bims-brabim 2021-11-28 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2021‒11‒28
33 papers selected by
João Victor Cabral-Costa
University of São Paulo

Sodium butyrate ameliorates the cognitive impairment of Alzheimer's disease by regulating the metabolism of astrocytes.
Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice.
RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.
Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer's Disease Pathogenesis?
The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?
NAD+ Metabolism and Diseases with Motor Dysfunction.
Hippocampal Function Is Impaired by a Short-Term High-Fat Diet in Mice: Increased Blood-Brain Barrier Permeability and Neuroinflammation as Triggering Events.
Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson's Disease.
Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.
Lipid-induced S-palmitoylation as a Vital Regulator of Cell Signaling and Disease Development.
Effects of Panthenol and N-Acetylcysteine on Changes in the Redox State of Brain Mitochondria under Oxidative Stress In Vitro.
Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer's Disease.
Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors.
Astrocyte Gliotransmission in the Regulation of Systemic Metabolism.
Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer's Disease.
TO901317 activation of LXR-dependent pathways mitigate amyloid-beta peptide-induced neurotoxicity in 3D human neural stem cell culture scaffolds and AD mice.
Serine protease HtrA2/Omi regulates adaptive mitochondrial reprogramming in the brain cortex after ischemia/reperfusion injury via UCP2-SIRT3-PGC1 axis.
De novo lipogenesis in astrocytes promotes the repair of blood-brain barrier after transient cerebral ischemia through interleukin-33.
Hippocampal neurons' cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep.
IDH knockdown alters foraging behavior in the termite Odontotermes formosanus in different social contexts.
Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging.
Effects of oxytocin and antagonist antidote atosiban on body weight and food intake of female mice, Mus musculus.
The Pleiotropic Potential of BDNF beyond Neurons: Implication for a Healthy Mind in a Healthy Body.
Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.
Connection Lost, MAM: Errors in ER-Mitochondria Connections in Neurodegenerative Diseases.
Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions.
Biochemical Alterations in White Matter Tracts of the Aging Mouse Brain Revealed by FTIR Spectroscopy Imaging.
Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease with Severe Reactive Gliosis.
Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer's Disease Dementia.
Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies.
Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model.
Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice.
Changes in metabolomics and lipidomics in brain tissue and their correlations with the gut microbiome after chronic food-derived arsenic exposure in mice.

Psychopharmacology (Berl). 2021 Nov 23.

Sodium butyrate ameliorates the cognitive impairment of Alzheimer's disease by regulating the metabolism of astrocytes.

Chen Wang, Dongpeng Zheng, Fanglin Weng, Yongzeng Jin, Ling He.

  RATIONALE: Energy metabolism disorder is a widespread feature that exists in the early clinical stages of Alzheimer's disease (AD). Astrocyte is the most numerous and the largest glial cell in the brain. By transporting energetic fuels such as lactate and ketones to neurons, astrocytes play a pivotal role in maintaining the cerebral energy homeostasis. Sodium butyrate (NaB), a type of short-chain fatty acid; its anti-inflammatory effect; and inhibition on histone deacetylases have been widely studied.METHODS: Spatial memory and cognitive ability of mice were assessed by using behavioral tests. Western blotting and ELISA kits were used to detect related protein levels and other biochemical markers, respectively.
OBJECTIVES: To prove the therapeutic effect of NaB on AD cognitive impairment and provide possible research ideas for mechanism exploration.
RESULTS: Administration of NaB could improve the cognitive impairments induced by Aβ25-35 in mice. Furthermore, NaB could promote the differentiation of astrocytes towards A2-neuron-protective subtype, astroglial mitochondrial function, and lactate shuttle between astrocytes and neurons.
CONCLUSION: These findings reveal the effect of sodium butyrate on astrocytes, which may improve the pathological status of AD and provide experimental basis for sodium butyrate treatment of AD.

Keywords:  Alzheimer’s disease; Astrocyte-neuron lactate shuttle; Astrocytes; Mitochondria function; Sodium butyrate

DOI:  https://doi.org/10.1007/s00213-021-06025-0
J Alzheimers Dis. 2021 Nov 18.

Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice.

Xu-Dong Yan, Xue-Song Qu, Jing Yin, Jin Qiao, Jun Zhang, Jin-Shun Qi, Mei-Na Wu.

  BACKGROUND: Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear.OBJECTIVE: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects.
METHODS: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10.
RESULTS: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice.
CONCLUSION: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

Keywords:  3xTg-AD mice; Adiponectin; learning and memory; long-term depression; long-term potentiation; neuroinflammation

DOI:  https://doi.org/10.3233/JAD-215063
Cells. 2021 Nov 10. pii: 3113. [Epub ahead of print]10(11):

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.

Sanjay Awasthi, Ashly Hindle, Neha A Sawant, Mathew George, Murali Vijayan, Sudhir Kshirsagar, Hallie Morton, Lloyd E Bunquin, Philip T Palade, J Josh Lawrence, Hafiz Khan, Chhanda Bose, P Hemachandra Reddy, Sharda P Singh.

  The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

Keywords:  Alzheimer’s disease; mitochondria; mitochondrial biogenesis; mitophagy; synaptic proteins

DOI:  https://doi.org/10.3390/cells10113113
Cells. 2021 Nov 12. pii: 3144. [Epub ahead of print]10(11):

Mechanosensing and the Hippo Pathway in Microglia: A Potential Link to Alzheimer's Disease Pathogenesis?

Lucrezia Bruno, Simge Karagil, Almas Mahmood, Ahmed Elbediwy, Michael Stolinski, Francesca E Mackenzie.

  The activation of microglia, the inflammatory cells of the central nervous system (CNS), has been linked to the pathogenesis of Alzheimer's disease and other neurodegenerative diseases. How microglia sense the changing brain environment, in order to respond appropriately, is still being elucidated. Microglia are able to sense and respond to the mechanical properties of their microenvironment, and the physical and molecular pathways underlying this mechanosensing/mechanotransduction in microglia have recently been investigated. The Hippo pathway functions through mechanosensing and subsequent protein kinase cascades, and is critical for neuronal development and many other cellular processes. In this review, we examine evidence for the potential involvement of Hippo pathway components specifically in microglia in the pathogenesis of Alzheimer's disease. We suggest that the Hippo pathway is worth investigating as a mechanosensing pathway in microglia, and could be one potential therapeutic target pathway for preventing microglial-induced neurodegeneration in AD.

Keywords:  Alzheimer’s disease; Hippo; MST1; YAP; immunometabolism; mechanosensing; mechanotransduction; microglia; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3390/cells10113144
Biomolecules. 2021 Nov 08. pii: 1652. [Epub ahead of print]11(11):

The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?

Lorena Perrone, Mariarosaria Valente.

  Alzheimer disease (AD) is the most frequent cause of dementia and up to now there is not an effective therapy to cure AD. In addition, AD onset occurs decades before the diagnosis, affecting the possibility to set up appropriate therapeutic strategies. For this reason, it is necessary to investigate the effects of risk factors, such as cardiovascular diseases, in promoting AD. AD shows not only brain dysfunction, but also alterations in peripheral tissues/organs. Indeed, it exists a reciprocal connection between brain and heart, where cardiovascular alterations participate to AD as well as AD seem to promote cardiovascular dysfunction. In addition, metabolic dysfunction promotes both cardiovascular diseases and AD. In this review, we summarize the pathways involved in the regulation of the brain-heart axis and the effect of metabolism on these pathways. We also present the studies showing the role of the gut microbiota on the brain-heart axis. Herein, we propose recent evidences of the function of Thioredoxin Interacting protein (TXNIP) in mediating the role of metabolism on the brain-heart axis. TXNIP is a key regulator of metabolism at both cellular and body level and it exerts also a pathological function in several cardiovascular diseases as well as in AD.

Keywords:  TXNIP; brain-heart axis; cardiovascular diseases; metabolism; microbiota

DOI:  https://doi.org/10.3390/biom11111652
Genes (Basel). 2021 Nov 09. pii: 1776. [Epub ahead of print]12(11):

NAD+ Metabolism and Diseases with Motor Dysfunction.

Samuel Lundt, Shinghua Ding.

  Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson's disease and Huntington's disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss-Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction.

Keywords:  NAD+; Nampt; energy metabolism; motor dysfunction; motor neuron diseases

DOI:  https://doi.org/10.3390/genes12111776
Front Neurosci. 2021 ;15 734158

Hippocampal Function Is Impaired by a Short-Term High-Fat Diet in Mice: Increased Blood-Brain Barrier Permeability and Neuroinflammation as Triggering Events.

Gabriela Cristina de Paula, Henver S Brunetta, Daiane F Engel, Joana M Gaspar, Licio A Velloso, David Engblom, Jade de Oliveira, Andreza Fabro de Bem.

  Worldwide, and especially in Western civilizations, most of the staple diets contain high amounts of fat and refined carbohydrates, leading to an increasing number of obese individuals. In addition to inducing metabolic disorders, energy dense food intake has been suggested to impair brain functions such as cognition and mood control. Here we demonstrate an impaired memory function already 3 days after the start of a high-fat diet (HFD) exposure, and depressive-like behavior, in the tail suspension test, after 5 days. These changes were followed by reduced synaptic density, changes in mitochondrial function and astrocyte activation in the hippocampus. Preceding or coinciding with the behavioral changes, we found an induction of the proinflammatory cytokines TNF-α and IL-6 and an increased permeability of the blood-brain barrier (BBB), in the hippocampus. Finally, in mice treated with a TNF-α inhibitor, the behavioral and BBB alterations caused by HFD-feeding were mitigated suggesting that inflammatory signaling was critical for the changes. In summary, our findings suggest that HFD rapidly triggers hippocampal dysfunction associated with BBB disruption and neuroinflammation, promoting a progressive breakdown of synaptic and metabolic function. In addition to elucidating the link between diet and cognitive function, our results might be relevant for the comprehension of the neurodegenerative process.

Keywords:  bioenergetics; blood–brain barrier; cognition; depression; high fat diet; memory; mitochondria; neuroinflammation

DOI:  https://doi.org/10.3389/fnins.2021.734158
Cells. 2021 Nov 04. pii: 3022. [Epub ahead of print]10(11):

Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson's Disease.

Maria Vizziello, Linda Borellini, Giulia Franco, Gianluca Ardolino.

  The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson's disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.3390/cells10113022
Int J Mol Sci. 2021 Nov 15. pii: 12310. [Epub ahead of print]22(22):

Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.

Junpei Takeishi, Yasuko Tatewaki, Taizen Nakase, Yumi Takano, Naoki Tomita, Shuzo Yamamoto, Tatsushi Mutoh, Yasuyuki Taki.

  Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer's disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-β accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.

Keywords:  Alzheimer’s disease; MCT oil; amyloid-beta; coconut oil; glucose metabolism; insulin resistance; ketogenic diet; ketone metabolism; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/ijms222212310
Int J Biol Sci. 2021 ;17(15): 4223-4237

Lipid-induced S-palmitoylation as a Vital Regulator of Cell Signaling and Disease Development.

Mengyuan Qu, Xuan Zhou, Xiaotong Wang, Honggang Li.

  Lipid metabolites are emerging as pivotal regulators of protein function and cell signaling. The availability of intracellular fatty acid is tightly regulated by glycolipid metabolism and may affect human body through many biological mechanisms. Recent studies have demonstrated palmitate, either from exogenous fatty acid uptake or de novo fatty acid synthesis, may serve as the substrate for protein palmitoylation and regulate protein function via palmitoylation. Palmitoylation, the most-studied protein lipidation, encompasses the reversible covalent attachment of palmitate moieties to protein cysteine residues. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane association and interaction with other effectors. Dysregulation of palmitoylation has been implicated in a plethora of diseases, such as metabolic syndrome, cancers, neurological disorders and infections. Accordingly, it could be one of the molecular mechanisms underlying the impact of palmitate metabolite on cellular homeostasis and human diseases. Herein, we explore the relationship between lipid metabolites and the regulation of protein function through palmitoylation. We review the current progress made on the putative role of palmitate in altering the palmitoylation of key proteins and thus contributing to the pathogenesis of various diseases, among which we focus on metabolic disorders, cancers, inflammation and infections, neurodegenerative diseases. We also highlight the opportunities and new therapeutics to target palmitoylation in disease development.

Keywords:  Cancer; Inflammation; Lipid metabolism; Neurodegeneration; Palmitoylation

DOI:  https://doi.org/10.7150/ijbs.64046
Antioxidants (Basel). 2021 Oct 27. pii: 1699. [Epub ahead of print]10(11):

Effects of Panthenol and N-Acetylcysteine on Changes in the Redox State of Brain Mitochondria under Oxidative Stress In Vitro.

Dmitry S Semenovich, Egor Yu Plotnikov, Oksana V Titko, Elena P Lukiyenko, Nina P Kanunnikova.

  The glutathione system in the mitochondria of the brain plays an important role in maintaining the redox balance and thiol-disulfide homeostasis, whose violations are the important component of the biochemical shifts in neurodegenerative diseases. Mitochondrial dysfunction is known to be accompanied by the activation of free radical processes, changes in energy metabolism, and is involved in the induction of apoptotic signals. The formation of disulfide bonds is a leading factor in the folding and maintenance of the three-dimensional conformation of many specific proteins that selectively accumulate in brain structures during neurodegenerative pathology. In this study, we estimated brain mitochondria redox status and functioning during induction of oxidative damage in vitro. We have shown that the development of oxidative stress in vitro is accompanied by inhibition of energy metabolism in the brain mitochondria, a shift in the redox potential of the glutathione system to the oxidized side, and activation of S-glutathionylation of proteins. Moreover, we studied the effects of pantothenic acid derivatives-precursors of coenzyme A (CoA), primarily D-panthenol, that exhibit high neuroprotective activity in experimental models of neurodegeneration. Panthenol contributes to the significant restoration of the activity of enzymes of mitochondrial energy metabolism, normalization of the redox potential of the glutathione system, and a decrease in the level of S-glutathionylated proteins in brain mitochondria. The addition of succinate and glutathione precursor N-acetylcysteine enhances the protective effects of the drug.

Keywords:  D-panthenol; brain mitochondria; glutathione system; oxidative stress; redox state; thiol–disulfide balance

DOI:  https://doi.org/10.3390/antiox10111699
Biomedicines. 2021 Oct 31. pii: 1587. [Epub ahead of print]9(11):

Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer's Disease.

Pamela J Yao, Erden Eren, Edward J Goetzl, Dimitrios Kapogiannis.

  Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer's disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction in AD is reflected in ETC and SOD1 levels and activity in plasma neuron-derived extracellular vesicles (NDEVs). We immunoprecipitated NDEVs targeting neuronal marker L1CAM from two cohorts: one including 22 individuals with early AD and 29 control subjects; and another including 14 individuals with early AD and 14 control subjects. In the first cohort, we measured levels of complexes I, III, IV, ATP synthase, and SOD1; in the second cohort, we measured levels and catalytic activity of complexes IV and ATP synthase. AD individuals had lower levels of complexes I (p < 0.0001), III (p < 0.0001), IV (p = 0.0061), and V (p < 0.0001), and SOD1 (p < 0.0001) compared to controls. AD individuals also had lower levels of catalytic activity of complex IV (p = 0.0214) and ATP synthase (p < 0.0001). NDEVs confirm quantitative and functional abnormalities in ECT complexes and SOD1 previously observed in AD models and during autopsy, opening the way for using them as biomarkers for mitochondrial dysfunction in AD.

Keywords:  Alzheimer’s disease; NADH; SOD1; Superoxide Dismutase 1; electron transport chain; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biomedicines9111587
Cells. 2021 Oct 27. pii: 2913. [Epub ahead of print]10(11):

Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors.

Reinier Alvarez, Debjani Mandal, Prashant Chittiboina.

  PFKFB3 is a bifunctional enzyme that modulates and maintains the intracellular concentrations of fructose-2,6-bisphosphate (F2,6-P2), essentially controlling the rate of glycolysis. PFKFB3 is a known activator of glycolytic rewiring in neoplastic cells, including central nervous system (CNS) neoplastic cells. The pathologic regulation of PFKFB3 is invoked via various microenvironmental stimuli and oncogenic signals. Hypoxia is a primary inducer of PFKFB3 transcription via HIF-1alpha. In addition, translational modifications of PFKFB3 are driven by various intracellular signaling pathways that allow PFKFB3 to respond to varying stimuli. PFKFB3 synthesizes F2,6P2 through the phosphorylation of F6P with a donated PO4 group from ATP and has the highest kinase activity of all PFKFB isoenzymes. The intracellular concentration of F2,6P2 in cancers is maintained primarily by PFKFB3 allowing cancer cells to evade glycolytic suppression. PFKFB3 is a primary enzyme responsible for glycolytic tumor metabolic reprogramming. PFKFB3 protein levels are significantly higher in high-grade glioma than in non-pathologic brain tissue or lower grade gliomas, but without relative upregulation of transcript levels. High PFKFB3 expression is linked to poor survival in brain tumors. Solitary or concomitant PFKFB3 inhibition has additionally shown great potential in restoring chemosensitivity and radiosensitivity in treatment-resistant brain tumors. An improved understanding of canonical and non-canonical functions of PFKFB3 could allow for the development of effective combinatorial targeted therapies for brain tumors.

Keywords:  CNS; PFK-2; PFKFB3; brain tumors; glycolysis; hypoxia; metabolic reprogramming; tumorigenic reprogramming

DOI:  https://doi.org/10.3390/cells10112913
Metabolites. 2021 Oct 26. pii: 732. [Epub ahead of print]11(11):

Astrocyte Gliotransmission in the Regulation of Systemic Metabolism.

Cahuê De Bernardis Murat, Cristina García-Cáceres.

  Normal brain function highly relies on the appropriate functioning of astrocytes. These glial cells are strategically situated between blood vessels and neurons, provide significant substrate support to neuronal demand, and are sensitive to neuronal activity and energy-related molecules. Astrocytes respond to many metabolic conditions and regulate a wide array of physiological processes, including cerebral vascular remodeling, glucose sensing, feeding, and circadian rhythms for the control of systemic metabolism and behavior-related responses. This regulation ultimately elicits counterregulatory mechanisms in order to couple whole-body energy availability with brain function. Therefore, understanding the role of astrocyte crosstalk with neighboring cells via the release of molecules, e.g., gliotransmitters, into the parenchyma in response to metabolic and neuronal cues is of fundamental relevance to elucidate the distinct roles of these glial cells in the neuroendocrine control of metabolism. Here, we review the mechanisms underlying astrocyte-released gliotransmitters that have been reported to be crucial for maintaining homeostatic regulation of systemic metabolism.

Keywords:  astrocytes; calcium signaling; energy balance; gliotransmission; systemic metabolism

DOI:  https://doi.org/10.3390/metabo11110732
Int J Mol Sci. 2021 Nov 12. pii: 12256. [Epub ahead of print]22(22):

Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer's Disease.

Estibaliz González de San Román, Alberto Llorente-Ovejero, Jonatan Martínez-Gardeazabal, Marta Moreno-Rodríguez, Lydia Giménez-Llort, Iván Manuel, Rafael Rodríguez-Puertas.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPPSwe, PS1M146V, and tauP301L transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [35S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB1, LPA1, and S1P1 Gi/0 coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB1 receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA1 activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P1 activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.

Keywords:  3xTg-AD mice; Alzheimer’s disease; G protein; LPA receptors; MALDI-MSI; [35S]GTPγS autoradiography; cannabinoid receptors; functional autoradiography; ligand binding; sphingosine 1-phosphate

DOI:  https://doi.org/10.3390/ijms222212256
Brain Res Bull. 2021 Nov 18. pii: S0361-9230(21)00322-1. [Epub ahead of print]

TO901317 activation of LXR-dependent pathways mitigate amyloid-beta peptide-induced neurotoxicity in 3D human neural stem cell culture scaffolds and AD mice.

Ming-Chang Chiang, Christopher J B Nicol, Shiang-Jiuun Chen, Rong-Nan Huang.

  Alzheimer's disease (AD) is the major cause of neurodegeneration worldwide and is characterized by the accumulation of amyloid beta (Aβ) in the brain, which is associated with neuronal loss and cognitive impairment. Liver X receptor (LXR), a critical nuclear receptor, and major regulator in lipid metabolism and inflammation, is suggested to play a protective role against the mitochondrial dysfunction noted in AD. In our study, our established 3D gelatin scaffold model and a well characterized in vivo (APP/PS1) murine model of AD were used to directly investigate the molecular, biochemical and behavioural effects of neuronal stem cell exposure to Aβ to improve understanding of the in vivo etiology of AD. Herein, human neural stem cells (hNSCs) in our 3D model were exposed to Aβ, and had significantly decreased cell viability, which correlated with decreased mRNA and protein expression of LXR, Bcl-2, CREB, PGC1α, NRF-1, and Tfam, and increased caspase 3 and 9 activities. Cotreatment with a synthetic agonist of LXR (TO901317) significantly abrogated these Aβ-mediated effects in hNSCs. Moreover, TO901317 cotreatment both significantly rescues hNSCs from Aβ-mediated decreases in ATP levels and mitochondrial mass, and significantly restores Aβ-induced fragmented mitochondria to almost normal morphology. TO901317 cotreatment also decreases tau aggregates in Aβ-treated hNSCs. Importantly, TO901317 treatment significantly alleviates the impairment of memory, decreases Aβ aggregates and increases proteasome activity in APP/PS1 mice; whereas, these effects were blocked by cotreatment with an LXR antagonist (GSK2033). Together, these novel results improve our mechanistic understanding of the central role of LXR in Aβ-mediated hNSC dysfunction. We also provide preclinical data unveiling the protective effects of using an LXR-dependent agonist, TO901317, to block the toxicity observed in Aβ-exposed hNSCs, which may guide future treatment strategies to slow or prevent neurodegeneration in some AD patients.

Keywords:  AD mice; Aβ; LXR; TO901317; hNSCs; mitochondrial function

DOI:  https://doi.org/10.1016/j.brainresbull.2021.11.004
Hum Cell. 2021 Nov 22.

Serine protease HtrA2/Omi regulates adaptive mitochondrial reprogramming in the brain cortex after ischemia/reperfusion injury via UCP2-SIRT3-PGC1 axis.

Hao Meng, Lian-Kun Sun, Jing Su, Wan-Yu Yan, Yao Jin, Xin Luo, Xian-Rui Jiang, Hong-Lei Wang.

  This study is to investigate the underlying mechanisms of mitochondrial quality control (MQC) regulated by HtrA2/Omi during ischemia/reperfusion (I/R). We utilized the mnd2 mouse model, which has a missense mutation in HtrA2/Omi, to investigate the HtrA2/Omi regulation in mitochondria after I/R injury in the cerebral cortex. Compared to homozygous (HtrA2mnd2) mice, heterozygous (HtrA2Hetero) mice showed aging signs at a later age, increased HtrA2/Omi expression in the brain cortex, and lesser neurodegenerative signs. The brain cortex of HtrA2Hetero mice had increased superoxide dismutase (SOD) activity; lower levels of malondialdehyde (MDA); higher expressions of mitochondrial unfolded protein response (mtUPR)-related proteins, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (Ndufs7), and uncoupling protein 2 (UCP2) proteins; more mitochondrial fission; higher levels of ATP and mtDNA copies; elevated sirtuin 3 (SIRT3) activity; and increased NAD+/NADH ratio. After 1.5 h of I/R, the brain cortex of HtrA2Hetero mice had a larger infarction size, reduced HtrA2/Omi expression, decreased S-X-linked inhibitor of apoptosis protein (XIAP), and increased C-Caspase3 than that of wild-type animals (WT). Mitochondria from the HtrA2Hetero brain cortex showed decreased ATP production and MQC deficiency after 1.5 h I/R. Genipin pre-treatment reduced the aforementioned I/R injury in the HtrA2Hetero brain cortex. In conclusion, mitochondrial function is compensated in the HtrA2Hetero brain cortex via the upregulation of the UCP2-SIRT3-PGC1 axis. Decreased HtrA2/Omi function damages mitochondrial quality in the HtrA2Hetero mouse brain cortex, leading to more brain I/R injury. Genipin pre-treatment ameliorates brain damages via the mitochondrial UCP2-SIRT3-PGC1 axis.

Keywords:  Genipin; HtrA2/Omi; Ischemia–reperfusion injury; Mitochondria; UCP2-SIRT3-PGC1 axis

DOI:  https://doi.org/10.1007/s13577-021-00610-3
Neuroscience. 2021 Nov 22. pii: S0306-4522(21)00585-6. [Epub ahead of print]

De novo lipogenesis in astrocytes promotes the repair of blood-brain barrier after transient cerebral ischemia through interleukin-33.

Haidong Wei, Luming Zhen, Shiquan Wang, Yuanyuan Zhang, Kui Wang, Pengyu Jia, Yan Zhang, Zhixin Wu, Qianzi Yang, Wugang Hou, Jianrui Lv, Pengbo Zhang.

  Astrocytes experience significant metabolic shifts in the "sensitive period" of neurological function recovery following cerebral ischemia. However, the changes in astrocyte lipid metabolism and their implications for neurological recovery remain unknown. In the present study, we employed a mouse middle cerebral artery occlusion model to investigate the changes in de novo lipogenesis and interleukin-33 (IL-33) production in astrocytes and elucidate their role in blood-brain barrier (BBB) repair in the subacute phase of cerebral ischemia. Neurological behavior evaluation was used to assess functional changes in mice. Pharmacological inhibition and astrocyte-specific downregulation of fatty acid synthase (FASN) were used to evaluate the role of de novo lipogenesis in brain injury. Intracerebroventricular administration of recombinant IL-33 was performed to study the contribution of IL-33 to BBB disruption. Extravasation of Evans blue dye, dextran and IgG were used to assess BBB integrity. Western blotting of tight junction proteins ZO-1, Occludin, and Claudin-5 were performed at defined time points to evaluate changes in BBB. It was found that de novo lipogenesis was activated, and IL-33 production increased in astrocytes at the subacute stage of cerebral ischemia injury. Inhibition of lipogenesis in astrocytes decreased IL-33 production in the peri-infarct area, deteriorated BBB damage and interfered with neurological recovery. In addition, supplementation of IL-33 alleviated BBB destruction and improved neurological recovery worsened by lipogenesis inhibition. These findings indicate that astrocyte lipogenesis increases the production of IL-33 in the peri-infarct area, which promotes BBB repair in the subacute phase of cerebral ischemia injury and improves long-term functional recovery.

Keywords:  brain repair; fatty acid synthase; ischemic stroke; neurological recovery

DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.026
Proc Natl Acad Sci U S A. 2021 Nov 30. pii: e2108534118. [Epub ahead of print]118(48):

Hippocampal neurons' cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep.

James Delorme, Lijing Wang, Varna Kodoth, Yifan Wang, Jingqun Ma, Sha Jiang, Sara J Aton.

  The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative "engram") neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.

Keywords:  bioinformatics; memory consolidation; ribosomes; synaptic plasticity; translation

DOI:  https://doi.org/10.1073/pnas.2108534118
Curr Zool. 2021 Dec;67(6): 609-620

IDH knockdown alters foraging behavior in the termite Odontotermes formosanus in different social contexts.

Huan Xu 徐焕, Qiuying Huang 黄求应, Yongyong Gao 高勇勇, Jia Wu 吴佳, Ali Hassan, Yutong Liu 刘昱彤.

  Foraging, as an energy-consuming behavior, is very important for colony survival in termites. How energy metabolism related to glucose decomposition and adenosine triphosphate (ATP) production influences foraging behavior in termites is still unclear. Here, we analyzed the change in energy metabolism in the whole organism and brain after silencing the key metabolic gene isocitrate dehydrogenase (IDH) and then investigated its impact on foraging behavior in the subterranean termite Odontotermes formosanus in different social contexts. The IDH gene exhibited higher expression in the abdomen and head of O. formosanus. The knockdown of IDH resulted in metabolic disorders in the whole organism. The dsIDH-injected workers showed significantly reduced walking activity but increased foraging success. Interestingly, IDH knockdown altered brain energy metabolism, resulting in a decline in ATP levels and an increase in IDH activity. Additionally, the social context affected brain energy metabolism and, thus, altered foraging behavior in O. formosanus. We found that the presence of predator ants increased the negative influence on the foraging behavior of dsIDH-injected workers, including a decrease in foraging success. However, an increase in the number of nestmate soldiers could provide social buffering to relieve the adverse effect of predator ants on worker foraging behavior. Our orthogonal experiments further verified that the role of the IDH gene as an inherent factor was dominant in manipulating termite foraging behavior compared with external social contexts, suggesting that energy metabolism, especially brain energy metabolism, plays a crucial role in regulating termite foraging behavior.

Keywords:  Odontotermes formosanus; energy supply; foraging success; isocitrate dehydrogenase; social contexts; walking activity

DOI:  https://doi.org/10.1093/cz/zoab032
Biomedicines. 2021 Nov 07. pii: 1635. [Epub ahead of print]9(11):

Human iPSC-Derived Neurons as A Platform for Deciphering the Mechanisms behind Brain Aging.

Chuan-Chuan Chao, Po-Wen Shen, Tsai-Yu Tzeng, Hsing-Jien Kung, Ting-Fen Tsai, Yu-Hui Wong.

  With an increased life expectancy among humans, aging has recently emerged as a major focus in biomedical research. The lack of in vitro aging models-especially for neurological disorders, where access to human brain tissues is limited-has hampered the progress in studies on human brain aging and various age-associated neurodegenerative diseases at the cellular and molecular level. In this review, we provide an overview of age-related changes in the transcriptome, in signaling pathways, and in relation to epigenetic factors that occur in senescent neurons. Moreover, we explore the current cell models used to study neuronal aging in vitro, including immortalized cell lines, primary neuronal culture, neurons directly converted from fibroblasts (Fib-iNs), and iPSC-derived neurons (iPSC-iNs); we also discuss the advantages and limitations of these models. In addition, the key phenotypes associated with cellular senescence that have been observed by these models are compared. Finally, we focus on the potential of combining human iPSC-iNs with genome editing technology in order to further our understanding of brain aging and neurodegenerative diseases, and discuss the future directions and challenges in the field.

Keywords:  CRISPR; brain aging; genome editing technology; human induced pluripotent stem cells (hiPSCs); induced neurons (iNs); neuronal senescence

DOI:  https://doi.org/10.3390/biomedicines9111635
Metabol Open. 2021 Dec;12 100146

Effects of oxytocin and antagonist antidote atosiban on body weight and food intake of female mice, Mus musculus.

Pratibha Thakur, Renu Shrivastava, Vinoy K Shrivastava.

  Growing evidence suggests that oxytocin (OT) plays an important factor for the control of food intake, body weight, and energy metabolism in human and non-human animals. It has reported previously, the downregulation in oxytocin receptors (OTRs) expression is linked with the development of obesity, but exogenous OT reverse body weight and food intake in obese animal model. It is important to know that, whether intraperitoneal administration crosses blood brain barrier. Therefore, in the present experiment, we study the impact of intraperitoneal administration of synthetic OT 0.0116 mg/kg and antagonist atosiban (OTA) 1 mg/kg on food intake, and body weight of female mice, Mus musculus for different duration i.e. 30, 60, and 90 days. In this study, it was observed that there was significant decrease (p<0.001, one-way analysis of variance [ANOVA]) in the body weight (BW), food intake, and gonadosmatic indices (GSI) after the intraperitoneal exposure of OT at dose 0.0116 mg/kg up to 90 days and inhibits via antagonist atosiban. These results indicates that intraperitoneal administration of OT can be used for treatment for longer duration without any side effects and maintains homeostasis in physiologic system regulates body weight and gonadal weight in female mice, which represent an important therapeutic tool for the obesity and metabolic disorder in female.

Keywords:  AN, Arcuate Nucleus; ANOVA, One-Way Analysis of Variance; BBB, Blood Brain Barrier; BW, Body Weight; Body weight; CNS, Central Nervous System; Energy metabolism; Food intake; GI, Gastrointestinal; GPCR, G-Protein Coupled Receptor; GSI, Gonadosomatic Indices; Gonadosomatic indices; HPG, Hypothalamic-Pituitary-Gonadal Axis; I.P., Intraperitoneal; ICV, Intracerebroventricular; NTS, Nucleus Tractus Solitarius; OT, Oxytocin; OTA, Antagonist Atosiban; OTRs, Oxytocin Receptors; Oxytocin; PCOS, Polycystic Ovary Syndrome; PVN, Paraventricular Nuclei; SEM, Standard Error of Mean; SIM1, Single Minded 1 Gene; SON, Supraoptic Nuclei; VP, Vasopressin; VTA, Ventral Tegmental Area

DOI:  https://doi.org/10.1016/j.metop.2021.100146
Life (Basel). 2021 Nov 17. pii: 1256. [Epub ahead of print]11(11):

The Pleiotropic Potential of BDNF beyond Neurons: Implication for a Healthy Mind in a Healthy Body.

Maria Carmela Di Rosa, Stefania Zimbone, Miriam Wissam Saab, Marianna Flora Tomasello.

  Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation of energy balance. BDNF and its receptor are extensively expressed in the hypothalamus, regions where peripheral signals, associated with feeding control and metabolism activation, and are integrated to elaborate anorexigenic and orexigenic effects. Thus, BDNF coordinates adaptive responses to fluctuations in energy intake and expenditure, connecting the central nervous system with peripheral tissues, including muscle, liver, and the adipose tissue in a complex operational network. This review discusses the latest literature dealing with the involvement of BDNF in the maintenance of energy balance. We have focused on the physiological and molecular mechanisms by which BDNF: (I) controls the mitochondrial function and dynamics; (II) influences thermogenesis and tissue differentiation; (III) mediates the effects of exercise on cognitive functions; and (IV) modulates insulin sensitivity and glucose transport at the cellular level. Deepening the understanding of the mechanisms exploited to maintain energy homeostasis will lay the groundwork for the development of novel therapeutical approaches to help people to maintain a healthy mind in a healthy body.

Keywords:  BDNF; energy balance; exercise; hypothalamus; metabolism; mitochondria; neurons; pleiotropic

DOI:  https://doi.org/10.3390/life11111256
Redox Biol. 2021 Nov 22. pii: S2213-2317(21)00357-8. [Epub ahead of print]48 102197

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.

Changjun Yang, Bianca P Lavayen, Lei Liu, Brian D Sanz, Kelly M DeMars, Jonathan Larochelle, Marjory Pompilus, Marcelo Febo, Yu-Yo Sun, Yi-Min Kuo, Mansour Mohamadzadeh, Susan A Farr, Chia-Yi Kuan, Andrew A Butler, Eduardo Candelario-Jalil.

  Adropin is a highly-conserved peptide that has been shown to preserve endothelial barrier function. Blood-brain barrier (BBB) disruption is a key pathological event in cerebral ischemia. However, the effects of adropin on ischemic stroke outcomes remain unexplored. Hypothesizing that adropin exerts neuroprotective effects by maintaining BBB integrity, we investigated the role of adropin in stroke pathology utilizing loss- and gain-of-function genetic approaches combined with pharmacological treatment with synthetic adropin peptide. Long-term anatomical and functional outcomes were evaluated using histology, MRI, and a battery of sensorimotor and cognitive tests in mice subjected to ischemic stroke. Brain ischemia decreased endogenous adropin levels in the brain and plasma. Adropin treatment or transgenic adropin overexpression robustly reduced brain injury and improved long-term sensorimotor and cognitive function in young and aged mice subjected to ischemic stroke. In contrast, genetic deletion of adropin exacerbated ischemic brain injury, irrespective of sex. Mechanistically, adropin treatment reduced BBB damage, degradation of tight junction proteins, matrix metalloproteinase-9 activity, oxidative stress, and infiltration of neutrophils into the ischemic brain. Adropin significantly increased phosphorylation of endothelial nitric oxide synthase (eNOS), Akt, and ERK1/2. While adropin therapy was remarkably protective in wild-type mice, it failed to reduce brain injury in eNOS-deficient animals, suggesting that eNOS is required for the protective effects of adropin in stroke. These data provide the first causal evidence that adropin exerts neurovascular protection in stroke through an eNOS-dependent mechanism. We identify adropin as a novel neuroprotective peptide with the potential to improve stroke outcomes.

Keywords:  Adropin; Blood-brain barrier; Endothelial nitric oxide synthase; Ischemic stroke; Neurobehavioral tests; Neurovascular unit; Permanent middle cerebral artery occlusion

DOI:  https://doi.org/10.1016/j.redox.2021.102197
Brain Sci. 2021 Oct 28. pii: 1437. [Epub ahead of print]11(11):

Connection Lost, MAM: Errors in ER-Mitochondria Connections in Neurodegenerative Diseases.

Ashu Johri, Abhishek Chandra.

  Mitochondria associated membranes (MAMs), as the name suggests, are the membranes that physically and biochemically connect mitochondria with endoplasmic reticulum. MAMs not only structurally but also functionally connect these two important organelles within the cell which were previously thought to exist independently. There are multiple points of communication between ER-mitochondria and MAMs play an important role in both ER and mitochondria functions such as Ca2+ homeostasis, proteostasis, mitochondrial bioenergetics, movement, and mitophagy. The number of disease-related proteins and genes being associated with MAMs has been continually on the rise since its discovery. There is an overwhelming overlap between the biochemical functions of MAMs and processes affected in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Thus, MAMs have received well-deserving and much delayed attention as modulators for ER-mitochondria communication and function. This review briefly discusses the recent progress made in this now fast developing field full of promise for very exciting future therapeutic discoveries.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondria associated membranes (MAMs)

DOI:  https://doi.org/10.3390/brainsci11111437
Biomedicines. 2021 Nov 05. pii: 1625. [Epub ahead of print]9(11):

Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions.

João Duarte Magalhães, Lígia Fão, Rita Vilaça, Sandra Morais Cardoso, Ana Cristina Rego.

  Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of evidence that associate protein misfolding and mitochondrial dysfunction in the etiology of Alzheimer's, Parkinson's, and Huntington's diseases. Macroautophagy has been implicated in the degradation of different protein aggregates such as Aβ, tau, alpha-synuclein (α-syn), and mutant huntingtin (mHtt) and in the clearance of dysfunctional mitochondria. Taking these into consideration, targeting autophagy might represent an effective therapeutic strategy to eliminate protein aggregates and to improve mitochondrial function in these disorders. The present review describes our current understanding on the role of macroautophagy in neurodegenerative disorders and focuses on possible strategies for its therapeutic modulation.

Keywords:  autophagy; mitophagy mitochondrial dysfunction; mutant proteins; neurodegenerative disorders; therapeutic strategies

DOI:  https://doi.org/10.3390/biomedicines9111625
Neurochem Res. 2021 Nov 24.

Biochemical Alterations in White Matter Tracts of the Aging Mouse Brain Revealed by FTIR Spectroscopy Imaging.

Kendra L Furber, R J Scott Lacombe, Sally Caine, Merlin P Thangaraj, Stuart Read, Scott M Rosendahl, Richard P Bazinet, Bogdan F Popescu, Adil J Nazarali.

  White matter degeneration in the central nervous system (CNS) has been correlated with a decline in cognitive function during aging. Ultrastructural examination of the aging human brain shows a loss of myelin, yet little is known about molecular and biochemical changes that lead to myelin degeneration. In this study, we investigate myelination across the lifespan in C57BL/6 mice using electron microscopy and Fourier transform infrared (FTIR) spectroscopic imaging to better understand the relationship between structural and biochemical changes in CNS white matter tracts. A decrease in the number of myelinated axons was associated with altered lipid profiles in the corpus callosum of aged mice. FTIR spectroscopic imaging revealed alterations in functional groups associated with phospholipids, including the lipid acyl, lipid ester and phosphate vibrations. Biochemical changes in white matter were observed prior to structural changes and most predominant in the anterior regions of the corpus callosum. This was supported by biochemical analysis of fatty acid composition that demonstrated an overall trend towards increased monounsaturated fatty acids and decreased polyunsaturated fatty acids with age. To further explore the molecular mechanisms underlying these biochemical alterations, gene expression profiles of lipid metabolism and oxidative stress pathways were investigated. A decrease in the expression of several genes involved in glutathione metabolism suggests that oxidative damage to lipids may contribute to age-related white matter degeneration.

Keywords:  Aging; Corpus callosum; FTIR spectroscopy imaging; Lipid metabolism; Myelin; Oxidative stress; Phospholipid

DOI:  https://doi.org/10.1007/s11064-021-03491-y
Mol Cell Proteomics. 2021 Nov 19. pii: S1535-9476(21)00152-3. [Epub ahead of print] 100180

Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease with Severe Reactive Gliosis.

Michael R Heaven, Anthony W Herren, Daniel L Flint, Natasha L Pacheco, Jiangtao Li, Alice Tang, Fatima Khan, James E Goldman, Brett S Phinney, Michelle L Olsen.

  Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild type mice confirmed upregulation of the glutathione metabolism pathway, and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway which had not been reported previously in AxD. Relative protein level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8 deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant 4-fold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located which was not observed in the GFAPTg;Gfap+/R236H mice.

Keywords:  Alexander disease; Fabp7; Ugt8; astrocytes; reactive gliosis

DOI:  https://doi.org/10.1016/j.mcpro.2021.100180
Int J Environ Res Public Health. 2021 Nov 19. pii: 12159. [Epub ahead of print]18(22):

Associations between Brain Reserve Proxies and Clinical Progression in Alzheimer's Disease Dementia.

Hyung-Jun Yoon, Seung-Gon Kim, Sang Hoon Kim, Jong Inn Woo, Eun Hyun Seo, For The Alzheimer's Disease Neuroimaing Initiative.

  The purpose of this study was to investigate whether brain and cognitive reserves were associated with the clinical progression of AD dementia. We included participants with AD dementia from the Alzheimer's Disease Neuroimaging Initiative, provided they were followed up at least once, and candidate proxies for cognitive (education for early-life reserve and Adult Reading Test for late-life reserve) or brain reserve (intracranial volume [ICV] for early-life reserve and the composite value of [18F] fluorodeoxyglucose positron emission tomography regions of interest (FDG-ROIs) for late-life reserve) were available. The final analysis included 120 participants. Cox proportional hazards model revealed that FDG-ROIs were the only significant predictor of clinical progression. Subgroup analysis revealed a significant association between FDG-ROIs and clinical progression only in the larger ICV group (HR = 0.388, p = 0.028, 95% CI 0.167-0.902). Our preliminary findings suggest that relatively preserved cerebral glucose metabolism might delay further clinical progression in AD dementia, particularly in the greater ICV group. In addition to ICV, cerebral glucose metabolism could play an important role as a late-life brain reserve in the process of neurodegeneration. Distinguishing between early- and late-life reserves, and considering both proxies simultaneously, would provide a wider range of factors associated with the prognosis of AD dementia.

Keywords:  Alzheimer’s disease; brain reserve; cerebral glucose metabolism; clinical progression; cognitive reserve; dementia

DOI:  https://doi.org/10.3390/ijerph182212159
Int J Mol Sci. 2021 Nov 13. pii: 12282. [Epub ahead of print]22(22):

Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies.

Paulina Cieślik, Anna Siekierzycka, Adrianna Radulska, Agata Płoska, Grzegorz Burnat, Piotr Brański, Leszek Kalinowski, Joanna M Wierońska.

  MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.

Keywords:  ADMA; Alzheimer’s disease; DDAH1; L-arginine; MK-801; NMMA; S-nitrosylation; SDAMA; cGMP; schizophrenia; scopolamine

DOI:  https://doi.org/10.3390/ijms222212282
Antioxidants (Basel). 2021 Oct 27. pii: 1702. [Epub ahead of print]10(11):

Induction of the Nrf2 Pathway by Sulforaphane Is Neuroprotective in a Rat Temporal Lobe Epilepsy Model.

Sereen Sandouka, Tawfeeq Shekh-Ahmad.

  Epilepsy is a chronic disease of the brain that affects over 65 million people worldwide. Acquired epilepsy is initiated by neurological insults, such as status epilepticus, which can result in the generation of ROS and induction of oxidative stress. Suppressing oxidative stress by upregulation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown to be an effective strategy to increase endogenous antioxidant defences, including in brain diseases, and can ameliorate neuronal damage and seizure occurrence in epilepsy. Here, we aim to test the neuroprotective potential of a naturally occurring Nrf2 activator sulforaphane, in in vitro epileptiform activity model and a temporal lobe epilepsy rat model. Sulforaphane significantly decreased ROS generation during epileptiform activity, restored glutathione levels, and prevented seizure-like activity-induced neuronal cell death. When given to rats after 2 h of kainic acid-induced status epilepticus, sulforaphane significantly increased the expression of Nrf2 and related antioxidant genes, improved oxidative stress markers, and increased the total antioxidant capacity in both the plasma and hippocampus. In addition, sulforaphane significantly decreased status epilepticus-induced neuronal cell death. Our results demonstrate that Nrf2 activation following an insult to the brain exerts a neuroprotective effect by reducing neuronal death, increasing the antioxidant capacity, and thus may also modify epilepsy development.

Keywords:  Nrf2-KEAP1 pathway; SFN; epilepsy; epileptogenesis; oxidative stress

DOI:  https://doi.org/10.3390/antiox10111702
Stroke. 2021 Dec;52(12): 4043-4053

Sirtuin 5-Mediated Lysine Desuccinylation Protects Mitochondrial Metabolism Following Subarachnoid Hemorrhage in Mice.

Zhi-Peng Xiao, Tao Lv, Pin-Pin Hou, Anatol Manaenko, Yuandong Liu, Yichao Jin, Li Gao, Feng Jia, Yang Tian, Peiying Li, John H Zhang, Qin Hu, Xiaohua Zhang.

  BACKGROUND AND PURPOSE: Sirt5 (Sirtuin 5) desuccinylates multiple metabolic enzymes and plays an important role in maintaining energy homeostasis. The goal of this study was to determine whether Sirt5-mediated desuccinylation restores the energy metabolism and protects brain against subarachnoid hemorrhage (SAH).METHODS: Male C57BL/6 or Sirt5-/- mice were used. The endovascular perforation SAH model was applied. Protein lysine succinylation in the brain cortex was examined using liquid chromatography-tandem mass spectrometry analysis. The brain metabolism was evaluated by measurement of brain pH as well as ATP and reactive oxygen species level. Neuronal cell death and neurobehavioral deficits were assessed 24 hours after SAH. The expression and desuccinylation activity of Sirt5, lysine succinylation of citrate synthase and ATP synthase subunits were investigated by Western blot, immunohistochemistry, and ELISA in SAH mice and patients. Furthermore, the benefits of resveratrol-mediated Sirt5 activation were investigated.
RESULTS: A total of 211 lysine succinylation sites were differentially expressed on 170 proteins in mice brain after SAH. Thirty-nine percent of these succinylated proteins were localized in mitochondria and they are related to energy metabolism. SAH caused a decrease of Sirt5 expression and succinylated citrate synthase as well as the subunits of ATP synthase, subsequently lowered brain pH, reduced ATP and increased reactive oxygen species production, leading to neuronal cell death, and neurological deficits. Knockdown of Sirt5 aggravated SAH-induced effects, mentioned above. Administration of resveratrol resulted in activation of Sirt5. The activation was accompanied both with restoration of the mitochondrial metabolism and alleviation of early brain injury as well as with desuccinylating citrate synthase and ATP synthase.
CONCLUSIONS: Protein lysine succinylation is a biochemical hallmark of metabolic crisis after SAH, and disruption of lysine succinylation through activation of Sirt5 might be a promising therapeutic strategy for the treatment of SAH.

Keywords:  brain injury; lysine; metabolism; sirtuins; subarachnoid hemorrhage

DOI:  https://doi.org/10.1161/STROKEAHA.121.034850
Ecotoxicol Environ Saf. 2021 Nov 18. pii: S0147-6513(21)01047-2. [Epub ahead of print]228 112935

Changes in metabolomics and lipidomics in brain tissue and their correlations with the gut microbiome after chronic food-derived arsenic exposure in mice.

Chenfei Wang, Hongyu Deng, Dongbin Wang, Jiating Wang, Hairong Huang, Jiayi Qiu, Yinfei Li, Tangbin Zou, Lianxian Guo.

  Arsenic can cause neurodegenerative diseases of the brain, but the definite mechanism is still unknown. In this study, to discuss the disturbances on brain metabolome and lipidome under subchronic arsenic exposure, we treated mice with the arsenic-containing feed (concentration of total arsenic = 30 mg/kg) prepared in accordance with the proportion of rice arsenicals for 16 weeks and performed metabolomics and lipidomics studies respectively using UHPLC-Triple-TOF-MS/MS and UHPLC-Q Exactive Focus MS/MS on mice brain. In addition, the distributions of arsenical metabolites along the feed-gut-blood-brain chain were analyzed by ICP-MS and HPLC-ICP-MS, and fecal microbial variations were investigated by 16 s sequencing. The data showed that although only a tiny amount of arsenic (DMA=0.101 mg/kg, uAs=0.071 mg/kg) enters the brain through the blood-brain barrier, there were significant changes in brain metabolism, including 118 metabolites and 17 lipids. These different metabolites were involved in 30 distinct pathways, including glycometabolism, and metabolisms of lipid, nucleic acid, and amino acid were previously reported to be correlated with neurodegenerative diseases. Additionally, these different metabolites were significantly correlated with 12 gut bacterial OTUs, among which Lachnospiraceae, Muribaculaceae, Ruminococcaceae, and Erysipelotrichaceae were also previously reported to be related to the distortion of metabolism, indicating that the disturbance of metabolism in the brain may be associated with the disturbance of gut microbes induced by arsenic. Thus, the current study demonstrated that the brain metabolome and lipidome were significantly disturbed under subchronic arsenic exposure, and the disturbances also significantly correlated with some gut microbiome and may be associated with neurodegenerative diseases. Although preliminary, the results shed some light on the pathophysiology of arsenic-caused neurodegenerative diseases.

Keywords:  Arsenic; Brain; Gut microbiome; Lipidomics; Metabolomics

DOI:  https://doi.org/10.1016/j.ecoenv.2021.112935