bims-medebr 2021-12-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2021–12–26
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.
Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model.
The role of fatty acid amide hydrolase enzyme inhibitors in Alzheimer's disease.
The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB.
Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.
Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine.
Surface Properties of Synaptosomes in the Presence of L-Glutamic and Kainic Acids: In Vitro Alteration of the ATPase and Acetylcholinesterase Activities.
Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.
Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives.
A Tale of Two Systems: Lessons Learned from Female Mid-Life Aging with Implications for Alzheimer's Prevention & Treatment.
Cholesterol Dysmetabolism in Alzheimer's Disease: A Starring Role for Astrocytes?
Protection of Cholinergic Neurons against Zinc Toxicity by Glial Cells in Thiamine-Deficient Media.
Creatine transporter deficient rat model shows motor dysfunction, cerebellar alterations and muscle creatine deficiency without muscle atrophy.
Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.
RalA, PLD and mTORC1 Are Required for Kinase-Independent Pathways in DGKβ-Induced Neurite Outgrowth.
The Novel Monoacylglycerol Lipase Inhibitor MJN110 Suppresses Neuroinflammation, Normalizes Synaptic Composition and Improves Behavioral Performance in the Repetitive Traumatic Brain Injury Mouse Model.
Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.
Alpha/Beta-Hydrolase Domain-Containing 6: Signaling and Function in the Central Nervous System.
The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models.
The dorsal hippocampal protein targeting to glycogen maintains ionotropic glutamate receptor subunits expression and contributes to working and short-term memories in mice.

Nat Commun. 2021 Dec 21. 12(1): 7362

Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.

Mergim Ramosaj, Sofia Madsen, Vanille Maillard, Valentina Scandella, Daniel Sudria-Lopez, Naoya Yuizumi, Ludovic Telley, Marlen Knobloch.

Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for NSPC proliferation, whereas break-down of lipids has been shown to regulate NSPC quiescence. Despite their central role for cellular lipid metabolism, the role of lipid droplets (LDs), the lipid storing organelles, in NSPCs remains underexplored. Here we show that LDs are highly abundant in adult mouse NSPCs, and that LD accumulation is significantly altered upon fate changes such as quiescence and differentiation. NSPC proliferation is influenced by the number of LDs, inhibition of LD build-up, breakdown or usage, and the asymmetric inheritance of LDs during mitosis. Furthermore, high LD-containing NSPCs have increased metabolic activity and capacity, but do not suffer from increased oxidative damage. Together, these data indicate an instructive role for LDs in driving NSPC behaviour.

DOI: https://doi.org/10.1038/s41467-021-27365-7
Int J Mol Sci. 2021 Dec 20. pii: 13629. [Epub ahead of print]22(24):

Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model.

Ola Gutziet, Roee Iluz, Hila Ben Asher, Linoy Segal, Dikla Ben Zvi, Yuval Ginsberg, Nizar Khatib, Osnat Zmora, Michael G Ross, Zeev Weiner, Ron Beloosesky.

  Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.

Keywords:  N-Acetyl Cysteine; brain injury; hypoxia; inflammation; oxidative stress; sensorimotor dysfunction

DOI:  https://doi.org/10.3390/ijms222413629
Cell Biochem Funct. 2021 Dec 21.

The role of fatty acid amide hydrolase enzyme inhibitors in Alzheimer's disease.

Smita Jain, Akansha Bisht, Kanika Verma, Swarnima Negi, Sarvesh Paliwal, Swapnil Sharma.

  Fatty acid amide hydrolase (FAAH) is a prominent enzyme of the endocannabinoid system that degrades endogenous cannabinoid anandamide and oleamide. These lipid amides are involved in reducing neuroinflammation, pain and regulation of other neurological-related activities including feeding behaviours, sleep patterns, body temperature, memory processes and locomotory activity. Many of these activities are affected in most neurological disorders. Increased levels of brain FAAH expressions are speculated to correlate with decreased levels of lipid amides and increased AD-related symptoms. Thus, inhibition of FAAH shows promising potential in amelioration of symptoms associated with Alzheimer's disease (AD). The review aims at establishing the detrimental role of increased FAAH expression in AD and highlights the translational potential and therapeutic application of FAAH inhibitors in AD.

Keywords:  Alzheimer's disease; cognition; fatty acid amide hydrolase; neuroinflammation; synaptic plasticity

DOI:  https://doi.org/10.1002/cbf.3680
Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01637-5. [Epub ahead of print]37(12): 110141

The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB.

Danila Di Meo, Priyadarshini Ravindran, Tanmay Sadhanasatish, Pratibha Dhumale, Andreas W Püschel.

  Neurons are highly polarized cells that display characteristic differences in the organization of their organelles in axons and dendrites. The kinases SadA and SadB (SadA/B) promote the formation of distinct axonal and dendritic extensions during the development of cortical and hippocampal neurons. Here, we show that SadA/B are required for the specific dynamics of axonal mitochondria. Ankyrin B (AnkB) stimulates the activity of SadA/B that function as regulators of mitochondrial dynamics through the phosphorylation of tau. Suppression of SadA/B or AnkB in cortical neurons induces the elongation of mitochondria by disrupting the balance of fission and fusion. SadA/B-deficient neurons show an accumulation of hyper-fused mitochondria and activation of the integrated stress response (ISR). The normal dynamics of axonal mitochondria could be restored by mild actin destabilization. Thus, the elongation after loss of SadA/B results from an excessive stabilization of actin filaments and reduction of Drp1 recruitment to mitochondria.

Keywords:  Ankyrin; Brsk1; Brsk2; Drp1; F-actin; Mapt; hyperfusion; mitochondrial dynamics; mitochondrial fission; neuronal polarity

DOI:  https://doi.org/10.1016/j.celrep.2021.110141
Int J Mol Sci. 2021 Dec 15. pii: 13470. [Epub ahead of print]22(24):

Insulin-Induced Recurrent Hypoglycemia Up-Regulates Glucose Metabolism in the Brain Cortex of Chemically Induced Diabetic Rats.

Susana Cardoso, Paula I Moreira.

  Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the metabolic alterations induced by recurrent hypoglycemia in the context of long-term hyperglycemia to further comprehend the effects beyond brain harm. To this end, chemically induced diabetic rats underwent a protocol of repeatedly insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, the pentose phosphate pathway and the Krebs cycle was measured by spectrophotometry in extracts or isolated mitochondria from brain cortical tissue. Western blot analysis was used to determine the protein content of glucose and monocarboxylate transporters, players in the insulin signaling pathway and mitochondrial biogenesis and dynamics. We observed that recurrent hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and the protein levels of mitochondrial transcription factor A (TFAM). Both insults increased the nuclear factor erythroid 2-related factor 2 (NRF2) protein content and induced divergent effects in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be down-regulated, and glycogen synthase kinase 3 beta (GSK3β) was found to be activated through both decreased phosphorylation at Ser9 and increased phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response element-binding protein (CREB), which plays a key role in neuronal plasticity and memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide experimental evidence that recurrent hypoglycemia, in the context of chronic hyperglycemia, has the capacity to evoke coordinated adaptive responses in the brain cortex that will ultimately contribute to sustaining brain cell health.

Keywords:  brain cortex; chemically induced diabetes; glucose metabolism; mitochondria; recurrent hypoglycemia; signaling pathways

DOI:  https://doi.org/10.3390/ijms222413470
Metabolites. 2021 Nov 29. pii: 813. [Epub ahead of print]11(12):

Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine.

Takeshi Hashimoto, Hayato Tsukamoto, Soichi Ando, Shigehiko Ogoh.

  It has been well established in epidemiological studies and randomized controlled trials that habitual exercise is beneficial for brain health, such as cognition and mental health. Generally, it may be reasonable to say that the physiological benefits of acute exercise can prevent brain disorders in late life if such exercise is habitually/chronically conducted. However, the mechanisms of improvement in brain function via chronic exercise remain incompletely understood because such mechanisms are assumed to be multifactorial, such as the adaptation of repeated acute exercise. This review postulates that cerebral metabolism may be an important physiological factor that determines brain function. Among metabolites, the provision of lactate to meet elevated neural activity and regulate the cerebrovascular system and redox states in response to exercise may be responsible for exercise-enhanced brain health. Here, we summarize the current knowledge regarding the influence of exercise on brain health, particularly cognitive performance, with the underlying mechanisms by means of lactate. Regarding the influence of chronic exercise on brain function, the relevance of exercise intensity and modality, particularly high-intensity interval exercise, is acknowledged to induce "metabolic myokine" (i.e., lactate) for brain health.

Keywords:  angiogenesis; brain-derived neurotrophic factor; cerebral blood flow; executive function; insulin-like growth factor-1; mental health; neurogenesis; nicotinamide adenine dinucleotide hydrate; vascular endothelial growth factor

DOI:  https://doi.org/10.3390/metabo11120813
Membranes (Basel). 2021 Dec 17. pii: 987. [Epub ahead of print]11(12):

Surface Properties of Synaptosomes in the Presence of L-Glutamic and Kainic Acids: In Vitro Alteration of the ATPase and Acetylcholinesterase Activities.

Virjinia Doltchinkova, Nevena Mouleshkova, Victoria Vitkova.

  Morphologically and functionally identical to brain synapses, the nerve ending particles synaptosomes are biochemically derived membrane structures responsible for the transmission of neural information. Their surface and mechanical properties, measured in vitro, provide useful information about the functional activity of synapses in the brain in vivo. Glutamate and kainic acid are of particular interest because of their role in brain pathology (including causing seizure, migraine, ischemic stroke, aneurysmal subarachnoid hemorrhage, intracerebral hematoma, traumatic brain injury and stroke). The effects of the excitatory neurotransmitter L-glutamic acid and its agonist kainic acid are tested on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic membranes prepared from the cerebral cortex of rat brain tissue. The surface parameters of synaptosome preparations from the cerebral cortex in the presence of L-glutamic and kainic acids are studied by microelectrophoresis for the first time. The studied neurotransmitters promote a significant increase in the electrophoretic mobility and surface electrical charge of synaptosomes at 1-4 h after isolation. The measured decrease in the bending modulus of model bimolecular membranes composed of monounsaturated lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine provides evidence for softer membranes in the presence of L-glutamate. Kainic acid does not affect membrane mechanical stability even at ten-fold higher concentrations. Both the L-glutamic and kainic acids reduce acetylcholinesterase activity and deviation from the normal functions of neurotransmission in synapses is presumed. The presented results regarding the modulation of the enzyme activity of synaptic membranes and surface properties of synaptosomes are expected by biochemical and biophysical studies to contribute to the elucidation of the molecular mechanisms of neurotransmitters/agonists' action on membranes.

Keywords:  L-glutamate; bending elasticity; electrophoretic mobility; enzyme activity; kainic acid; surface electrical charge; synaptosomes

DOI:  https://doi.org/10.3390/membranes11120987
Curr Oncol. 2021 Dec 01. 28(6): 5041-5053

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

Astrid Ellen Grams, Stephanie Mangesius, Ruth Steiger, Ivan Radovic, Andreas Rietzler, Lisa Maria Walchhofer, Malik Galijašević, Julian Mangesius, Martha Nowosielski, Christian Franz Freyschlag, Johannes Kerschbaumer, Elke Ruth Gizewski.

  Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably "normal-appearing" brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest "contrast-enhancing (CE) tumor" (if present), "adjacent to the (former) tumor", "ipsilateral distant" hemisphere, and "contralateral" hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to "normalize" under therapy. In different "normal-appearing" brain areas of GB patients, the energy and membrane metabolism either "normalized" or were "disturbed", in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

Keywords:  ATP; cerebral energy metabolism; chemoradiation; glioblastoma; normal-appearing brain tissue; phosphorous magnetic resonance spectroscopy (31P-MRS); tumor infiltration

DOI:  https://doi.org/10.3390/curroncol28060424
Antioxidants (Basel). 2021 Dec 18. pii: 2012. [Epub ahead of print]10(12):

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives.

Silvia Martini, Laura Castellini, Roberta Parladori, Vittoria Paoletti, Arianna Aceti, Luigi Corvaglia.

  Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

Keywords:  brain injury; free radicals; hypoxic-ischemic encephalopathy; intraventricular hemorrhage; neonate; oxidative stress; perinatal asphyxia; periventricular leukomalacia; preterm infants; white matter injury

DOI:  https://doi.org/10.3390/antiox10122012
Ageing Res Rev. 2021 Dec 17. pii: S1568-1637(21)00289-0. [Epub ahead of print] 101542

A Tale of Two Systems: Lessons Learned from Female Mid-Life Aging with Implications for Alzheimer's Prevention & Treatment.

Aarti Mishra, Yiwei Wang, Fei Yin, Francesca Vitali, Kathleen E Rodgers, Maira Soto, Lisa Mosconi, Tian Wang, Roberta D Brinton.

  Neurological aging is frequently viewed as a linear process of decline, whereas in reality, it is a dynamic non-linear process. The dynamic nature of neurological aging is exemplified during midlife in the female brain. To investigate fundamental mechanisms of midlife aging that underlie risk for development of Alzheimer's disease (AD) in late life, we investigated the brain at greatest risk for the disease, the aging female brain. Outcomes of our research indicate that mid-life aging in the female is characterized by the emergence of three phases: early chronological (pre-menopause), endocrinological (peri-menopause) and late chronological (post-menopause) aging. The endocrinological aging program is sandwiched between early and late chronological aging. Throughout the three stages of midlife aging, two systems of biology, metabolic and immune, are tightly integrated through a network of signaling cascades. The network of signaling between these two systems of biology underlie an orchestrated sequence of adaptative starvation responses that shift the brain from near exclusive dependence on a single fuel, glucose, to utilization of an auxiliary fuel derived from lipids, ketone bodies. The dismantling of the estrogen control of glucose metabolism during mid-life aging is a critical contributor to the shift in fuel systems and emergence of dynamic neuroimmune phenotype. The shift in fuel reliance, puts the largest reservoir of local fatty acids, white matter, at risk for catabolism as a source of lipids to generate ketone bodies through astrocytic beta oxidation. APOE4 genotype accelerates the tipping point for emergence of the bioenergetic crisis. While outcomes derived from research conducted in the female brain are not directly translatable to the male brain, the questions addressed in a female centric program of research are directly applicable to investigation of the male brain. Like females, males with AD exhibit deficits in the bioenergetic system of the brain, activation of the immune system and hallmark Alzheimer's pathologies. The drivers and trajectory of mechanisms underlying neurodegeneration in the male brain will undoubtedly share common aspects with the female in addition to factors unique to the male. Preclinical and clinical evidence indicate that midlife endocrine aging can also be a transitional bridge to autoimmune disorders. Collectively, the data indicate that endocrinological aging is a critical period "tipping point" in midlife which can initiate emergence of the prodromal stage of late-onset-Alzheimer's disease. Interventions that target both immune and metabolic shifts that occur during midlife aging have the potential to alter the trajectory of Alzheimer's risk in late life. Further, to achieve precision medicine for AD, chromosomal sex is a critical variable to consider along with APOE genotype, other genetic risk factors and stage of disease.

Keywords:  APOE; Aging; Alzheimer’s Disease; Inflammation; Metabolism; Sex Difference

DOI:  https://doi.org/10.1016/j.arr.2021.101542
Antioxidants (Basel). 2021 Nov 26. pii: 1890. [Epub ahead of print]10(12):

Cholesterol Dysmetabolism in Alzheimer's Disease: A Starring Role for Astrocytes?

Erica Staurenghi, Serena Giannelli, Gabriella Testa, Barbara Sottero, Gabriella Leonarduzzi, Paola Gamba.

  In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer's disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development.

Keywords:  Alzheimer’s disease; astrocyte reactivity; astrocytes; cholesterol; neurodegeneration; neuroinflammation; oxidative stress; oxysterols

DOI:  https://doi.org/10.3390/antiox10121890
Int J Mol Sci. 2021 Dec 11. pii: 13337. [Epub ahead of print]22(24):

Protection of Cholinergic Neurons against Zinc Toxicity by Glial Cells in Thiamine-Deficient Media.

Sylwia Gul-Hinc, Anna Michno, Marlena Zyśk, Andrzej Szutowicz, Agnieszka Jankowska-Kulawy, Anna Ronowska.

  Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency. The excessive cell loss is caused by Zn interference with acetyl-CoA metabolism. The aim of this work was to investigate whether and how astroglial C6 cells alleviated the neurotoxicity of Zn to cultured SN56 cells in thiamine-deficient media. Low Zn concentrations did not affect astroglial C6 and primary glial cell viability in thiamine-deficient conditions. Additionally, parameters of energy metabolism were not significantly changed. Amprolium (a competitive inhibitor of thiamine uptake) augmented thiamine pyrophosphate deficits in cells, while co-treatment with Zn enhanced the toxic effect on acetyl-CoA metabolism. SN56 cholinergic neuronal cells were more susceptible to these combined insults than C6 and primary glial cells, which affected pyruvate dehydrogenase activity and the acetyl-CoA level. A co-culture of SN56 neurons with astroglial cells in thiamine-deficient medium eliminated Zn-evoked neuronal loss. These data indicate that astroglial cells protect neurons against Zn and thiamine deficiency neurotoxicity by preserving the acetyl-CoA level.

Keywords:  acetyl-CoA; energy metabolism; thiamine pyrophosphate; zinc toxicity

DOI:  https://doi.org/10.3390/ijms222413337
J Inherit Metab Dis. 2021 Dec 22.

Creatine transporter deficient rat model shows motor dysfunction, cerebellar alterations and muscle creatine deficiency without muscle atrophy.

Lara Duran-Trio, Gabriella Fernandes-Pires, Jocelyn Grosse, Ines Soro-Arnaiz, Clothilde Roux-Petronelli, Pierre-Alain Binz, Katrien De Bock, Cristina Cudalbu, Carmen Sandi, Olivier Braissant.

Creatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Creatine Deficiency Syndromes (CDS). CDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12470
Front Aging Neurosci. 2021 ;13 766306

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.

Sandra Lizbeth Morales-Rosales, Roberto Santín-Márquez, Pedro Posadas-Rodriguez, Ruth Rincon-Heredia, Teresa Montiel, Raúl Librado-Osorio, Armando Luna-López, Nadia Alejandra Rivero-Segura, Claudio Torres, Agustina Cano-Martínez, Alejandro Silva-Palacios, Paulina Cortés-Hernández, Julio Morán, Lourdes Massieu, Mina Konigsberg.

  The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

Keywords:  aging; astrocyte; cellular senescence; mitochondria; redox state

DOI:  https://doi.org/10.3389/fnagi.2021.766306
Antioxidants (Basel). 2021 Dec 14. pii: 1991. [Epub ahead of print]10(12):

The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.

Janine Mett.

  Alzheimer's disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

Keywords:  Alzheimer’s disease; amyloid-β; antioxidants; decanoic acid; docosahexaenoic acid; eicosapentaenoic acid; energy metabolism; medium chain fatty acids; oxidative stress; polyunsaturated fatty acids

DOI:  https://doi.org/10.3390/antiox10121991
Biomolecules. 2021 Dec 02. pii: 1814. [Epub ahead of print]11(12):

RalA, PLD and mTORC1 Are Required for Kinase-Independent Pathways in DGKβ-Induced Neurite Outgrowth.

Takuya Kano, Ryosuke Tsumagari, Akio Nakashima, Ushio Kikkawa, Shuji Ueda, Minoru Yamanoue, Nobuyuki Takei, Yasuhito Shirai.

  Diacylglycerol kinase β (DGKβ) is an enzyme that converts diacylglycerol to phosphatidic acid and is mainly expressed in the cerebral cortex, hippocampus and striatum. We previously reported that DGKβ induces neurite outgrowth and spinogenesis, contributing to higher brain functions, including emotion and memory. To elucidate the mechanisms involved in neuronal development by DGKβ, we investigated the importance of DGKβ activity in the induction of neurite outgrowth using human neuroblastoma SH-SY5Y cells. Interestingly, both wild-type DGKβ and the kinase-negative (KN) mutant partially induced neurite outgrowth, and these functions shared a common pathway via the activation of mammalian target of rapamycin complex 1 (mTORC1). In addition, we found that DGKβ interacted with the small GTPase RalA and that siRNA against RalA and phospholipase D (PLD) inhibitor treatments abolished DGKβKN-induced neurite outgrowth. These results indicate that binding of RalA and activation of PLD and mTORC1 are involved in DGKβKN-induced neurite outgrowth. Taken together with our previous reports, mTORC1 is a key molecule in both kinase-dependent and kinase-independent pathways of DGKβ-mediated neurite outgrowth, which is important for higher brain functions.

Keywords:  RalA; diacylglycerol kinase; mammalian target of rapamycin; neurite; phosphatidic acid; phospholipase D (PLD)

DOI:  https://doi.org/10.3390/biom11121814
Cells. 2021 Dec 08. pii: 3454. [Epub ahead of print]10(12):

The Novel Monoacylglycerol Lipase Inhibitor MJN110 Suppresses Neuroinflammation, Normalizes Synaptic Composition and Improves Behavioral Performance in the Repetitive Traumatic Brain Injury Mouse Model.

Prabhuanand Selvaraj, Mikiei Tanaka, Jie Wen, Yumin Zhang.

  Modulation of the endocannabinoid system has emerged as an effective approach for the treatment of many neurodegenerative and neuropsychological diseases. However, the underlying mechanisms are still uncertain. Using a repetitive mild traumatic brain injury (mTBI) mouse model, we found that there was an impairment in locomotor function and working memory within two weeks post-injury, and that treatment with MJN110, a novel inhibitor of the principal 2-arachidononyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase dose-dependently ameliorated those behavioral changes. Spatial learning and memory deficits examined by Morris water maze between three and four weeks post-TBI were also reversed in the drug treated animals. Administration of MJN110 selectively elevated the levels of 2-AG and reduced the production of arachidonic acid (AA) and prostaglandin E2 (PGE2) in the TBI mouse brain. The increased production of proinflammatory cytokines, accumulation of astrocytes and microglia in the TBI mouse ipsilateral cerebral cortex and hippocampus were significantly reduced by MJN110 treatment. Neuronal cell death was also attenuated in the drug treated animals. MJN110 treatment normalized the expression of the NMDA receptor subunits NR2A and NR2B, the AMPA receptor subunits GluR1 and GluR2, and the GABAA receptor subunits α1, β2,3 and γ2, which were all reduced at 1, 2 and 4 weeks post-injury. The reduced inflammatory response and restored glutamate and GABA receptor expression likely contribute to the improved motor function, learning and memory in the MJN110 treated animals. The therapeutic effects of MJN110 were partially mediated by activation of CB1 and CB2 cannabinoid receptors and were eliminated when it was co-administered with DO34, a novel inhibitor of the 2-AG biosynthetic enzymes. Our results suggest that augmentation of the endogenous levels of 2-AG can be therapeutically useful in the treatment of TBI by suppressing neuroinflammation and maintaining the balance between excitatory and inhibitory neurotransmission.

Keywords:  2-arachidonyl glycerol; GABA receptors; glutamate receptors; hippocampus; microglia; monoacylglycerol lipase inhibitor; neuronal cell death; repetitive mTBI

DOI:  https://doi.org/10.3390/cells10123454
Oxid Med Cell Longev. 2021 ;2021 5586052

Directly Reprogrammed Human Neurons to Understand Age-Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration.

Camila Gudenschwager, Isadora Chavez, Cesar Cardenas, Christian Gonzalez-Billault.

Brain aging is characterized by several molecular and cellular changes grouped as the hallmarks or pillars of aging, including organelle dysfunction, metabolic and nutrition-sensor changes, stem cell attrition, and macromolecular damages. Separately and collectively, these features degrade the most critical neuronal function: transmission of information in the brain. It is widely accepted that aging is the leading risk factor contributing to the onset of the most prevalent pathological conditions that affect brain functions, such as Alzheimer's, Parkinson's, and Huntington's disease. One of the limitations in understanding the molecular mechanisms involved in those diseases is the lack of an appropriate cellular model that recapitulates the "aged" context in human neurons. The advent of the cellular reprogramming of somatic cells, i.e., dermal fibroblasts, to obtain directly induced neurons (iNs) and induced pluripotent stem cell- (iPSC-) derived neurons is technical sound advances that could open the avenues to understand better the contribution of aging toward neurodegeneration. In this review, we will summarize the commonalities and singularities of these two approaches for the study of brain aging, with an emphasis on the role of mitochondrial dysfunction and redox biology. We will address the evidence showing that iNs retain age-related features in contrast to iPSC-derived neurons that lose the aging signatures during the reprogramming to pluripotency, rendering iNs a powerful strategy to deepen our knowledge of the processes driving normal cellular function decline and neurodegeneration in a human adult model. We will finally discuss the potential utilization of these novel technologies to understand the differential contribution of genetic and epigenetic factors toward neuronal aging, to identify and develop new drugs and therapeutic strategies.

DOI: https://doi.org/10.1155/2021/5586052
Front Pharmacol. 2021 ;12 784202

Alpha/Beta-Hydrolase Domain-Containing 6: Signaling and Function in the Central Nervous System.

Haofuzi Zhang, Xin Li, Dan Liao, Peng Luo, Xiaofan Jiang.

  Endocannabinoid (eCB) signaling plays an important role in the central nervous system (CNS). α/β-Hydrolase domain-containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes monoacylglycerol (MAG) lipids such as endocannabinoid 2-arachidonoyl glycerol (2-AG). ABHD6 participates in neurotransmission, inflammation, brain energy metabolism, tumorigenesis and other biological processes and is a potential therapeutic target for various neurological diseases, such as traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, mental illness, and pain. This review summarizes the molecular mechanisms of action and biological functions of ABHD6, particularly its mechanism of action in the pathogenesis of neurological diseases, and provides a theoretical basis for new pharmacological interventions via targeting of ABHD6.

Keywords:  ABHD6; AMPA receptor; CPT1C; endocannabinoid system; neurological diseases

DOI:  https://doi.org/10.3389/fphar.2021.784202
Int J Mol Sci. 2021 Dec 08. pii: 13231. [Epub ahead of print]22(24):

The Endocannabinoid System in Glial Cells and Their Profitable Interactions to Treat Epilepsy: Evidence from Animal Models.

Jon Egaña-Huguet, Edgar Soria-Gómez, Pedro Grandes.

  Epilepsy is one of the most common neurological conditions. Yearly, five million people are diagnosed with epileptic-related disorders. The neuroprotective and therapeutic effect of (endo)cannabinoid compounds has been extensively investigated in several models of epilepsy. Therefore, the study of specific cell-type-dependent mechanisms underlying cannabinoid effects is crucial to understanding epileptic disorders. It is estimated that about 100 billion neurons and a roughly equal number of glial cells co-exist in the human brain. The glial population is in charge of neuronal viability, and therefore, their participation in brain pathophysiology is crucial. Furthermore, glial malfunctioning occurs in a wide range of neurological disorders. However, little is known about the impact of the endocannabinoid system (ECS) regulation over glial cells, even less in pathological conditions such as epilepsy. In this review, we aim to compile the existing knowledge on the role of the ECS in different cell types, with a particular emphasis on glial cells and their impact on epilepsy. Thus, we propose that glial cells could be a novel target for cannabinoid agents for treating the etiology of epilepsy and managing seizure-like disorders.

Keywords:  endocannabinoid system; epilepsy; glial cells; neuroinflammation

DOI:  https://doi.org/10.3390/ijms222413231
J Pharmacol Sci. 2022 Jan;pii: S1347-8613(21)00103-1. [Epub ahead of print]148(1): 108-115

The dorsal hippocampal protein targeting to glycogen maintains ionotropic glutamate receptor subunits expression and contributes to working and short-term memories in mice.

Yuki Kambe, Thu Nguyen Thi, Kohei Hashiguchi, Yoshimune Sameshima, Akira Yamashita, Takashi Kurihara, Atsuro Miyata.

  Brain glycogen metabolism is known to be involved in the learning and memory processes. Protein targeting to glycogen (PTG) is a crucial molecule for glycogenesis, and its expression level is shown to be increased in the dorsal hippocampus during fear memory acquisition and recall, suggesting that PTG may contribute to the memory process. However, its detailed role in the dorsal hippocampus remains unclear. Therefore, we knocked down the expression of PTG in the dorsal hippocampus and attempted to analyze its function behaviorally. PTG expression was found to be enriched in astrocytes. Furthermore, short hairpin RNA against PTG suppressed the expression of PTG in astrocytes. Mice with knockdown of PTG in the dorsal hippocampus showed suppressed alternation behavior in the Y-maze test and reduced memory recall at the first hour after acquisition in the passive avoidance test. Knockdown of mouse dorsal hippocampal astrocyte-specific PTG also impaired working memory in the Y-maze test. GluR1, GluR2, and NR2a subunits expressions were significantly down-regulated in the dorsal hippocampus of mice in which PTG was knocked down. These results indicate that PTG in the dorsal hippocampal astrocytes may contribute to working and short-term memories by maintaining the expression of glutamate receptor subunits.

Keywords:  Astrocytes; Ionotropic glutamate receptors; Protein targeting to glycogen; Short-term memory; Working memory

DOI:  https://doi.org/10.1016/j.jphs.2021.10.008