar phenomenon between human neurons and AD astrocytes, and in murine hippocampi in vivo. The results suggest the involvement of S100a4 in impaired mitochondrial transfer between neurons and AD astrocytes together with significant increases in the mitophagy regulator and reactive oxygen species in aged AD astrocytes. These findings demonstrate altered neuron-supporting functions of AD astrocytes and provide a starting point for studying the molecular mechanisms of transmitophagy in AD.

Keywords:  Alzheimer's disease; Astrocytes; Mitochondria; Mitophagy; Transmitophagy

DOI:  https://doi.org/10.1016/j.nbd.2022.105753
Front Nutr. 2022 ;9 770796

Long Term Survivals in Aggressive Primary Brain Malignancies Treated With an Adjuvant Ketogenic Diet.

Kenneth A Schwartz, Mary Noel, Michele Nikolai, Lawrence K Olson, Norman G Hord, Micheal Zakem, Justin Clark, Mohamed Elnabtity, Bryan Figueroa, Howard T Chang.

  Aggressive primary brain tumors (APBT) glioblastoma multiforme and grade IV astrocytoma are treated with multimodality treatments that include surgery to remove as much tumor as possible without sacrificing neurological function followed by radiation therapy and chemotherapy usually temozolomide. Survivals in adults are in the range of 8-16 months. The addition of a ketogenic diet (KD) to rodents with transplanted brain tumors increased survival in nine of 11 animals to over 299 days compared to survival in untreated controls of 33 days and radiation only controls of 38 days. We treated humans with APBT with standard of care neurosurgery immediately followed by 6 weeks of an adjuvant ketogenic diet concurrent with radiation therapy and temozolomide. Twice daily measurements of blood ketones and glucose were recorded and the patients' diet was modified toward the goal of maintaining blood ketone levels approaching 3 mM. Of the nine patients who completed the protocol three younger patients age 32, 28, and 22 at enrollment are alive and employed with clinically stable disease and brain images 74, 58, and 52 months since diagnosis. All the six older patients mean age 55 have died with disease progression detected on average 8 months after Dx. In conclusion: 1. It is possible to implement and maintain dietary induced ketosis in patients with APBT; 2. The longer survivals observed in younger patients treated with KD need to be confirmed in larger studies that should be focused on younger patients possibly under age 40.

Keywords:  diet therapy; glioblastoma multiforme; ketogenic diet; long term survival; verified ketosis

DOI:  https://doi.org/10.3389/fnut.2022.770796
J Neurosci. 2022 May 18. pii: JN-RM-2389-21. [Epub ahead of print]

Oxidative stress-induced damage to the developing hippocampus is mediated by GSK3beta.

Joseph Abbah, Claire-Marie Vacher, Evan Z Goldstein, Zhen Li, Srikanya Kundu, Brooke Talbot, Surajit Bhattacharya, Kazue Hashimoto-Torii, Li Wang, Payal Banerjee, Joseph Scafidi, Nathan A Smith, Li-Jin Chew, Vittorio Gallo.

Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents and dentate progenitor proliferation. Post-injury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and Somatostatin, HO aberrantly activated Glycogen synthase kinase 3 beta activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 beta during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.Significance StatementPremature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurological outcomes. Due to its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study utilizes perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.

DOI: https://doi.org/10.1523/JNEUROSCI.2389-21.2022
Front Aging Neurosci. 2022 ;14 876826

The Roles of Long-Term Hyperhomocysteinemia and Micronutrient Supplementation in the AppNL-G-F Model of Alzheimer's Disease.

Hendrik Nieraad, Natasja de Bruin, Olga Arne, Martine C J Hofmann, Nina Pannwitz, Eduard Resch, Sonja Luckhardt, Ann-Kathrin Schneider, Sandra Trautmann, Yannick Schreiber, Robert Gurke, Michael J Parnham, Uwe Till, Gerd Geisslinger.

  A causal contribution of hyperhomocysteinemia to cognitive decline and Alzheimer's disease (AD), as well as potential prevention or mitigation of the pathology by dietary intervention, have frequently been subjects of controversy. In the present in vivo study, we attempted to further elucidate the impact of elevated homocysteine (HCys) and homocysteic acid (HCA) levels, induced by dietary B-vitamin deficiency, and micronutrient supplementation on AD-like pathology, which was simulated using the amyloid-based AppNL-G-F knock-in mouse model. For this purpose, cognitive assessment was complemented by analyses of ex vivo parameters in whole blood, serum, CSF, and brain tissues from the mice. Furthermore, neurotoxicity of HCys and HCA was assessed in a separate in vitro assay. In confirmation of our previous study, older AppNL-G-F mice also exhibited subtle phenotypic impairment and extensive cerebral amyloidosis, whereas dietary manipulations did not result in significant effects. As revealed by proximity extension assay-based proteome analysis, the AppNL-G-F genotype led to an upregulation of AD-characteristic neuronal markers. Hyperhomocysteinemia, in contrast, indicated mainly vascular effects. Overall, since there was an absence of a distinct phenotype despite both a significant amyloid-β burden and serum HCys elevation, the results in this study did not corroborate the pathological role of amyloid-β according to the "amyloid hypothesis," nor of hyperhomocysteinemia on cognitive performance. Nevertheless, this study aided in further characterizing the AppNL-G-F model and in elucidating the role of HCys in diverse biological processes. The idea of AD prevention with the investigated micronutrients, however, was not supported, at least in this mouse model of the disease.

Keywords:  Alzheimer’s disease; amyloid betapeptides; hyperhomocysteinemia; memory and learning tests; proteomics; vitamin B deficiency

DOI:  https://doi.org/10.3389/fnagi.2022.876826
Front Aging Neurosci. 2022 ;14 875989

Age-Dependent Alterations of Cognition, Mitochondrial Function, and Beta-Amyloid Deposition in a Murine Model of Alzheimer's Disease-A Longitudinal Study.

Martina Reutzel, Rekha Grewal, Aljoscha Joppe, Gunter P Eckert.

  Aging is the main risk factor for sporadic Alzheimer's disease (AD), which is characterized by the cerebral deposition of β-amyloid peptides (Aβ) and cognitive decline. Mitochondrial dysfunction is also characteristic of the disease and represents a hallmark of both, aging and neurodegeneration. We longitudinally followed Aβ levels, cognition, and mitochondrial function in the same cohort of Thy1-APP751SL mice representing a murine model of AD. In the course of time, changes were most prominent at an age of 13 months including the latency time in the passive avoidance test, the activity of complexes I and IV of the mitochondrial respiration chain, and expression of genes related to mitochondrial biogenesis and synaptic plasticity including Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), CAMP responsive element binding protein 1 (CREB1), and Synaptophysin 1 (SYP1). These changes occurred in parallel with massively increasing cerebral Aβ levels. Other parameters were changed in younger mice including the alteration rate in the Y-maze test and the nesting score when Aβ levels were not changed yet. The results are consistent in the cohort described. However, previous, non-longitudinal studies reported divergent time points for the occurrence of the parameters studied. These findings are discussed in light of the current results.

Keywords:  Alzheimers’s disease; amyloid-beta; longitudinal studies; mitochondrial dysfunction; transgenic mouse models

DOI:  https://doi.org/10.3389/fnagi.2022.875989
Int J Neurosci. 2022 May 18. 1-17

Demonstration of Ameliorating Effect of Vardenafil Through Its Anti-Inflammatory and Neuroprotective Properties in Autism Spectrum Disorder Induced by Propionic Acid on Rat Model.

Bahattin Özkul, Furkan Ertürk Urfalı, İbrahim Halil Sever, Mehmet Fatih Bozkurt, İbrahim Söğüt, Çağrı Serdar Elgörmüş, Mumin Alper Erdogan, Oytun Erbaş.

  Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. In this study, we aimed to determine the ameliorating effects of vardenafil in the ASD rat model induced by propionic acid (PPA) in terms of neurobehavioral changes and also support these effects with histopathological changes, brain biochemical analysis and magnetic resonance spectroscopy (MRS) findings.Materials and Methods: Twenty-one male rats were randomly assigned into 3 groups. Group 1 (control, 7 rats) did not receive treatment. Rats in groups 2 and 3 were given PPA at the dose of 250 mg/kg/day intraperitoneally for 5 days. After PPA administration, animals in group 2 (PPAS, 7 rats) were given saline and animals in group 3 (PPAV, 7 rats) were given vardenafil. Behavioral tests were performed between the 20th and 24th days of the study. The rats were taken for MRS on the 25th day. At the end of the study, brain levels of interleukin-2 (IL-2), IL-17, tumor necrosis factor-α, nerve growth factor, cGMP and lactate levels were measured. In the cerebellum and the CA1 and CA3 regions of the hippocampus, counts of neurons and Purkinje cells and glial fibrillary acidic protein (associated with gliosis) were evaluated histologically.Results: Three chamber sociability and passive avoiding test, histopathological results, lactate levels derived from MRS, and biochemical biomarkers revealed significant differences among the PPAV and PPAS groups.Conclusion: We concluded that vardenafil improves memory and social behaviors and prevent loss of neuronal and Purkinje cell through its anti-inflammatory and neuroprotective effect.

Keywords:  Autism; Gliosis; Inflammation; Mitochondrial dysfunction; Vardenafil

DOI:  https://doi.org/10.1080/00207454.2022.2079507
Front Pediatr. 2022 ;10 825515

PC Splice-Site Variant c.1825+5G>A Caused Intron Retention in a Patient With Pyruvate Carboxylase Deficiency: A Case Report.

DongYing Tao, HuiQin Zhang, Jingmin Yang, HuanHong Niu, JingJing Zhang, Minghua Zeng, ShengQuan Cheng.

   Background: Pyruvate carboxylase deficiency (PCD; MIM#266150) is a rare autosomal recessive disorder characterized by a wide range of clinical features, including delayed neurodevelopment, elevated pyruvate levels, lactic acidosis, elevated ketone levels, and hyperammonemia. The pyruvate carboxylase (PC) gene was identified to be the disease-causing gene for PCD. A novel homozygous splice variant in the PC gene was identified in a Chinese boy, but the pathogenicity is still unclear. The objective of the present study was to determine the effect of this splice-site variant by reverse transcription analysis.
Methods: We reported the clinical course of a 20-month-old Chinese pediatric patient who was diagnosed with PCD using whole-exome sequencing (WES). The effects of the variant on mRNA splicing were analyzed through the transcript analysis in vivo.
Results: The results of metabolic blood and urine screening suggested PCD by employing tandem mass spectrometry. WES revealed a novel homozygous splice-site variant (c.1825+5G>A) in the PC gene. in vivo transcript analysis indicated that the splice-site variant caused the retention of 192 bp of the intron.
Conclusion: Thus, c.1825+5G>A was established as a pathogenic variant, thereby enriching the mutational spectrum of the PC gene and providing a basis for the genetic diagnosis of PCD.

Keywords:  PC gene; c.1825+5G>A; pathogenic variant; pyruvate carboxylase deficiency; splice-site variant

DOI:  https://doi.org/10.3389/fped.2022.825515
eNeuro. 2022 May 18. pii: ENEURO.0176-22.2022. [Epub ahead of print]

AGING-ASSOCIATED COGNITIVE DECLINE IS REVERSED BY D-SERINE SUPPLEMENTATION.

L Nava-Gómez, I Calero-Vargas, F Higinio-Rodríguez, B Vázquez-Prieto, R Olivares-Moreno, J Ortiz-Retana, P Aranda, N Hernández-Chan, G Rojas-Piloni, S Alcauter, M López-Hidalgo.

  Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction due to a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear if D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeutic target to reverse age-related brain alterations.SIGNIFICANT STATEMENTAge-related behavioral changes in cognitive performance occur as a physiological process of aging. Then, it is important to explore possible therapeutics to decrease, retard or reverse aging effects on the brain. NMDA receptor hypofunction contributes to the aging-associated cognitive decline. In the aged brain, there is a reduction in the brain levels of the NMDAR co-agonist, D-Serine. However, it is unclear if chronic D-serine supplementation could revert the age-detriment in brain functions. Our results show that D-serine supplementation reverts the age-associated decrease in cognitive flexibility, functional brain connectivity, and neuronal morphology. Our findings raise the possibility that restoring the brain levels of D-serine could be used as a therapeutic target to recover brain alterations associated with aging.

Keywords:  Aging; Cognitive Flexibility; D-serine; Functional brain connectivity; fMRI

DOI:  https://doi.org/10.1523/ENEURO.0176-22.2022
J Neuroinflammation. 2022 May 14. 19(1): 110

High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

Olivia J Gannon, Lisa S Robison, Abigail E Salinero, Charly Abi-Ghanem, Febronia M Mansour, Richard D Kelly, Alvira Tyagi, Rebekah R Brawley, Jordan D Ogg, Kristen L Zuloaga.

   BACKGROUND: Approximately 70% of Alzheimer's disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3× more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD.
METHODS: Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet from 3 to 7 months of age. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain.
RESULTS: In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, AD/MxD females had more amyloid beta plaques and hippocampal levels of insoluble amyloid beta 40 and 42 than AD/MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis.
CONCLUSIONS: High-fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.

Keywords:  Alzheimer’s disease; Cerebral hypoperfusion; Dementia; Diabetes; Glucose intolerance; High-fat diet; Inflammation; Metabolic; Obesity; Sex; Vascular

DOI:  https://doi.org/10.1186/s12974-022-02466-2
Geroscience. 2022 May 18.

Glucose metabolism patterns: A potential index to characterize brain ageing and predict high conversion risk into cognitive impairment.

Alzheimer’s Disease Neuroimaging Initiative

  Exploring individual hallmarks of brain ageing is important. Here, we propose the age-related glucose metabolism pattern (ARGMP) as a potential index to characterize brain ageing in cognitively normal (CN) elderly people. We collected 18F-fluorodeoxyglucose (18F-FDG) PET brain images from two independent cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 127) and the Xuanwu Hospital of Capital Medical University, Beijing, China (N = 84). During follow-up (mean 80.60 months), 23 participants in the ADNI cohort converted to cognitive impairment. ARGMPs were identified using the scaled subprofile model/principal component analysis method, and cross-validations were conducted in both independent cohorts. A survival analysis was further conducted to calculate the predictive effect of conversion risk by using ARGMPs. The results showed that ARGMPs were characterized by hypometabolism with increasing age primarily in the bilateral medial superior frontal gyrus, anterior cingulate and paracingulate gyri, caudate nucleus, and left supplementary motor area and hypermetabolism in part of the left inferior cerebellum. The expression network scores of ARGMPs were significantly associated with chronological age (R = 0.808, p < 0.001), which was validated in both the ADNI and Xuanwu cohorts. Individuals with higher network scores exhibited a better predictive effect (HR: 0.30, 95% CI: 0.1340 ~ 0.6904, p = 0.0068). These findings indicate that ARGMPs derived from CN participants may represent a novel index for characterizing brain ageing and predicting high conversion risk into cognitive impairment.

Keywords:  Brain ageing; Glucose metabolism; Pattern; Positron emission tomography

DOI:  https://doi.org/10.1007/s11357-022-00588-2
Front Mol Neurosci. 2022 ;15 867935

Altered Mitochondrial Protein Homeostasis and Proteinopathies.

Aya Jishi, Xin Qi.

  Increasing evidence implicates mitochondrial dysfunction as key in the development and progression of various forms of neurodegeneration. The multitude of functions carried out by mitochondria necessitates a tight regulation of protein import, dynamics, and turnover; this regulation is achieved via several, often overlapping pathways that function at different levels. The development of several major neurodegenerative diseases is associated with dysregulation of these pathways, and growing evidence suggests direct interactions between some pathogenic proteins and mitochondria. When these pathways are compromised, so is mitochondrial function, and the resulting deficits in bioenergetics, trafficking, and mitophagy can exacerbate pathogenic processes. In this review, we provide an overview of the regulatory mechanisms employed by mitochondria to maintain protein homeostasis and discuss the failure of these mechanisms in the context of several major proteinopathies.

Keywords:  mitochondrial dysfunction; mitochondrial quality control; neurodegeneration; protein homeostasis; proteinopathies

DOI:  https://doi.org/10.3389/fnmol.2022.867935
Cereb Cortex. 2022 May 19. pii: bhac196. [Epub ahead of print]

Midlife omega-3 fatty acid intake predicts later life white matter microstructure in an age- and APOE-dependent manner.

Amaryllis A Tsiknia, Jaclyn Bergstrom, Emilie T Reas.

  Omega-3 intake has been positively associated with healthy brain aging, yet it remains unclear whether high omega-3 intake beginning early in life may optimize its protective effects against brain aging. We examined whether omega-3 intake is associated with brain microstructure over 2 decades later among dementia-free older adults. The 128 participants (62% women; age at magnetic resonance imaging: 76.6 ± 7.9) from the Rancho Bernardo Study of Healthy Aging completed at least 1 dietary assessment between 1984 and 1996 and underwent restriction spectrum imaging (RSI) 22.8 ± 3.1 years later. We evaluated associations between prior omega-3 intake and RSI metrics of gray and white matter (WM) microstructure. Higher prior omega-3 intake was associated with greater restricted diffusion in the superior cortico-striatal fasciculus. A correlation between higher prior omega-3 intake and greater cingulum restricted diffusion was stronger among participants >80 years old. Higher omega-3 intake correlated with greater restricted diffusion in the inferior longitudinal and inferior fronto-occipital fasciculus more strongly for apolipoprotein E (APOE) ε4 carriers than noncarriers. Associations were not modified by adjustment for dietary pattern, health, or lifestyle. High omega-3 intake in midlife may help to maintain WM integrity into older age, particularly in the latest decades of life and among APOE ε4 carriers.

Keywords:  brain aging; brain microstructure; dietary patterns; diffusion MRI; omega-3 fatty acids; restriction spectrum imaging

DOI:  https://doi.org/10.1093/cercor/bhac196