bims-medebr 2022-10-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–10–23
thirty-six papers selected by
Regina F. Fernández, Johns Hopkins University

Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions.
Metabolic Recruitment in Brain Tissue.
A high sucrose diet modifies brain oxylipins in a sex-dependent manner.
Lower brain glucose metabolism in normal ageing is predominantly frontal and temporal: A systematic review and pooled effect size and activation likelihood estimates meta-analyses.
Discrepant Modulating Effects of Dietary Docosahexaenoic Acid on Cerebral Lipids, Fatty Acid Transporter Expression and Soluble Beta-Amyloid Levels in ApoE-/- and C57BL/6J mice.
The pattern of brain metabolism in chronic steno-occlusive cerebral artery disease.
Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.
Spatial Regulation Control of Oxygen Metabolic Consumption in Mouse Brain.
Brain-specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury.
Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.
GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting.
Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke.
Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study.
Probing changes in brain esterified oxylipin concentrations during the early stages of pathogenesis in Alzheimer's Disease transgenic rats.
Lipids reroute mitochondria.
Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease : Cascades of Secondary Metabolic Errors Can Generate Complex Pathologies (in LSDs).
History of Previous Midlife Estradiol Treatment Permanently Alters Interactions of Brain Insulin-like Growth Factor-1 Signaling and Hippocampal Estrogen Synthesis to Enhance Cognitive Aging in a Rat Model of Menopause.
The monoacylglycerol lipase inhibitor, JZL184, has comparable effects to therapeutic hypothermia, attenuating global cerebral injury in a rat model of cardiac arrest.
Brain O-GlcNAcylation: From Molecular Mechanisms to Clinical Phenotype.
Brain insulin resistance and cognitive function: influence of exercise.
Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.
A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations.
Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
Ganglioside Microdomains on Cellular and Intracellular Membranes Regulate Neuronal Cell Fate Determination.
Synthesis of O-Linked Glycoconjugates in the Nervous System.
Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4-/- mice.
Hindbrain insulin controls feeding behavior.
Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses.
Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.
The effects of a 6-week controlled, hypocaloric ketogenic diet, with and without exogenous ketone salts, on cognitive performance and mood states in overweight and obese adults.
Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature.
Glycans and Carbohydrate-Binding/Transforming Proteins in Axon Physiology.
Mesenchymal stem cell bioenergetics and apoptosis are associated with risk for bronchopulmonary dysplasia in extremely low birth weight infants.
Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains.
Approaches to investigating metabolism in human neurodevelopment using organoids: insights from intestinal and cancer studies.
Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.

Front Hum Neurosci. 2022 ;16 846183

Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions.

Naomi Elyse Omori, Geoffrey Hubert Woo, Latt Shahril Mansor.

  Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies.

Keywords:  brain; exogenous; injury; ketones; lactate; metabolism dysfunction; neurodegenerative; traumatic

DOI:  https://doi.org/10.3389/fnhum.2022.846183
Annu Rev Physiol. 2022 Oct 21.

Metabolic Recruitment in Brain Tissue.

L F Barros, I Ruminot, T Sotelo-Hitschfeld, R Lerchundi, I Fernández-Moncada.

Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K+ that mirrors workload. Astrocytes sense K+ in exquisite fashion thanks to their unique coexpression of NBCe1 and α2β2 Na+[Formula: see text]K+ ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-021422-091035
Prostaglandins Leukot Essent Fatty Acids. 2022 Oct 08. pii: S0952-3278(22)00118-1. [Epub ahead of print]186 102506

A high sucrose diet modifies brain oxylipins in a sex-dependent manner.

Jennifer E Norman, Saivageethi Nuthikattu, Dragan Milenkovic, John C Rutledge, Amparo C Villablanca.

   BACKGROUND: Oxylipins have been implicated in many biological processes and diseases. Dysregulation of cerebral lipid homeostasis and altered lipid metabolites have been associated with the onset and progression of dementia. Although most dietary interventions have focused on modulation of dietary fats, the impact of a high sucrose diet on the brain oxylipin profile is unknown.
METHODS: Male and female C57BL/6J mice were fed a high sucrose diet (HSD, 34%) in comparison to a control low sucrose diet (LSD, 12%) for 12 weeks beginning at 20 weeks of age. The profile of 53 free oxylipins was then measured in brain by ultra-high performance liquid chromatography tandem mass spectrometry. Serum glucose and insulin were measured enzymatically. We first assessed whether there were any effects of the diet on the brain oxylipin profile, then assessed for sex differences.
RESULTS: There were no differences in fasting serum glucose between the sexes for mice fed a HSD or in fasting serum insulin levels for mice on either diet. The HSD altered the brain oxylipin profile in both sexes in distinctly different patterns: there was a reduction in three oxylipins (by 47-61%) and an increase in one oxylipin (16%) all downstream of lipoxygenase enzymes in males and a reduction in eight oxylipins (by 14-94%) mostly downstream of cyclooxygenase activity in females. 9-oxo-ODE and 6-trans-LTB4 were most influential in the separation of the oxylipin profiles by diet in male mice, whereas 5-HEPE and 12-HEPE were most influential in the separation by diet in female mice. Oxylipins 9‑hydroxy-eicosatetraenoic acid (HETE), 11-HETE, and 15-HETE were higher in the brains of females, regardless of diet.
CONCLUSION: A HSD substantially changes brain oxylipins in a distinctly sexually dimorphic manner. Results are discussed in terms of potential mechanisms and links to metabolic disease. Sex and diet effects on brain oxylipin composition may provide future targets for the management of neuroinflammatory diseases, such as dementia.

Keywords:  Brain; Dementia; High sucrose diet; Oxylipin; Sex differences

DOI:  https://doi.org/10.1016/j.plefa.2022.102506
Hum Brain Mapp. 2022 Oct 21.

Lower brain glucose metabolism in normal ageing is predominantly frontal and temporal: A systematic review and pooled effect size and activation likelihood estimates meta-analyses.

Hamish A Deery, Robert Di Paolo, Chris Moran, Gary F Egan, Sharna D Jamadar.

  This review provides a qualitative and quantitative analysis of cerebral glucose metabolism in ageing. We undertook a systematic literature review followed by pooled effect size and activation likelihood estimates (ALE) meta-analyses. Studies were retrieved from PubMed following the PRISMA guidelines. After reviewing 635 records, 21 studies with 22 independent samples (n = 911 participants) were included in the pooled effect size analyses. Eight studies with eleven separate samples (n = 713 participants) were included in the ALE analyses. Pooled effect sizes showed significantly lower cerebral metabolic rates of glucose for older versus younger adults for the whole brain, as well as for the frontal, temporal, parietal, and occipital lobes. Among the sub-cortical structures, the caudate showed a lower metabolic rate among older adults. In sub-group analyses controlling for changes in brain volume or partial volume effects, the lower glucose metabolism among older adults in the frontal lobe remained significant, whereas confidence intervals crossed zero for the other lobes and structures. The ALE identified nine clusters of lower glucose metabolism among older adults, ranging from 200 to 2640 mm3 . The two largest clusters were in the left and right inferior frontal and superior temporal gyri and the insula. Clusters were also found in the inferior temporal junction, the anterior cingulate and caudate. Taken together, the results are consistent with research showing less efficient glucose metabolism in the ageing brain. The findings are discussed in the context of theories of cognitive ageing and are compared to those found in neurodegenerative disease.

Keywords:  PET; PRISMA; ageing; brain glucose metabolism; lifespan; meta-analysis; systematic review

DOI:  https://doi.org/10.1002/hbm.26119
Neuropathol Appl Neurobiol. 2022 Oct 19. e12855

Discrepant Modulating Effects of Dietary Docosahexaenoic Acid on Cerebral Lipids, Fatty Acid Transporter Expression and Soluble Beta-Amyloid Levels in ApoE-/- and C57BL/6J mice.

Jingjing Xu, Xiaochen Huang, Yujie Guo, Xiaojun Ma, Pengfei Li, Shaobo Zhou, Chi Zhang, Rui Chen, Nicholas Van Halm-Lutterodt, Linhong Yuan.

   AIMS: The study was designed to explore the role of ApoE deficiency concomitant with dietary DHA treatment on brain β-amyloid (Aβ) and lipid levels.
METHOD: A 5-month dietary DHA intervention was conducted in ApoE-deficient mice (ApoE-/- ) and wild type C57BL/6J (C57wt) mice. The Morris water maze test was performed to assess the behaviour of the animals. The cortical contents of soluble Aβ1-40 and Aβ1-42 were detected by ELISA. Cortical fatty acid levels were detected by gas chromatography. Gene and protein expression of molecules associated with cerebral Aβ and lipid metabolism were measured using real-time PCR, Western blot and histological methods.
RESULTS: DHA treatment increased the content of cortical DHA and n-3 PUFAs, but decreased the ratio of n-6/n-3 PUFAs in ApoE-/- mice; while the content of cortical DHA, n-3 PUFAs in C57wt mice remained unchanged after DHA treatment. Fabp5 and Cd36 gene expression were significantly down-regulated in DHA-fed C57wt mice; cerebral Cd36 and Scarb1 gene expression were significantly up-regulated, while Fabp5 gene expression was down-regulated in DHA-fed ApoE-/- mice. In comparison with C57wt mice, the content of cortical soluble Aβ1-42 , TC, and LDL-C increased, while the level of HDL-C decreased in ApoE-/- mice. Interestingly, these differences were significantly reversed by DHA dietary treatment.
CONCLUSION: DHA intervention has discrepant impacts on cerebral lipids, fatty acid transporter expression and soluble Aβ levels in ApoE-/- and C57wt mice, suggesting the modifying role of ApoE status on the responses of cerebral lipids and Aβ metabolism to DHA treatment.

Keywords:  ApoE-/- Mice; Cholesterol; DHA; Lipids; β-Amyloid

DOI:  https://doi.org/10.1111/nan.12855
Ann Transl Med. 2022 Sep;10(18): 1003

The pattern of brain metabolism in chronic steno-occlusive cerebral artery disease.

Lingyan Meng, Zhaodi Huang, Hui Li.

   Background: Dispersion of gray matter and white matter and abnormal hemodynamic changes are common in patients with chronic stenosis cerebral artery disease. It is not easy to capture these abnormal changes with conventional magnetic resonance imaging (MRI). Magnetic resonance spectroscopy (MRS) is useful for obtaining metabolic information in either preclinical or clinical applications. The aim of our study was to apply MRS to non-invasively investigate changes in brain metabolism in MRI-negative patients with chronic cerebral artery steno-occlusive disease.
Methods: We performed MRS examinations with 3.0T MRI on 34 patients with severe unilateral middle cerebral artery (MCA) stenosis or occlusion without parenchymal abnormalities. Additionally, N-acetylaspartic acid (NAA), creatine (Cr), choline (Cho), NAA/Cr, and Cho/Cr in the coronal, parenchymal, and thalamic regions of the affected brain and contralateral brain were determined. The mean concentrations of NAA, Cr, Cho, NAA/Cr, and Cho/Cr in the coronal, parenchymal, and thalamic regions of the ipsilateral and contralateral brains were compared using the 2-tailed paired t-test.
Results: At the ipsilateral corona radiata and lenticular nucleus, the mean NAA was significantly lower, whereas the Cho and Cho/Cr were significantly higher than the contralateral corona radiata and lentiform nucleus (P<0.05). In addition, the creatine and NAA/Cr values in the coronal region of the affected side were significantly lower than those in the opposite side (P<0.05), but there was no significant difference between the pectin nuclei on both sides. No metabolic changes were found at the ipsilateral thalamus.
Conclusions: In this study, we demonstrated that MRS could reveal metabolic changes and that the NAA, NAA/Cr, Cho, and Cho/Cr concentration might be used as indexes for evaluating neuronal damage in the chronic steno-occlusive cerebral artery disease, treatment strategies, and treatment effectiveness.

Keywords:  Cerebral arterial steno-occlusive disease; magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS)

DOI:  https://doi.org/10.21037/atm-22-3993
Neural Regen Res. 2023 May;18(5): 1023-1024

Endocannabinoid control of neuroinflammation in traumatic brain injury by monoacylglycerol lipase in astrocytes.

Chu Chen.

DOI: https://doi.org/10.4103/1673-5374.355755
Adv Sci (Weinh). 2022 Oct 18. e2204468

Spatial Regulation Control of Oxygen Metabolic Consumption in Mouse Brain.

Lin Zhou, Xinru Li, Bin Su.

  The mammalian brain relies on significant oxygen metabolic consumption to fulfill energy supply, brain function, and neural activity. In this study, in vivo electrochemistry is combined with physiological and ethological analyses to explore oxygen metabolic consumption in an area of the mouse brain that includes parts of the primary somatosensory cortex, primary motor cortex, hippocampus, and striatum. The oxygen levels at different locations of this boundary section are spatially resolved by measuring the electrical current in vivo using ingeniously designed anti-biofouling carbon fiber microelectrodes. The characteristics of the current signals are further interpreted by simultaneously recording the physiological responses of the mice. Additionally, ethological tests are performed to validate the correlation between oxygen levels and mouse behavior. It is found that high-dose caffeine injection can evoke spatial variability in oxygen metabolic consumption between the four neighboring brain regions. It is proposed that the oxygen metabolic consumption in different brain regions is not independent of each other but is subject to spatial regulation control following the rules of "rank of brain region" and "relative distance." Furthermore, as revealed by in vivo wireless electrochemistry and ethological analysis, mice are at risk of neuronal damage from long-term intake of high-dose caffeine.

Keywords:  caffeine; in vivo electrochemistry; neighboring brain regions; oxygen metabolic consumption; spatial regulation control

DOI:  https://doi.org/10.1002/advs.202204468
Brain Pathol. 2022 Oct 21. e13126

Brain-specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury.

Heng Xu, Le-Xin Zheng, Xue-Shi Chen, Qiu-Yu Pang, Ya-Nan Yan, Rong Liu, Han-Mu Guo, Zhi-Yang Ren, Yan Yang, Zhi-Ya Gu, Cheng Gao, Yuan Gao, Cheng-Liang Luo, Ying Zhao, Ying Wang, Tao Wang, Lu-Yang Tao.

  Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.

Keywords:  ATP-binding cassette G1; bexarotene; cholesterol metabolism; neurological deficits; pyroptosis; traumatic brain injury

DOI:  https://doi.org/10.1111/bpa.13126
Mov Disord. 2022 Oct;37(10): 2099-2109

Brain Metabolic Correlates of Dopaminergic Denervation in Prodromal and Early Parkinson's Disease.

Ryul Kim, Heejung Kim, Yu Kyeong Kim, Eun Jin Yoon, Hyun Woo Nam, Beomseok Jeon, Jee-Young Lee.

   BACKGROUND: It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD).
OBJECTIVE: To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD.
METHODS: This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (denovo PD), and 28 healthy controls (HCs) who underwent two positron emission tomography scans with 18 F-fluorodeoxyglucose (all participants) and 18 F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane (except for one denovo PD patient and 15 HCs). We analyzed striatal and voxel-wise whole-brain glucose metabolism in relation to nigrostriatal dopaminergic integrity and comparatively investigated the whole-brain metabolic connectivity among the groups. We also assessed longitudinal metabolic changes against progressive dopaminergic denervation over 4 years in the iRBD group.
RESULTS: From HCs to iRBD and finally to the denovo PD, dopaminergic integrity positively correlated with metabolic activity in the caudate, whereas a negative correlation was observed in the posterior putamen. In the iRBD group, there was a metabolic increase in the inferior orbitofrontal cortex against putaminal dopaminergic denervation at baseline, but negative correlations were newly observed in the superior orbitofrontal cortex and superior frontal gyrus at the 4-year follow-up. The denovo PD group showed negative correlations in the cerebellum and fusiform gyrus. Intra- and inter-regional metabolic connectivities in the parieto-occipital cortices were enhanced in the iRBD group compared with the denovo PD and HC groups. In the iRBD group, overall metabolic connectivity was strengthened along with enhanced basal ganglia-frontal connection by advancing dopaminergic denervation.
CONCLUSIONS: Our findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Keywords:  Parkinson's disease; REM sleep behavior disorder; connectivity; dopamine; metabolic

DOI:  https://doi.org/10.1002/mds.29177
Sci Rep. 2022 Oct 21. 12(1): 17717

GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting.

M J Barahona, F Langlet, G Labouèbe, S Croizier, A Picard, Bernard Thorens, María A García-Robles.

Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

DOI: https://doi.org/10.1038/s41598-022-22489-2
Oxid Med Cell Longev. 2022 ;2022 3119649

Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke.

Eryi Sun, Jing Zhang, Yan Deng, Jun Wang, Qi Wu, Wei Chen, Xiaodong Ma, Siyuan Chen, Xin Xiang, Yujie Chen, Tairong Wu, Yang Yang, Bo Chen.

Mitophagy, the selective removal of damaged mitochondria through autophagy, is crucial for mitochondrial turnover and quality control. Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, protects mitochondria in various diseases. This study aimed to investigate the neuroprotective role of DHA in ischaemic stroke models in vitro and in vivo and its involvement in mitophagy and mitochondrial dysfunction. A mouse model of ischaemic stroke was established through middle cerebral artery occlusion (MCAO). To simulate ischaemic stroke in vitro, PC12 cells were subjected to oxygen-glucose deprivation (OGD). Immunofluorescence analysis, western blotting (WB), electron microscopy (EM), functional behavioural tests, and Seahorse assay were used for analysis. DHA treatment significantly alleviated the brain infarction volume, neuronal apoptosis, and behavioural dysfunction in mice with ischaemic stroke. In addition, DHA enhanced mitophagy by significantly increasing the number of autophagosomes and LC3-positive mitochondria in neurons. The Seahorse assay revealed that DHA increased glutamate and succinate metabolism in neurons after ischaemic stroke. JC-1 and MitoSox staining, and evaluation of ATP levels indicated that DHA-induced mitophagy alleviated reactive oxygen species (ROS) accumulation and mitochondrial injury. Mechanistically, DHA improved mitochondrial dynamics by increasing the expression of dynamin-related protein 1 (Drp1), LC3, and the mitophagy clearance protein Pink1/Parkin. Mdivi-1, a specific mitophagy inhibitor, abrogated the neuroprotective effects of DHA, indicating that DHA protected neurons by enhancing mitophagy. Therefore, DHA can protect against neuronal apoptosis after stroke by clearing the damaged mitochondria through Pink1/Parkin-mediated mitophagy and by alleviating mitochondrial dysfunction.

DOI: https://doi.org/10.1155/2022/3119649
Schizophr Bull. 2022 Oct 21. pii: sbac147. [Epub ahead of print]

Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study.

Felice Iasevoli, Luigi D'Ambrosio, Mariateresa Ciccarelli, Annarita Barone, Valeria Gaudieri, Sirio Cocozza, Giuseppe Pontillo, Arturo Brunetti, Alberto Cuocolo, Andrea de Bartolomeis, Sabina Pappatà.

   BACKGROUND AND HYPOTHESIS: Treatment resistant schizophrenia (TRS) affects almost 30% of patients with schizophrenia and has been considered a different phenotype of the disease. In vivo characterization of brain metabolic patterns associated with treatment response could contribute to elucidate the neurobiological underpinnings of TRS. Here, we used 2-[18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) to provide the first head-to-head comparative analysis of cerebral glucose metabolism in TRS patients compared to schizophrenia responder patients (nTRS), and controls. Additionally, we investigated, for the first time, the differences between clozapine responders (Clz-R) and non-responders (Clz-nR).
STUDY DESIGN: 53 participants underwent FDG-PET studies (41 patients and 12 controls). Response to conventional antipsychotics and to clozapine was evaluated using a standardized prospective procedure based on PANSS score changes. Maps of relative brain glucose metabolism were processed for voxel-based analysis using Statistical Parametric Mapping software.
STUDY RESULTS: Restricted areas of significant bilateral relative hypometabolism in the superior frontal gyrus characterized TRS compared to nTRS. Moreover, reduced parietal and frontal metabolism was associated with high PANSS disorganization factor scores in TRS (P < .001 voxel level uncorrected, P < .05 cluster level FWE-corrected). Only TRS compared to controls showed significant bilateral prefrontal relative hypometabolism, more extensive in CLZ-nR than in CLZ-R (P < .05 voxel level FWE-corrected). Relative significant hypermetabolism was observed in the temporo-occipital regions in TRS compared to nTRS and controls.
CONCLUSIONS: These data indicate that, in TRS patients, altered metabolism involved discrete brain regions not found affected in nTRS, possibly indicating a more severe disrupted functional brain network associated with disorganization symptoms.

Keywords:  antipsychotics; clozapine; dopamine; glutamate; prefrontal cortex; superior frontal gyrus

DOI:  https://doi.org/10.1093/schbul/sbac147
Neurosci Lett. 2022 Oct 18. pii: S0304-3940(22)00482-7. [Epub ahead of print] 136921

Probing changes in brain esterified oxylipin concentrations during the early stages of pathogenesis in Alzheimer's Disease transgenic rats.

Qing Shen, Kelley T Patten, Anthony Valenzuela, Pamela J Lein, Ameer Y Taha.

  Despite known pathological hallmarks of Alzheimer's Disease (AD) including neuronal loss, gliosis (inflammation), beta-amyloid plaque deposition and neurofibrillary tangle accumulation in the brain, little is known about inflammation resolution in early AD pathogenesis. In the brain, inflammation and resolution are mediated by free oxylipins which are mostly bound (i.e. esterified), and therefore must be released (i.e. become free) to exert bioactivity. Recently, we showed reductions in brain esterified pro-resolving oxylipins in a transgenic rat model of AD (TgF344-AD rat) at 15 months of age, suggesting deficits in the source and availability of free pro-resolving oxylipins. In the present study, we tested whether these changes are discernable earlier in the disease process, i.e., at age of 10 months. We observed significant reductions in esterified pro-resolving 8(9)-epoxyeicosatrienoic acid (8(9)-EpETrE), 13-hydroxy-octadecatrienoic acid (13-HOTrE) and 15-hydroxy-eicosapentaenoic acid (15-HEPE) and in pro-inflammatory 13-hydroxy-octadecadienoic acid (13-HODE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 15-deoxy-prostaglandin J2 (15-deoxy-PGJ2) and prostaglandin E2 (PGE2) in male and/or female transgenic AD rats compared to wildtype controls. These findings point to a deficit in esterified pro-resolving lipid mediators in the early stages of AD. Changes in esterified pro-inflammatory lipid mediators were confined to a few compounds between time-points, possibly due to enhanced engagement of resolution pathways with disease progression.

Keywords:  Alzheimer’s Disease; esterified oxylipins; inflammation resolution; lipid mediator; rat brain

DOI:  https://doi.org/10.1016/j.neulet.2022.136921
Nat Metab. 2022 Oct;4(10): 1218

Lipids reroute mitochondria.

Michael Attwaters.

DOI: https://doi.org/10.1038/s42255-022-00662-1
Adv Neurobiol. 2023 ;29 333-390

Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease : Cascades of Secondary Metabolic Errors Can Generate Complex Pathologies (in LSDs).

Roger Sandhoff, Konrad Sandhoff.

  Glycosphingolipids (GSLs) are a diverse group of membrane components occurring mainly on the surfaces of mammalian cells. They and their metabolites have a role in intercellular communication, serving as versatile biochemical signals (Kaltner et al, Biochem J 476(18):2623-2655, 2019) and in many cellular pathways. Anionic GSLs, the sialic acid containing gangliosides (GGs), are essential constituents of neuronal cell surfaces, whereas anionic sulfatides are key components of myelin and myelin forming oligodendrocytes. The stepwise biosynthetic pathways of GSLs occur at and lead along the membranes of organellar surfaces of the secretory pathway. After formation of the hydrophobic ceramide membrane anchor of GSLs at the ER, membrane-spanning glycosyltransferases (GTs) of the Golgi and Trans-Golgi network generate cell type-specific GSL patterns for cellular surfaces. GSLs of the cellular plasma membrane can reach intra-lysosomal, i.e. luminal, vesicles (ILVs) by endocytic pathways for degradation. Soluble glycoproteins, the glycosidases, lipid binding and transfer proteins and acid ceramidase are needed for the lysosomal catabolism of GSLs at ILV-membrane surfaces. Inherited mutations triggering a functional loss of glycosylated lysosomal hydrolases and lipid binding proteins involved in GSL degradation cause a primary lysosomal accumulation of their non-degradable GSL substrates in lysosomal storage diseases (LSDs). Lipid binding proteins, the SAPs, and the various lipids of the ILV-membranes regulate GSL catabolism, but also primary storage compounds such as sphingomyelin (SM), cholesterol (Chol.), or chondroitin sulfate can effectively inhibit catabolic lysosomal pathways of GSLs. This causes cascades of metabolic errors, accumulating secondary lysosomal GSL- and GG- storage that can trigger a complex pathology (Breiden and Sandhoff, Int J Mol Sci 21(7):2566, 2020).

Keywords:  Alzheimer; Catabolism; Degradation; Development; Endosomal pathway; Frontal lobe dementia; Ganglio-series; Ganglioside; Genetic disease; Glycolipid; Glycosphingolipid; Glycosyltransferase; Hydrolase; Intra-lysosomal luminal vesicle (ILV); Lysosomal storage disease (LSD); Lysosome; Membrane-surface; Metabolism; Neurodegenerative disease; Neuron; Organelle; Parkinson; Receptor; Secondary storage; Secretory pathway; Sphingolipid-binding protein (SAP); Sphingolipid-transfer protein; Topology

DOI:  https://doi.org/10.1007/978-3-031-12390-0_12
J Neurosci. 2022 Oct 19. 42(42): 7969-7983

History of Previous Midlife Estradiol Treatment Permanently Alters Interactions of Brain Insulin-like Growth Factor-1 Signaling and Hippocampal Estrogen Synthesis to Enhance Cognitive Aging in a Rat Model of Menopause.

Nina E Baumgartner, Shannon M McQuillen, Samantha F Perry, Sangtawan Miller, Matthieu J Maroteaux, Robert B Gibbs, Jill M Daniel.

  Across species, including humans, elevated levels of brain estrogen receptor (ER) α are associated with enhanced cognitive aging, even in the absence of circulating estrogens. In rodents, short-term estrogen treatment, such as that commonly used in the menopausal transition, results in long-term increases in ERα levels in the hippocampus, leading to enhanced memory long after termination of estrogen treatment. However, mechanisms by which increased levels of brain ERα enhances cognitive aging remain unclear. Here we demonstrate in aging female rats that insulin-like growth factor-1 (IGF-1), which can activate ER via ligand-independent mechanisms, requires concomitant synthesis of brain-derived neuroestrogens to phosphorylate ERα via MAPK signaling, ultimately resulting in enhanced memory. In a rat model of menopause involving long-term ovarian hormone deprivation, hippocampal neuroestrogen activity decreases, altering IGF-1 activity and resulting in impaired memory. However, this process is reversed by short-term estradiol treatment. Forty days of estradiol exposure following ovariectomy results in maintenance of neuroestrogen levels that persist beyond the period of hormone treatment, allowing for continued interactions between IGF-1 and neuroestrogen signaling, elevated levels of hippocampal ERα, and ultimately enhanced memory. Collectively, results demonstrate that short-term estradiol use following loss of ovarian function has long-lasting effects on hippocampal function and memory by dynamically regulating cellular mechanisms that promote activity of ERα in the absence of circulating estrogens. Translational impacts of these findings suggest lasting cognitive benefits of short-term estrogen use near menopause and highlight the importance of hippocampal ERα, independent from the role of circulating estrogens, in regulating memory in aging females.SIGNIFICANCE STATEMENT Declines in ovarian hormones following menopause coincide with increased risk of cognitive decline. Because of potential health risks, current recommendations are that menopausal estrogen therapy be limited to a few years. Long-term consequences for the brain and memory of this short-term midlife estrogen therapy are unclear. Here, in a rodent model of menopause, we determined mechanisms by which short-term midlife estrogen exposure can enhance hippocampal function and memory with cognitive benefits and molecular changes enduring long after termination of estrogen exposure. Our model indicates long-lasting benefits of maintaining hippocampal estrogen receptor function in the absence of ongoing estrogen exposure and suggests potential strategies for combating age-related cognitive decline.

Keywords:  IGF-1; aging; estrogen; hippocampus; memory; menopause

DOI:  https://doi.org/10.1523/JNEUROSCI.0588-22.2022
Biomed Pharmacother. 2022 Oct 14. pii: S0753-3322(22)01236-7. [Epub ahead of print]156 113847

The monoacylglycerol lipase inhibitor, JZL184, has comparable effects to therapeutic hypothermia, attenuating global cerebral injury in a rat model of cardiac arrest.

Jing Xu, Guanghui Zheng, Juntao Hu, Weiwei Ge, Jennifer L Bradley, Joseph P Ornato, Wanchun Tang.

  Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100β, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100β and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA).

Keywords:  Blood brain barrier; Cardiac arrest; Cerebral injury; Hypothermia; JZL184

DOI:  https://doi.org/10.1016/j.biopha.2022.113847
Adv Neurobiol. 2023 ;29 255-280

Brain O-GlcNAcylation: From Molecular Mechanisms to Clinical Phenotype.

Batuhan Uygar, Olof Lagerlöf.

  O-GlcNAc is the attachment of β-N-acetylglucosamine to the hydroxyl group of serine and threonine in nuclear and cytoplasmic proteins. It is generally not further elongated but exists as a monosaccharide that can be rapidly added or removed. Thousands of proteins involved in gene transcription, protein translation and degradation as well as the regulation of signal transduction contain O-GlcNAc. Brain is one of the tissues where O-GlcNAc is the most highly expressed and deletion of neuronal O-GlcNAc leads to death early in development. O-GlcNAc is also important for normal adult brain function, where dynamic processes like learning and memory at least in part depend on the modification of specific proteins by O-GlcNAc. Conversely, too much or too little O-GlcNAc in the brain contributes to several disorders including obesity, intellectual disability and Alzheimer's disease. In this chapter, we describe the expression and regulation of O-GlcNAc in the nervous system.

Keywords:  Alzheimer’s disease; Food intake; Learning and memory; Neurodegeneration; Nutrient sensing; O-GlcNAc; O-linked N-acetylglucosamine; Obesity; Post-translational modifications; Signaling

DOI:  https://doi.org/10.1007/978-3-031-12390-0_9
J Appl Physiol (1985). 2022 Oct 21.

Brain insulin resistance and cognitive function: influence of exercise.

Steven K Malin, Nathan R Stewart, Andrew A Ude, Brandon L Alderman.

  Exercise has systemic health benefits in people, in part, through improving whole-body insulin sensitivity. The brain is an insulin sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. While brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition. Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, we provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.

Keywords:  executive function; intranasal insulin; memory; mitochondria function; physical activity

DOI:  https://doi.org/10.1152/japplphysiol.00375.2022
Neural Regen Res. 2023 May;18(5): 991-995

Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.

Diogo Trigo, José João Vitória, Odete A B da Cruz E Silva.

  In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors (such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer's disease and Parkinson's disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.

Keywords:  Alzheimer’s disease; Parkinson’s disease; axon; energy homeostasis; glymphatic system; mitochondria; mitostasis; neurodegeneration; neuroregeneration; therapeutical strategies

DOI:  https://doi.org/10.4103/1673-5374.355750
Neurobiol Dis. 2022 Oct 13. pii: S0969-9961(22)00288-1. [Epub ahead of print]174 105896

A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations.

Víctor Valcárcel-Hernández, Marina Guillén-Yunta, Miranda Bueno-Arribas, Ana Montero-Pedrazuela, Carmen Grijota-Martínez, Suzy Markossian, Ángel García-Aldea, Frédéric Flamant, Soledad Bárez-López, Ana Guadaño-Ferraz.

  Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.

Keywords:  CRISPR/Cas9; GABAergic system; MCT8; Murine model; Thyroid hormone transport; Thyroid hormones

DOI:  https://doi.org/10.1016/j.nbd.2022.105896
Nat Chem Biol. 2022 Oct 20.

Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.

Gretchen L Seim, Steven V John, Nicholas L Arp, Zixiang Fang, David J Pagliarini, Jing Fan.

Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.

DOI: https://doi.org/10.1038/s41589-022-01153-w
Adv Neurobiol. 2023 ;29 281-304

Ganglioside Microdomains on Cellular and Intracellular Membranes Regulate Neuronal Cell Fate Determination.

Yutaka Itokazu, Robert K Yu.

  Gangliosides are sialylated glycosphingolipids (GSLs) with essential but enigmatic functions in brain activities and neural stem cell (NSC) maintenance. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of NSC activity and differentiation. The primary localization of gangliosides is on cell-surface microdomains and the drastic dose and composition changes during neural differentiation strongly suggest that they are not only important as biomarkers, but also are involved in modulating NSC fate determination. Ganglioside GD3 is the predominant species in NSCs and GD3-synthase knockout (GD3S-KO) revealed reduction of postnatal NSC pools with severe behavioral deficits. Exogenous administration of GD3 significantly restored the NSC pools and enhanced the stemness of NSCs with multipotency and self-renewal. Since morphological changes during neurogenesis require a huge amount of energy, mitochondrial functions are vital for neurogenesis. We discovered that a mitochondrial fission protein, the dynamin-related protein-1 (Drp1), as a novel GD3-binding protein, and GD3 regulates mitochondrial dynamics. Furthermore, we discovered that GM1 ganglioside promotes neuronal differentiation by an epigenetic regulatory mechanism. Nuclear GM1 binds with acetylated histones on the promoters of N-acetylgalactosaminyltransferase (GalNAcT; GM2 synthase) as well as on the NeuroD1 genes in differentiated neurons. In addition, epigenetic activation of the GalNAcT gene was detected as accompanied by an apparent induction of neuronal differentiation in NSCs responding to an exogenous supplement of GM1. GM1 is indeed localized in the nucleus where it can interact with transcriptionally active histones. Interestingly, GM1 could induce epigenetic activation of the tyrosine hydroxylase (TH) gene, with recruitment of nuclear receptor related 1 (Nurr1, also known as NR4A2), a dopaminergic neuron-associated transcription factor, to the TH promoter region. In this way, GM1 epigenetically regulates dopaminergic neuron specific gene expression. GM1 interacts with active chromatin via acetylated histones to recruit transcription factors at the nuclear periphery, resulting in changes in gene expression for neuronal differentiation. The significance is that multifunctional gangliosides modulate lipid microdomains to regulate functions of important molecules on multiple sites: the plasma membrane, mitochondrial membrane, and nuclear membrane. Versatile gangliosides could regulate functional neurons as well as sustain NSC functions via modulating protein and gene activities on ganglioside microdomains.

Keywords:  Carbohydrate; Epigenetic regulation; Ganglioside; Glycosphingolipid; Lipid membrane; Microdomain; Mitochondrion: Neural stem cell; Neural development; Neurogenesis; Neuronal differentiation; Nucleus: Plasma membrane

DOI:  https://doi.org/10.1007/978-3-031-12390-0_10
Adv Neurobiol. 2023 ;29 95-116

Synthesis of O-Linked Glycoconjugates in the Nervous System.

Jin-Ichi Inokuchi, Shinji Go, Yoshio Hirabayashi.

  Glycoproteins carrying O-linked N-acetylgalactosamine, N-acetylglucosamine, mannose, fucose, glucose, and xylose are found in the nervous system. Lipids are glycosylated by distinct glycosylation enzymes as well. Membrane lipid, ceramide, is modified by the addition of either glucose or galactose to form glycosphingolipid, galactosylceramide, or glucosylceramide. Recent careful analyses by MS have identified glucosylated lipids of cholesterol and phosphatidic acid. These O-linked carbohydrate residues are found primarily on the outer surface of the plasma membrane or in the extracellular space. Their expression is cell or tissue specific and developmentally regulated. Due to their structural diversity, they play important roles in a variety of biological processes such as membrane transport, metabolic stress responses, cell-cell interactions and so on. Discoveries of human diseases associated with glycosylation enzyme deficits have proved modification of lipids and proteins with carbohydrates play critical roles in human health and disease in the nervous systems.

Keywords:  Ceramide; Chondroitin sulfate; Ganglioside; Glucosylceramide; Glycosphingolipid; Glycosyltransferase; Heparan sulfate; Keratan sulfate; Mucin; Sulfation

DOI:  https://doi.org/10.1007/978-3-031-12390-0_4
Brain. 2022 Oct 21. 145(10): 3405-3414

Double administration of self-complementary AAV9NDUFS4 prevents Leigh disease in Ndufs4-/- mice.

Samantha Corrà, Raffaele Cerutti, Valeria Balmaceda, Carlo Viscomi, Massimo Zeviani.

  Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of Leigh disease are mimicked by the ablation of the mouse mitochondrial respiratory chain subunit Ndufs4-/-, which is part of, and crucial for, normal Complex I activity and assembly, particularly in the brains of both children and mice. We previously conveyed the human NDUFS4 gene to the mouse brain using either single-stranded adeno-associated viral 9 recombinant vectors or the PHP.B adeno-associated viral vector. Both these approaches significantly prolonged the lifespan of the Ndufs4-/- mouse model but the extension of the survival was limited to a few weeks by the former approach, whereas the latter was applicable to a limited number of mouse strains, but not to primates. Here, we exploited the recent development of new, self-complementary adeno-associated viral 9 vectors, in which the transcription rate of the recombinant gene is markedly increased compared with the single-stranded adeno-associated viral 9 and can be applied to all mammals, including humans. Either single intra-vascular or double intra-vascular and intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously conveyed the human NDUFS4 gene product in Ndufs4-/- mice, doubling the lifespan from 45 to ≈100 days after birth, when the mice developed rapidly progressive neurological failure. However, the double, contemporary intra-vascular and intra-cerebroventricular administration of self-complementary-adeno-associated viral NDUFS4 prolonged healthy lifespan up to 9 months of age. These mice were well and active at euthanization, at 6, 7, 8 and 9 months of age, to investigate the brain and other organs post-mortem. Robust expression of hNDUFS4 was detected in different cerebral areas preserving normal morphology and restoring Complex I activity and assembly. Our results warrant further investigation on the translatability of self-complementary-adeno-associated viral 9 NDUFS4-based therapy in the prodromal phase of the disease in mice and eventually humans.

Keywords:   Ndufs4 ; Complex I; Leigh disease; gene therapy; mitochondrial disease

DOI:  https://doi.org/10.1093/brain/awac182
Mol Metab. 2022 Oct 13. pii: S2212-8778(22)00183-1. [Epub ahead of print] 101614

Hindbrain insulin controls feeding behavior.

Kim Eerola, Francesco Longo, Thomas Reinbothe, Jennifer Richard, Olesya T Shevchouk, Lorena López-Ferreras, Devesh Mishra, Mohammed Asker, Johan Tolö, Caroline Miranda, Saliha Musovic, Charlotta S Olofsson, Patrik Rorsman, Karolina P Skibicka.

   OBJECTIVE: Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred published reports suggest that insulin is also produced in the brain, with most focusing on hypothalamic or cortical insulin-producing cells.However, specific function for insulin produced within the brain remains poorly understood. Here we identify insulin expression in the hindbrain's dorsal vagal complex (DVC), and determine the role of this source of insulin in feeding and metabolism, as well as its response to diet-induced obesity in mice.
METHODS: To determine the contribution of Ins2-producing neurons to feeding behavior in mice, we used the cross of transgenic RipHER-cre mouse and channelrhodopsin-2 expressing animals, which allowed us to optogenetically stimulate neurons expressing Ins2 in vivo. To confirm the presence of insulin expression in Rip-labeled DVC cells, in situ hybridization was used. To ascertain the specific role of insulin in effects discovered via optogenetic stimulation a selective, CNS applied, insulin receptor antagonist was used. To understand the physiological contribution of insulin made in the hindbrain a virogenetic knockdown strategy was used.
RESULTS: Insulin gene expression and presence of insulin-promoter driven fluorescence in rat insulin promoter (Rip)-transgenic mice were detected in the hypothalamus, but also in the DVC. Insulin mRNA was present in nearly all fluorescently labeled cells in DVC. Diet-induced obesity in mice altered brain insulin gene expression, in a neuroanatomically divergent manner; while in the hypothalamus the expected obesity-induced reduction was found, in the DVC diet-induced obesity resulted in increased expression of the insulin gene. This led us to hypothesize a potentially divergent energy balance role of insulin in these two brain areas. To determine the acute impact of activating insulin-producing neurons in the DVC, optic stimulation of light-sensitive channelrhodopsin 2 in Rip-transgenic mice was utilized. Optogenetic photoactivation induced hyperphagia after acute activation of the DVC insulin neurons. This hyperphagia was blocked by central application of the insulin receptor antagonist S961, suggesting the feeding response was driven by insulin. To determine whether DVC insulin has a necessary contribution to feeding and metabolism, virogenetic insulin gene knockdown (KD) strategy, which allows for site-specific reduction of insulin gene expression in adult mice, was used. While chow-fed mice failed to reveal any changes of feeding or thermogenesis in response to the KD, mice challenged with a high-fat diet consumed less food. No changes in body weight were identified, possibly resulting from compensatory reduction in thermogenesis.
CONCLUSIONS: Together, our data suggest an important role for hindbrain insulin and insulin-producing cells in energy homeostasis.

Keywords:  Diet-induced obesity; Dorsal vagal complex; Food intake; Hindbrain; Insulin

DOI:  https://doi.org/10.1016/j.molmet.2022.101614
Am J Clin Nutr. 2022 Oct 17. pii: nqac236. [Epub ahead of print]

Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses.

Alzheimer's Disease Neuroimaging Initiative

   BACKGROUND: The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established.
OBJECTIVES: The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults.
METHODS: A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-β (Aβ) and tau] were considered as outcomes in regression models.
RESULTS: Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aβ and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aβ accumulation (adjusted β = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted β = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted β = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers.
CONCLUSIONS: Longitudinally, low ω-3 index was associated with greater Aβ accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.

Keywords:  Alzheimer disease; biomarkers; brain imaging; cognition; docosahexaenoic acid; eicosapentaenoic acid; mild cognitive impairment; omega-3

DOI:  https://doi.org/10.1093/ajcn/nqac236
Vet Pathol. 2022 Oct 17. 3009858221128920

Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.

Marina P Lorenzett, Aníbal G Armién, Luan C Henker, Claiton I Schwertz, Raquel A S Cruz, Welden Panziera, Claudio S L de Barros, David Driemeier, Saulo P Pavarini.

  This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Keywords:  Wallerian degeneration; ataxia; chromatolysis; conscious proprioception; cuneocerebellar tract; dorsal column-medial lemniscus pathway; motor neurons; pantothenic acid; paresis; spinocerebellar tract; swine; thoracic nucleus; unconscious proprioception; vitamin B5

DOI:  https://doi.org/10.1177/03009858221128920
Front Neurosci. 2022 ;16 971144

The effects of a 6-week controlled, hypocaloric ketogenic diet, with and without exogenous ketone salts, on cognitive performance and mood states in overweight and obese adults.

Madison L Kackley, Milene L Brownlow, Alex Buga, Chris D Crabtree, Teryn N Sapper, Annalouise O'Connor, Jeff S Volek.

   Background: Ketogenic diets are a commonly used weight loss method, but little is known how variations in sodium content and ketones influence cognition and mood during the early keto-adaptation period.
Objectives: To investigate the effects of an exogenous ketone salt (KS) as part of a hypocaloric KD on mood and cognitive outcomes in overweight and obese adults. A secondary objective was to evaluate changes in biochemical markers associated with inflammatory and cognitive responses.
Materials and methods: Adults who were overweight or obese participated in a 6-week controlled-feeding intervention comparing hypocaloric diets (∼75% of energy expenditure). KD groups received twice daily ketone salt (KD + KS; n = 12) or a flavor-matched placebo, free of minerals (KD + PL; n = 13). A separate group of age and BMI matched adults were later assigned to an isoenergetic low-fat diet (LFD; n = 12) as comparison to KD. Mood was assessed by shortened Profile of Mood States and Visual Analog Mood Scale surveys. Cognitive function was determined by the Automated Neuropsychological Assessment Metrics mental test battery.
Results: Both KD groups achieved nutritional ketosis. Fasting serum glucose decreased in both KD groups, whereas glucose was unaffected in the LFD. Insulin decreased at week 2 and remained lower in all groups. At week 2, depression scores in the KD + PL group were higher compared to KD + KS. Performance in the math processing and go/no-go cognitive tests were lower for KD + PL and LFD participants, respectively, compared to KD + KS. Serum leptin levels decreased for all groups throughout the study but were higher for KD + KS group at week 6. Serum TNF-α steadily increased for LFD participants, reaching significance at week 6.
Conclusion: During a short-term hypocaloric diet, no indication of a consistent decline in mood or cognitive function were seen in participants following either KD, despite KD + PL being relatively low in sodium. WK2 scores of "anger" and "depression" were higher in the LFD and KD + PL groups, suggesting that KS may attenuate negative mood parameters during the early intervention stages.

Keywords:  BDNF; BHB; cognition; keto-adaptation; ketogenic diet; ketone salts; mood; sodium

DOI:  https://doi.org/10.3389/fnins.2022.971144
Clin Case Rep. 2022 Oct;10(10): e6307

Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature.

Mohammed Almuqbil, Ahlam AbuMelha, Daniah Albokhari.

  The FAR1-related phenotypes caused by the FAR1 gene encodes the peroxisomal protein fatty acyl-CoA reductase 1 (FAR1), which is required to reduce fatty acids to fatty alcohols used to form ether-linked alkyl bonds. Biallelic loss-of-function variants have been associated with severe psychomotor developmental delay, seizures, cataracts, growth retardation with microcephaly, and spasticity. However, heterozygous variants in FAR1 have been recently linked to a rare genetic disorder called cataracts, spastic paraparesis, and speech delay (CSPSD). Here, we present the first Middle Eastern patient with a de novo pathogenic heterozygous variant in FAR1 identified by exome sequencing (ES) analysis and a detailed overview of the reported clinical phenotypes and genotypes. Our patient represents the milder end of the clinical spectrum, with medication-free seizures by the first year of life, proper speech and fine motor development, as well as an absence of other previously reported features such as learning difficulties, axial hypotonia, and joint contracture. In addition, she had developmental dysplasia of the hip (DDH) that failed medical management, as well as faltering growth. Our patient adds to the small number of patients recognized to date and expands the clinical spectrum to provide better clinical delineation, improve diagnosis, and develop precision medicine approaches for this disorder.

Keywords:  CSPSD; Cataracts; FAR1‐related syndrome; Spastic paraparesis; seizures; speech delay

DOI:  https://doi.org/10.1002/ccr3.6307
Adv Neurobiol. 2023 ;29 185-217

Glycans and Carbohydrate-Binding/Transforming Proteins in Axon Physiology.

José Abad-Rodríguez, María Elvira Brocca, Alonso Miguel Higuero.

  The mature nervous system relies on the polarized morphology of neurons for a directed flow of information. These highly polarized cells use their somatodendritic domain to receive and integrate input signals while the axon is responsible for the propagation and transmission of the output signal. However, the axon must perform different functions throughout development before being fully functional for the transmission of information in the form of electrical signals. During the development of the nervous system, axons perform environmental sensing functions, which allow them to navigate through other regions until a final target is reached. Some axons must also establish a regulated contact with other cells before reaching maturity, such as with myelinating glial cells in the case of myelinated axons. Mature axons must then acquire the structural and functional characteristics that allow them to perform their role as part of the information processing and transmitting unit that is the neuron. Finally, in the event of an injury to the nervous system, damaged axons must try to reacquire some of their immature characteristics in a regeneration attempt, which is mostly successful in the PNS but fails in the CNS. Throughout all these steps, glycans perform functions of the outermost importance. Glycans expressed by the axon, as well as by their surrounding environment and contacting cells, encode key information, which is fine-tuned by glycan modifying enzymes and decoded by glycan binding proteins so that the development, guidance, myelination, and electrical transmission functions can be reliably performed. In this chapter, we will provide illustrative examples of how glycans and their binding/transforming proteins code and decode instructive information necessary for fundamental processes in axon physiology.

Keywords:  Axon; Axon guidance; Axon initial segment; Axon outgrowth; Axon regeneration; Differentiation; Ganglioside; Glycoconjugate; Glycosylation; Ion channels; Microbiota-Gut-Brain axis; Neuron

DOI:  https://doi.org/10.1007/978-3-031-12390-0_7
Sci Rep. 2022 Oct 19. 12(1): 17484

Mesenchymal stem cell bioenergetics and apoptosis are associated with risk for bronchopulmonary dysplasia in extremely low birth weight infants.

Snehashis Hazra, Rui Li, Bianca M Vamesu, Tamas Jilling, Scott W Ballinger, Namasivayam Ambalavanan, Jegen Kandasamy.

Oxidant stress contributes significantly to the pathogenesis of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Mitochondrial function regulates oxidant stress responses as well as pluripotency and regenerative ability of mesenchymal stem cells (MSCs) which are critical mediators of lung development. This study was conducted to test whether differences in endogenous MSC mitochondrial bioenergetics, proliferation and survival are associated with BPD risk in ELBW infants. Umbilical cord-derived MSCs of ELBW infants who later died or developed moderate/severe BPD had lower oxygen consumption and aconitase activity but higher extracellular acidification-indicative of mitochondrial dysfunction and increased oxidant stress-when compared to MSCs from infants who survived with no/mild BPD. Hyperoxia-exposed MSCs from infants who died or developed moderate/severe BPD also had lower PINK1 expression but higher TOM20 expression and numbers of mitochondria/cell, indicating that these cells had decreased mitophagy. Finally, these MSCs were also noted to proliferate at lower rates but undergo more apoptosis in cell cultures when compared to MSCs from infants who survived with no/mild BPD. These results indicate that mitochondrial bioenergetic dysfunction and mitophagy deficit induced by oxidant stress may lead to depletion of the endogenous MSC pool and subsequent disruption of lung development in ELBW infants at increased risk for BPD.

DOI: https://doi.org/10.1038/s41598-022-22478-5
Alzheimers Dement. 2022 Oct 17.

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains.

Dominantly Inherited Alzheimer Network (DIAN) Study Group

   INTRODUCTION: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain.
METHODS: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD).
RESULTS: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration.
DISCUSSION: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation.
HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.

Keywords:  APOE; APP; PSEN1; PSEN2; TREM2; autosomal dominant Alzheimer's disease; lipidomics; metabolomics; β-citrylglutamate

DOI:  https://doi.org/10.1002/alz.12800
Development. 2022 Oct 15. pii: dev200506. [Epub ahead of print]149(20):

Approaches to investigating metabolism in human neurodevelopment using organoids: insights from intestinal and cancer studies.

Alexandria Morales, Madeline G Andrews.

  Interrogating the impact of metabolism during development is important for understanding cellular and tissue formation, organ and systemic homeostasis, and dysregulation in disease states. To evaluate the vital functions metabolism coordinates during human brain development and disease, pluripotent stem cell-derived models, such as organoids, provide tractable access to neurodevelopmental processes. Despite many strengths of neural organoid models, the extent of their replication of endogenous metabolic programs is currently unclear and requires direct investigation. Studies in intestinal and cancer organoids that functionally evaluate dynamic bioenergetic changes provide a framework that can be adapted for the study of neural metabolism. Validation of in vitro models remains a significant challenge; investigation using in vivo models and primary tissue samples is required to improve our in vitro model systems and, concomitantly, improve our understanding of human development.

Keywords:   In vitro models; Metabolism; Neural development; Organoids

DOI:  https://doi.org/10.1242/dev.200506
Neuropeptides. 2022 Oct 10. pii: S0143-4179(22)00069-5. [Epub ahead of print]96 102294

Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.

Ekram Mohammadi, Farnaz Nikbakht, Mahmoud Barati, Mehrdad Roghani, Somayeh Vazifekhah, Ali Mohammad Khanizadeh, Zahra Heidari.

  Understanding the underlying molecular mechanisms involved in epilepsy is critical for the development of more effective therapies. It is believed that mTOR (Mechanistic Target of Rapamycin kinases) activity and the mitochondrial dynamic balance change during epilepsy. mTOR affects mitochondrial fission by stimulating the translation of mitochondrial fission process 1 (MTFP1). In This study, the protective role of N-acetylcysteine was studied in temporal lobe epilepsy (TLE) through the regulation of mTOR and mitochondrial dynamic proteins. Rats received N-acetylcysteine (oral administration) seven days before induction of epilepsy, followed by one day after epilepsy. TLE was induced by microinjection of kainite into the left lateral ventricle. The total mTOR and Drp1 levels in the hippocampus were evaluated by western blotting. MFN1 was assessed using immunohistochemistry, and the expression of Fis.1 and MTFP1 (fission-related proteins) and OPA (fusion-related protein) were detected by real-time PCR. The mitochondrial membrane potential was measured by Rhodamin 123. The results showed that 72 h after induction of epilepsy, the mTOR protein level increased, and the balance of the mitochondrial dynamic was disturbed; however, oral administration of NAC decreased the mTOR protein level and improved the mitochondrial dynamic. These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level, which can improve the imbalance in the mitochondrial dynamic.

Keywords:  Mitochondrial dynamic; N-acetyl cysteine; Temporal lobe epilepsy; mTOR

DOI:  https://doi.org/10.1016/j.npep.2022.102294