bims-medebr 2022-11-20 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–11–20
28 papers selected by
Regina F. Fernández, Johns Hopkins University

Citrate shuttling in astrocytes is required for processing cocaine-induced neuron-derived excess peroxidated fatty acids.
Therapeutics for mitochondrial dysfunction-linked diseases in Down syndrome.
Increased unsaturated lipids underlie lipid peroxidation in synucleinopathy brain.
Mitochondria play an essential role in the trajectory of adolescent neurodevelopment and behavior in adulthood: evidence from a schizophrenia rat model.
Glial TGFβ activity promotes neuron survival in peripheral nerves.
Mass Spectrometry Analysis of the Human Brain Sphingolipidome.
Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.
Paternal preconceptional diet enriched with n-3 polyunsaturated fatty acids affects offspring brain function in mice.
Mass Spectrometry for the Advancement of Lipid Analysis in Alzheimer's Research.
A Tale of Two Lipids: Lipid Unsaturation Commands Ferroptosis Sensitivity.
Mitochondrial DNA copy number changes, heteroplasmy, and mutations in plasma-derived exosomes and brain tissue of glioblastoma patients.
Neuroinflammation regulates the balance between hippocampal neuron death and neurogenesis in an ex vivo model of thiamine deficiency.
P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases.
Lactate supply overtakes glucose when neural computational and cognitive loads scale up.
Effects of Omega-3 Polyunsaturated Fatty Acids on Brain Functions: A Systematic Review.
Dexmedetomidine (Dex) exerts protective effects on rat neuronal cells injured by cerebral ischemia/reperfusion via regulating the Sphk1/S1P signaling pathway.
Long-Lasting Impact of Sugar Intake on Neurotrophins and Neurotransmitters from Adolescence to Young Adulthood in Rat Frontal Cortex.
Differential biochemical-inflammatory patterns in the astrocyte-neuron axis of the hippocampus and frontal cortex in Wistar rats with metabolic syndrome induced by high fat or carbohydrate diets.
Angiotensin receptor blockade with olmesartan alleviates brain pathology in obese OLETF rats.
Resolvins lipid mediators: Potential therapeutic targets in Alzheimer and Parkinson disease.
Role of SIRT3 in neurological diseases and rehabilitation training.
Intermittent fasting protects the nigral dopaminergic neurons from MPTP-mediated dopaminergic neuronal injury in mice.
Alterations of mitochondrial dynamics in serotonin transporter knockout rats: A possible role in the fear extinction recall mechanisms.
APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease.
Structural and functional insights of the human peroxisomal ABC transporter ALDP.
Atlas-based data integration for mapping the connections and architecture of the brain.
Effect of MCI-186 on Lipid Peroxidation in Experimental Traumatic Brain Damage in Rats.
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.

iScience. 2022 Nov 18. 25(11): 105407

Citrate shuttling in astrocytes is required for processing cocaine-induced neuron-derived excess peroxidated fatty acids.

Kalimuthusamy Natarajaseenivasan, Alvaro Garcia, Prema Velusamy, Santhanam Shanmughapriya, Dianne Langford.

  Disturbances in lipid metabolism in the CNS contribute to neurodegeneration and cognitive impairments. Through tight metabolic coupling, astrocytes provide energy to neurons by delivering lactate and cholesterol and by taking up and processing neuron-derived peroxidated fatty acids (pFA). Disruption of CNS lipid homeostasis is observed in people who use cocaine and in several neurodegenerative disorders, including HIV. The brain's main source of energy is aerobic glycolysis, but numerous studies report a switch to β-oxidation of FAs in response to cocaine. Unlike astrocytes, in response to cocaine, neurons cannot efficiently consume excess pFAs for energy. Accumulation of pFA in neurons induces autophagy and release of pFA. Astrocytes endocytose the pFA for oxidation as an energy source. Our data show that blocking mitochondrial/cytosolic citrate transport reduces the neurotrophic capacity of astrocytes, leading to decreased neuronal fitness.

Keywords:  Cell biology; Cellular neuroscience; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2022.105407
Mitochondrion. 2022 Nov 09. pii: S1567-7249(22)00092-7. [Epub ahead of print]

Therapeutics for mitochondrial dysfunction-linked diseases in Down syndrome.

Bani Bandana Ganguly, Nitin N Kadam.

  Genome-wide deregulation contributes to mitochondrial dysfunction and impairment in oxidative phosphorylation (OXPHOS) mechanism resulting in oxidative stress, increased production of reactive oxygen species (ROS) and cell death in individuals with Down syndrome (DS). The cells, which require more energy, such as muscles, brain and heart are greatly affected. Impairment in mitochondrial network has a direct link with patho-mechanism at cellular and systemic levels at the backdrop of generalized metabolic perturbations in DS patients. Myriads of clinico-phenotypic features, including intellectual disability, early aging and neurodegeneration, and Alzheimer disease (AD)-related dementia are inevitable in DS-population where mitochondrial dysfunctions play the central role. Collectively, the mitochondrial abnormalities and altered energy metabolism perturbs several signaling pathways, particularly related to neurogenesis, which are directly associated with cognitive development and early onset of AD in individuals with DS. Therefore, therapeutic challenges for amelioration of the mitochondrial defects were perceived to improve the quality of life of DS population. A number of pharmacologically active natural compounds such as polyphenols, antioxidants and flavonoids have shown convincing outcome for reversal of the dysfunctional mitochondrial network and oxidative metabolism, and improvement in intellectual skill in mouse models of DS and DS patients.

Keywords:  Down syndrome; antioxidants; diseases of Down syndrome; mitochondrial dysfunction; mitochondrial therapeutics; polyphenols

DOI:  https://doi.org/10.1016/j.mito.2022.11.003
Acta Neuropathol Commun. 2022 Nov 14. 10(1): 165

Increased unsaturated lipids underlie lipid peroxidation in synucleinopathy brain.

YuHong Fu, Ying He, Katherine Phan, Surabhi Bhatia, Russell Pickford, Ping Wu, Nicolas Dzamko, Glenda M Halliday, Woojin Scott Kim.

  Lipid peroxidation is a process of oxidative degradation of cellular lipids that is increasingly recognized as an important factor in the pathogenesis of neurodegenerative diseases. We were therefore interested in the manifestation of lipid peroxidation in synucleinopathies, a group of neurodegenerative diseases characterized by the central pathology of α-synuclein aggregates, including Parkinson's disease, multiple system atrophy, dementia with Lewy bodies and Alzheimer's disease with Lewy bodies. We assessed lipid peroxidation products, lipid aldehydes, in the amygdala, a common disease-affected region in synucleinopathies, and in the visual cortex, a disease-unaffected region. We found that the levels of lipid aldehydes were significantly increased in the amygdala, but not in the visual cortex. We hypothesized that these increases are due to increases in the abundance of unsaturated lipids, since lipid aldehydes are formed from unsaturated lipids. We undertook a comprehensive analysis of membrane lipids using liquid chromatography-mass spectrometry and found that unsaturated phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and sphingomyelin were specifically elevated in the amygdala and correlated with increases in lipid aldehydes. Furthermore, unsaturated phosphatidylethanolamine levels were associated with soluble α-synuclein. Put together, these results suggest that manifestation of lipid peroxidation is prevalent in synucleinopathies and is likely to be due to increases in unsaturated membrane lipids. Our findings underscore the importance of lipid peroxidation in α-synuclein pathology and in membrane structure maintenance.

Keywords:  Lipid aldehydes; Lipid peroxidation; Parkinson’s disease; Synucleinopathies; Unsaturated lipids

DOI:  https://doi.org/10.1186/s40478-022-01469-7
Mol Psychiatry. 2022 Nov 15.

Mitochondria play an essential role in the trajectory of adolescent neurodevelopment and behavior in adulthood: evidence from a schizophrenia rat model.

Hila M Ene, Rachel Karry, Dorit Farfara, Dorit Ben-Shachar.

Ample evidence implicate mitochondria in early brain development. However, to the best of our knowledge, there is only circumstantial data for mitochondria involvement in late brain development occurring through adolescence, a critical period in the pathogenesis of various psychiatric disorders, specifically schizophrenia. In schizophrenia, neurodevelopmental abnormalities and mitochondrial dysfunction has been repeatedly reported. Here we show a causal link between mitochondrial transplantation in adolescence and brain functioning in adulthood. We show that transplantation of allogenic healthy mitochondria into the medial prefrontal cortex of adolescent rats was beneficial in a rat model of schizophrenia, while detrimental in healthy control rats. Specifically, disparate initial changes in mitochondrial function and inflammatory response were associated with opposite long-lasting changes in proteome, neurotransmitter turnover, neuronal sprouting and behavior in adulthood. A similar inverse shift in mitochondrial function was also observed in human lymphoblastoid cells deived from schizophrenia patients and healthy subjects due to the interference of the transplanted mitochondria with their intrinsic mitochondrial state. This study provides fundamental insights into the essential role of adolescent mitochondrial homeostasis in the development of normal functioning adult brain. In addition, it supports a therapeutic potential for mitochondria manipulation in adolescence in disorders with neurodevelopmental and bioenergetic deficits, such as schizophrenia, yet emphasizes the need to monitor individuals' state including their mitochondrial function and immune response, prior to intervention.

DOI: https://doi.org/10.1038/s41380-022-01865-4
J Cell Biol. 2023 Jan 02. pii: e202111053. [Epub ahead of print]222(1):

Glial TGFβ activity promotes neuron survival in peripheral nerves.

Alexandria P Lassetter, Megan M Corty, Romina Barria, Amy E Sheehan, Jo Q Hill, Sue A Aicher, A Nicole Fox, Marc R Freeman.

Maintaining long, energetically demanding axons throughout the life of an animal is a major challenge for the nervous system. Specialized glia ensheathe axons and support their function and integrity throughout life, but glial support mechanisms remain poorly defined. Here, we identified a collection of secreted and transmembrane molecules required in glia for long-term axon survival in vivo. We showed that the majority of components of the TGFβ superfamily are required in glia for sensory neuron maintenance but not glial ensheathment of axons. In the absence of glial TGFβ signaling, neurons undergo age-dependent degeneration that can be rescued either by genetic blockade of Wallerian degeneration or caspase-dependent death. Blockade of glial TGFβ signaling results in increased ATP in glia that can be mimicked by enhancing glial mitochondrial biogenesis or suppressing glial monocarboxylate transporter function. We propose that glial TGFβ signaling supports axon survival and suppresses neurodegeneration through promoting glial metabolic support of neurons.

DOI: https://doi.org/10.1083/jcb.202111053
Methods Mol Biol. 2023 ;2561 233-243

Mass Spectrometry Analysis of the Human Brain Sphingolipidome.

Xin Ying Chua, Ryan Huang, Deron Herr, Mitchell K P Lai, Markus R Wenk, Federico Torta.

  In recent decades, mass spectrometry-based lipidomics has provided a fertile environment for scientific investigations of biochemical and mechanistic processes in biological systems. Notably, this approach has been used to characterize physiological and pathological processes relevant to the central nervous system by identifying changes in the sphingolipid content in the brain, cerebral spinal fluid, and blood plasma. However, despite a preponderance of studies identifying correlations between specific lipids and disease progression, this powerful resource has not yet substantively translated into clinically useful diagnostic assays. Part of this gap may be explained by insufficient depth of the lipidomic profiles in many studies, by lab-to-lab inconsistencies in methodology, and a lack of absolute quantification. These issues limit the identification of specific molecular species and the harmonization of results across independent studies. In this chapter, we contextualize these issues with recent reports identifying correlations between brain lipids and neurological diseases, and we describe the workflow our group has optimized for analysis of the blood plasma sphingolipidome, adapted to the characterization of the human brain tissue.

Keywords:  Alzheimer’s disease; Brain; Clinical correlation; LC-MS/MS methodology; Lipidomics; Mass spectrometry; Neurological disease; Plasma; Sphingolipidomics; Sphingolipids; Sphingosine 1-Phosphate

DOI:  https://doi.org/10.1007/978-1-0716-2655-9_12
J Cell Biol. 2023 Jan 02. pii: e202203019. [Epub ahead of print]222(1):

Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.

Olesia Ignatenko, Satu Malinen, Sofiia Rybas, Helena Vihinen, Joni Nikkanen, Aleksander Kononov, Eija S Jokitalo, Gulayse Ince-Dunn, Anu Suomalainen.

Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.

DOI: https://doi.org/10.1083/jcb.202203019
Front Nutr. 2022 ;9 969848

Paternal preconceptional diet enriched with n-3 polyunsaturated fatty acids affects offspring brain function in mice.

Muhan Li, Qiaoyu Shi, Xueyi Jiang, Xuanyi Liu, Wei Han, Xiuqin Fan, Ping Li, Kemin Qi.

  Recent studies demonstrate that paternal nutrition prior to conception may determine offspring development and health through epigenetic modification. This study aims to investigate the effects of paternal supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the brain development and function, and associated gene imprinting in the offspring. Three to four-week-old male C57BL/6J mice (founder) were fed with an n-3 PUFA-deficient diet (n-3 D), and two n-3 PUFA supplementation diets - a normal n-3 PUFA content diet (n-3 N) and a high n-3 PUFA content diet (n-3 H) for 12 weeks. Then they were mated to 10-week-old virgin female C57BL/6J mice to generate the offspring. The results showed that paternal n-3 PUFA supplementation in preconception reduced the anxiety- and depressive-like behavior, and improved sociability, learning and memory in the offspring, along with increased synaptic number, upregulated expressions of neuron specific enolase, myelin basic protein, glial fibrillary acidic protein, brain-derived neurotrophic factor in the hippocampus and cerebral cortex, and altered expressions of genes associated with mitochondria biogenesis, fusion, fission and autophagy. Furthermore, with paternal n-3 PUFA supplementation, the expression of imprinted gene Snrpn was downregulated both in testes of the founder mice and their offspring, but upregulated in the cerebral cortex and hippocampus, with altered DNA methylation in its differentially methylated region. The data suggest that higher paternal intake of n-3 PUFAs in preconception may help to maintain optimal brain development and function in the offspring, and further raise the possibility of paternal nutritional intervention for mental health issues in subsequent generations.

Keywords:  gene imprinting; mouse; n-3 polyunsaturated fatty acids; offspring brain; paternal nutrition

DOI:  https://doi.org/10.3389/fnut.2022.969848
Methods Mol Biol. 2023 ;2561 245-259

Mass Spectrometry for the Advancement of Lipid Analysis in Alzheimer's Research.

Jonatan Martínez-Gardeazabal, Marta Moreno-Rodríguez, Estíbaliz González de San Román, Beatriz Abad, Iván Manuel, Rafael Rodríguez-Puertas.

  Recent technical advances in mass spectrometry, as applied to the analytical chemistry of lipid molecules, enable the simultaneous detection of the multiplicity of lipid complex species present in the human brain. This, in combination with quantitative studies carried out in plasma samples, helps to identify disease biomarkers including for Alzheimer's disease (AD). Mass spectrometry imaging (MSI) is particularly powerful for the anatomical localization of lipids in brain slices, identifying lipid modifications in postmortem frozen samples from AD patients.Human brain tissues are sectioned in a cryostat and then covered with a chemical matrix, such as mercaptobenzothiazole (MBT) or α-cyano-4-hydroxycinnamic acid (CHCA), to ionize the lipid molecules either by sublimation or by spraying. We describe the use of matrix-assisted laser desorption ionization (MALDI) in an LTQ-Orbitrap-XL mass spectrometer to scan brain tissue slices with high spatial resolution, analyzing 50 μm cell layers. The lipid spectra obtained for each pixel are transformed to color-coded intensity maps of hundreds of lipid species included those within a single tissue slice.

Keywords:  Alzheimer’s disease; Biomarkers; Lipid; MALDI-MSI; Mass spectroscopy; Neurolipid; UHPLC-MS

DOI:  https://doi.org/10.1007/978-1-0716-2655-9_13
Proteomics. 2022 Nov 18. e2100308

A Tale of Two Lipids: Lipid Unsaturation Commands Ferroptosis Sensitivity.

Jason Rodencal, Scott J Dixon.

  Membrane lipids play important roles in the regulation of cell fate, including the execution of ferroptosis. Ferroptosis is a non-apoptotic cell death mechanism defined by iron-dependent membrane lipid peroxidation. Phospholipids containing polyunsaturated fatty acids (PUFAs) are highly vulnerable to peroxidation and are essential for ferroptosis execution. By contrast, the incorporation of less oxidizable monounsaturated fatty acids (MUFAs) in membrane phospholipids protects cells from ferroptosis. The enzymes and pathways that govern PUFA and MUFA metabolism therefore play a critical role in determining cellular sensitivity to ferroptosis. Here, we review three lipid metabolic processes fatty acid biosynthesis, ether lipid biosynthesis, and phospholipid remodeling-that govern ferroptosis sensitivity by regulating the balance of PUFAs and MUFAs in membrane phospholipids. This article is protected by copyright. All rights reserved.

Keywords:  PUFA; ether lipid; ferroptosis; iron; membrane; necrosis

DOI:  https://doi.org/10.1002/pmic.202100308
Mol Cell Probes. 2022 Nov 12. pii: S0890-8508(22)00086-X. [Epub ahead of print] 101875

Mitochondrial DNA copy number changes, heteroplasmy, and mutations in plasma-derived exosomes and brain tissue of glioblastoma patients.

Beáta Soltész, Ondrej Pös, Zuzana Wlachovska, Jaroslav Budis, Rastislav Hekel, Lucia Strieskova, Jana Bozenka Liptak, Werner Krampl, Jakub Styk, Nikolett Németh, Judit Sz Keserű, Adrienn Jenei, Gergely Buglyó, Álmos Klekner, Bálint Nagy, Tomas Szemes.

  Glioblastoma is the most common malignant cancer of the central nervous system (CNS) in adults. Glioblastoma cells show increased glucose consumption associated with poor prognosis. Since mitochondria play a crucial role in energy metabolism, mitochondrial mutations and mitochondrial DNA copy number changes may function as biomarkers. As the brain is difficult to access, analysis of mitochondria directly from the brain tissue represents a challenge for neuropathology. Exosome analysis is an alternative (still poorly explored) approach to investigate molecular changes in CNS tumors. Here we analyze characteristics of brain tissue DNA and plasma-derived exosomal DNA (exoDNA) of 44 glioblastoma patients and 40 control individuals. Quantitative real-time PCR was performed to determine mtDNA copy numbers and the Kruskal-Wallis and Mann-Whitney U test were used for statistical analysis of data. Subsequently, sequencing libraries were prepared and sequenced on the MiSeq platform to identify mtDNA point mutations. Tissue mtDNA copy number was different among controls and patients in multiple comparisons. A similar tendency was detected in exosomes. Based on NGS analysis, several mtDNA point mutations showed slightly different frequencies between cases and controls, but the clinical relevance of these observations is difficult to assess and likely less than that of overall mtDNA copy number changes. Allele frequencies of variants were used to determine the level of heteroplasmy (found to be higher in exo-mtDNA of control individuals). Despite the suggested potential, the use of such a biomarker for the screening and/or diagnosis of glioblastomas is still limited, thus further study will be required.

Keywords:  Copy number; Exosome; Glioblastoma; Heteroplasmy; Mitochondrial DNA; Mutations

DOI:  https://doi.org/10.1016/j.mcp.2022.101875
J Neuroinflammation. 2022 Nov 14. 19(1): 272

Neuroinflammation regulates the balance between hippocampal neuron death and neurogenesis in an ex vivo model of thiamine deficiency.

Larissa M G Cassiano, Marina S Oliveira, Jeanne Pioline, Anna C M Salim, Roney S Coimbra.

   BACKGROUND: Thiamine (vitamin B1) is a cofactor for enzymes of central energy metabolism and its deficiency (TD) impairs oxidative phosphorylation, increases oxidative stress, and activates inflammatory processes that can lead to neurodegeneration. Wernicke-Korsakoff syndrome (WKS) is a consequence of chronic TD, which leads to extensive neuronal death, and is associated with neuropathological disorders, including cognitive deficits and amnesia. The hippocampus is one of the brain areas most affected by WKS. B1 replacement may not be enough to prevent the irreversible cognitive deficit associated with WKS.
MATERIALS AND METHODS: An organotypic hippocampal slice culture (OHC) model was developed to investigate, using immunofluorescence and confocal microscopy and transcriptome analysis, the molecular mechanisms underlying the neurodegeneration associated with TD. The effect of anti-inflammatory pharmacological intervention with resveratrol (RSV) was also assessed in B1-deprived OHCs.
RESULTS: In OHCs cultured without B1, neuronal density decayed after 5 days and, on the 7th day, the epigenetic markings H3K4me3 and H3K9me3 were altered in mature neurons likely favoring gene transcription. Between the 7th and the 14th day, a pulse of neurogenesis was observed followed by a further massive neuron loss. Transcriptome analysis at day nine disclosed 89 differentially expressed genes in response to B1 deprivation. Genes involved in tryptophan metabolism and lysine degradation KEGG pathways, and those with Gene Ontology (GO) annotations related to the organization of the extracellular matrix, cell adhesion, and positive regulation of synaptic transmission were upregulated. Several genes of the TNF and FoxO signaling pathways and with GO terms related to inflammation were inhibited in response to B1 deprivation. Nsd1, whose product methylates histone H3 lysine 36, was upregulated and the epigenetic marking H3K36me3, associated with negative regulation of neurogenesis, was increased in neurons. Treating B1-deprived OHCs with RSV promoted an earlier neurogenesis pulse.
CONCLUSION: Neuroregeneration occurs in B1-deficient hippocampal tissue during a time window. This phenomenon depends on reducing neuroinflammation and, likely, on metabolic changes, allowing acetyl-CoA synthesis from amino acids to ensure energy supply via oxidative phosphorylation. Thus, neuroinflammation is implicated as a major regulator of hippocampal neurogenesis in TD opening a new search space for treating WKS.

Keywords:  Neurodegeneration; Neurogenesis. inflammation; Neuroregeneration; Organotypic hippocampal culture; Thiamine deficiency

DOI:  https://doi.org/10.1186/s12974-022-02624-6
eNeuro. 2022 Nov-Dec;9(6):pii: ENEURO.0092-22.2022. [Epub ahead of print]9(6):

P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases.

Alexsandra S Zelentsova, Alexei V Deykin, Vladislav O Soldatov, Anastasia A Ulezko, Alina Y Borisova, Veronika S Belyaeva, Marina Y Skorkina, Plamena R Angelova.

  Mitochondrial dysfunction is one of the basic hallmarks of cellular pathology in neurodegenerative diseases. Since the metabolic activity of neurons is highly dependent on energy supply, nerve cells are especially vulnerable to impaired mitochondrial function. Besides providing oxidative phosphorylation, mitochondria are also involved in controlling levels of second messengers such as Ca2+ ions and reactive oxygen species (ROS). Interestingly, the critical role of mitochondria as producers of ROS is closely related to P2XR purinergic receptors, the activity of which is modulated by free radicals. Here, we review the relationships between the purinergic signaling system and affected mitochondrial function. Purinergic signaling regulates numerous vital biological processes in the CNS. The two main purines, ATP and adenosine, act as excitatory and inhibitory neurotransmitters, respectively. Current evidence suggests that purinergic signaling best explains how neuronal activity is related to neuronal electrical activity and energy homeostasis, especially in the development of Alzheimer's and Parkinson's diseases. In this review, we focus on the mechanisms underlying the involvement of the P2RX7 purinoreceptor in triggering mitochondrial dysfunction during the development of neurodegenerative disorders. We also summarize various avenues by which the purine signaling pathway may trigger metabolic dysfunction contributing to neuronal death and the inflammatory activation of glial cells. Finally, we discuss the potential role of the purinergic system in the search for new therapeutic approaches to treat neurodegenerative diseases.

Keywords:  exosomes; mitochondrion; oxidative stress; purinergic metabolome; tau protein; α-synuclein

DOI:  https://doi.org/10.1523/ENEURO.0092-22.2022
Proc Natl Acad Sci U S A. 2022 Nov 22. 119(47): e2212004119

Lactate supply overtakes glucose when neural computational and cognitive loads scale up.

Yulia Dembitskaya, Charlotte Piette, Sylvie Perez, Hugues Berry, Pierre J Magistretti, Laurent Venance.

  Neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high-stimulation load activity patterns and high attentional load in cognitive tasks and glucose being sufficient for less demanding neural computation and learning tasks. Indeed, we show that lactate is mandatory for demanding neural computation, such as theta-burst stimulation, while glucose is sufficient for lighter forms of activity-dependent long-term potentiation (LTP), such as spike timing-dependent plasticity (STDP). We find that subtle variations of spike number or frequency in STDP are sufficient to shift the on-demand fueling from glucose to lactate. Finally, we demonstrate that lactate is necessary for a cognitive task requiring high attentional load, such as the object-in-place task, and for the corresponding in vivo hippocampal LTP expression but is not needed for a less demanding task, such as a simple novel object recognition. Overall, these results demonstrate that glucose and lactate metabolism are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.

Keywords:  glucose; lactate; learning and memory; neuroenergetic; synaptic plasticity

DOI:  https://doi.org/10.1073/pnas.2212004119
Cureus. 2022 Oct;14(10): e30091

Effects of Omega-3 Polyunsaturated Fatty Acids on Brain Functions: A Systematic Review.

Ibrahim M Dighriri, Abdalaziz M Alsubaie, Fatimah M Hakami, Dalal M Hamithi, Maryam M Alshekh, Fatimah A Khobrani, Fatimah E Dalak, Alanoud A Hakami, Efham H Alsueaadi, Laila S Alsaawi, Saad F Alshammari, Abdullah S Alqahtani, Ibrahim A Alawi, Amal A Aljuaid, Mohammed Q Tawhari.

  Omega is a polyunsaturated fatty acid (PUFA) that has an essential impact on cognitive performance at all stages of life. Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA) are essential for brain functions. DHA, the dominant omega-3 in the brain, impacts neurotransmitters and functions of the brain. This systematic review aimed to assess the effects of omega-3 on brain functions. We searched for articles from 2010 to 2022 in PubMed, electronic databases: discover, academic search complete (EBSCO), and Cochrane. To increase search efficiency, search terms include database-specific indexed phrases and keywords. Search terms included "omega three," "DHA," "fish oil," "eicosapentaenoic acid," "EPA," "docosahexaenoic acid," "omega-3," "cognition," "brain," "mental health," and "PUFAs".We conducted a review of only randomized clinical trials (RCTs) that were published in English. We evaluated the quality of the studies using the Cochrane Collaboration bias assessment tool. Our search strategy yielded 174 articles, out of which 33 full-text articles were reviewed and nine articles were selected for data abstraction. The overall number of individuals in all nine studies was 1319. Of the participants, 591 (44.81%) were men, and 728 (55.19%) were women. Participants who received omega-3 were 700 (65.06%) compared to 376 (34.94%) who received a placebo, and their mean age was 45. Ingestion of omega-3 fatty acids increases learning, memory, cognitive well-being, and blood flow in the brain. Omega-3 treatments are advantageous, well-tolerated, and risk-free. Lonelier people, the elderly, and those who eat fewer healthy foods containing omega-3 may benefit from an omega-3 supplement. We suggest that natural omega-3 consumption through the diet should be promoted.

Keywords:  brain; dha; epa; fatty acids; mental health; omega; pufas

DOI:  https://doi.org/10.7759/cureus.30091
J Stroke Cerebrovasc Dis. 2022 Nov 14. pii: S1052-3057(22)00588-2. [Epub ahead of print]32(1): 106896

Dexmedetomidine (Dex) exerts protective effects on rat neuronal cells injured by cerebral ischemia/reperfusion via regulating the Sphk1/S1P signaling pathway.

Dawei Cong, Yunlong Yu, Yan Meng, Xia Qi.

   AIM: To investigate the influence of dexmedetomidine (Dex) on cerebral ischemia/reperfusion (I/R)-injured rat neuronal cells by regulating the Sphk1/S1P pathway.
METHODS: The rats were divided into the following groups, with 18 rats in each group categorized on the basis of random number tables: sham (Sham), I/R (I/R), Dex, Sphk1 inhibitor (PF-543), and Dex together with the Sphk1 agonist phorbol-12-myristate-13-acetate (Dex+PMA). The neurological functions of the rats were assessed by the Longa scoring system at 24 h post reperfusion. The area of brain infarction was inspected using 2,3,5-triphenyltetrazolium chloride staining, and the water content of brain tissue was determined by the dry-wet weight method. The morphology of neurons in the CA1 region of the rat hippocampus was inspected using Nissl staining, while the apoptosis of neurons in this region was detected by terminal-deoxynucleotidyl transferase mediated nick end labeling staining. The Sphk1 and S1P protein levels were determined by immunofluorescence and western blotting, respectively.
RESULTS: Compared to the I/R group, rats in the Dex, PF-543, and Dex+PMA groups had a significantly lower neurological function score, as well as lower brain water content and a decreased infarction area. Moreover, the apoptotic index of the neurons and the Sphk1 and S1P levels in the hippocampal CA1 region were significantly lower in these groups (p<0.05). PMA, an agonist of Sphk1, was able to reverse the protective effects of Dex on I/R-induced neuronal cell injury.
CONCLUSION: Dex could protect cerebral I/R-induced neuronal cell injury by suppressing the Sphk1/S1P signaling pathway.

Keywords:  Dexmedetomidine; I/R; S1P; Sphk1

DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106896
Mol Neurobiol. 2022 Nov 17.

Long-Lasting Impact of Sugar Intake on Neurotrophins and Neurotransmitters from Adolescence to Young Adulthood in Rat Frontal Cortex.

Maria Stefania Spagnuolo, Arianna Mazzoli, Martina Nazzaro, Antonio Dario Troise, Cristina Gatto, Claudia Tonini, Mayra Colardo, Marco Segatto, Andrea Scaloni, Valentina Pallottini, Susanna Iossa, Luisa Cigliano.

  The detrimental impact of fructose, a widely used sweetener in industrial foods, was previously evidenced on various brain regions. Although adolescents are among the highest consumers of sweet foods, whether brain alterations induced by the sugar intake during this age persist until young adulthood or are rescued returning to a healthy diet remains largely unexplored. To shed light on this issue, just weaned rats were fed with a fructose-rich or control diet for 3 weeks. At the end of the treatment, fructose-fed rats underwent a control diet for a further 3 weeks until young adulthood phase and compared with animals that received from the beginning the healthy control diet. We focused on the consequences induced by the sugar on the main neurotrophins and neurotransmitters in the frontal cortex, as its maturation continues until late adolescence, thus being the last brain region to achieve a full maturity. We observed that fructose intake induces inflammation and oxidative stress, alteration of mitochondrial function, and changes of brain-derived neurotrophic factor (BDNF) and neurotrophin receptors, synaptic proteins, acetylcholine, dopamine, and glutamate levels, as well as increased formation of the glycation end-products Nε-carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL). Importantly, many of these alterations (BDNF, CML, CEL, acetylcholinesterase activity, dysregulation of neurotransmitters levels) persisted after switching to the control diet, thus pointing out to the adolescence as a critical phase, in which extreme attention should be devoted to limit an excessive consumption of sweet foods that can affect brain physiology also in the long term.

Keywords:  Adolescent rat; Brain-derived neurotrophic factor; Frontal cortex; Fructose diet; Inflammation; Mitochondria; Neurotransmitters

DOI:  https://doi.org/10.1007/s12035-022-03115-8
J Chem Neuroanat. 2022 Oct 28. pii: S0891-0618(22)00116-8. [Epub ahead of print]126 102186

Differential biochemical-inflammatory patterns in the astrocyte-neuron axis of the hippocampus and frontal cortex in Wistar rats with metabolic syndrome induced by high fat or carbohydrate diets.

Samuel Treviño, Alfonso Díaz, Getsemaní González-López, Jorge Guevara.

  Metabolic syndrome (MetS) is a public health problem and a risk of developing cardiometabolic and neurodegenerative diseases. The biochemical-inflammatory impairment in brain areas related to learning and memory has not been differentiated between MetS models. We aimed to compare the effect of the MetS generated by consuming high-fat (HFD) or -carbohydrate diets (HCD) on the hippocampus and frontal cortex, related to astrocyte-neuron metabolism and neuroinflammation origin. Sixty male Wistar rats were separated into three groups: 1) control group, 2) HCD group, and 3) HFD group. After 3 months, we evaluated zoometry, a serum bioclinical profile, and in the hippocampus and frontal cortex, we performed biochemical assays (concentration of lactate, glutamate, fatty acids, and ASAT, ALAT, and LDH activity), immunoreactivity tests (GFAP, COX2, CD36, and BDNF), and immunoassays (TNF-α, IL-1β, IL-6, and PGE2). The bioclinical parameters showed that both diets induce MetS. At the brain level, it is noteworthy that the HCD group had an increase in lactate and glutamate concentration, reactive astrogliosis, immunoreactive COX2 neurons in the CA1 subfield hippocampus and frontal cortex, and high levels of PGE2, TNF-α, IL-1β, and IL-6, and low BDNF immunoreactivity. Meanwhile, the HFD is highlighted by increased fatty acid levels and CD36 expression in the hippocampus and frontal cortex, strong reactive astrogliosis and COX2 immunoreactivity, and the greatest inflammation with the lowest BDNF immunoreactivity. In conclusion, MetS induction by an HFD or HCD generates different biochemical, cellular, and inflammatory patterns in the hippocampus and frontal cortex.

Keywords:  Astrocyte-neuron axis; Frontal cortex; Hippocampus; Hypercaloric diets; Inflammation; Metabolic syndrome

DOI:  https://doi.org/10.1016/j.jchemneu.2022.102186
Clin Exp Pharmacol Physiol. 2022 Nov 18.

Angiotensin receptor blockade with olmesartan alleviates brain pathology in obese OLETF rats.

Carlos J Rodriguez-Ortiz, Max A Thorwald, Ruben Rodriguez, Marina Mejias-Ortega, Zanett Kieu, Neilabjo Maitra, Charlesice Hawkins, Joanna Valenzuela, Marcus Peng, Akira Nishiyama, Rudy M Ortiz, Masashi Kitazawa.

  Metabolic syndrome (MetS) is a rapidly increasing health concern during midlife and is an emerging risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). While angiotensin receptor blockers (ARB) are widely used for MetS-associated hypertension and kidney disease, its therapeutic potential in the brain during MetS are not well-described. Here, we tested whether treatment with ARB could alleviate the brain pathology and inflammation associated with MetS using the Otsuka Long Evans Tokushima Fatty (OLETF) rat. Here, we report that chronic ARB treatment with olmesartan (10 mg/kg/day by oral gavage for 6 weeks) partially but significantly ameliorated accumulation of oxidized and ubiquitinated proteins, astrogliosis and transformation to neurotoxic astrocytes in the brain of old OLETF rats, which otherwise exhibit the progression of these pathological hallmarks associated with MetS. Additionally, olmesartan treatment restored claudin-5 and ZO-1, markers of the structural integrity of the blood brain barrier as well as synaptic protein PSD-95, which were otherwise decreased in old OLETF rats, particularly in the hippocampus, a critical region in cognition, memory and AD. These data demonstrate that the progression of MetS in OLETF rats is associated with deterioration of various aspects of neuronal integrity that may manifest neurodegenerative conditions and that overactivation of angiotensin receptor directly or indirectly contributes to these detriments. Thus, olmesartan treatment may slow or delay the onset of degenerative process in the brain and subsequent neurological disorders associated with MetS.

Keywords:  blood brain barrier; cerebrovasculature; gliosis; hippocampus; neurodegeneration; synapse

DOI:  https://doi.org/10.1111/1440-1681.13738
Neuroscience. 2022 Nov 10. pii: S0306-4522(22)00546-2. [Epub ahead of print]

Resolvins lipid mediators: Potential therapeutic targets in Alzheimer and Parkinson disease.

Santosh Anand, Mohammad Azam Ansari, Sambamurthy Kumaraswamy Sukrutha, Mohammad N Alomary, Anmar Anwar Khan, Abozer Y Elderdery.

  Inflammation and resolution are highly programmed processes involving a plethora of immune cells. Lipid mediators synthesized from arachidonic acid metabolism play a pivotal role in orchestrating the signaling cascades in the game of inflammation. The majority of the studies carried out so far on inflammation were aimed at inhibiting the generation of inflammatory molecules, whereas recent research has shifted more towards understanding the resolution of inflammation. Owing to chronic inflammation as evident in neuropathophysiology, the resolution of inflammation together with the class of lipid mediators actively involved in its regulation has attracted the attention of the scientific community as therapeutic targets. Both omega-three polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, orchestrate a vital regulatory role in inflammation development. Resolvins derived from these fatty acids comprise the D-and E-series resolvins. A growing body of evidence using in vitro and in vivo models has revealed the pro-resolving and anti-inflammatory potential of resolvins. This systematic review sheds light on the synthesis, specialized receptors, and resolution of inflammation mediated by resolvins in Alzheimer's and Parkinson's disease.

Keywords:  Alzheimer’s disease; Parkinson’s disease; Resolvins; arachidonic acid; lipid mediators

DOI:  https://doi.org/10.1016/j.neuroscience.2022.11.001
Metab Brain Dis. 2022 Nov 14.

Role of SIRT3 in neurological diseases and rehabilitation training.

Yanlin Li, Jing Li, Guangbin Wu, Hua Yang, Xiaosong Yang, Dongyu Wang, Yanhui He.

  Sirtuin3 (SIRT3) is a deacetylase that plays an important role in normal physiological activities by regulating a variety of substrates. Considerable evidence has shown that the content and activity of SIRT3 are altered in neurological diseases. Furthermore, SIRT3 affects the occurrence and development of neurological diseases. In most cases, SIRT3 can inhibit clinical manifestations of neurological diseases by promoting autophagy, energy production, and stabilization of mitochondrial dynamics, and by inhibiting neuroinflammation, apoptosis, and oxidative stress (OS). However, SIRT3 may sometimes have the opposite effect. SIRT3 can promote the transfer of microglia. Microglia in some cases promote ischemic brain injury, and in some cases inhibit ischemic brain injury. Moreover, SIRT3 can promote the accumulation of ceramide, which can worsen the damage caused by cerebral ischemia-reperfusion (I/R). This review comprehensively summarizes the different roles and related mechanisms of SIRT3 in neurological diseases. Moreover, to provide more ideas for the prognosis of neurological diseases, we summarize several SIRT3-mediated rehabilitation training methods.

Keywords:  Deacetylase; Neurological diseases; Rehabilitation training; SIRT3

DOI:  https://doi.org/10.1007/s11011-022-01111-4
J Nutr Biochem. 2022 Nov 09. pii: S0955-2863(22)00280-7. [Epub ahead of print] 109212

Intermittent fasting protects the nigral dopaminergic neurons from MPTP-mediated dopaminergic neuronal injury in mice.

Uttam Ojha, Shristi Khanal, Pil-Hoon Park, Jin Tae Hong, Dong-Young Choi.

  Dietary restriction through low-calorie intake or intermittent fasting benefits many organs, including the brain. This study investigated the neuroprotective effects of fasting in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. We found that fasting every other day rather than weekly increased the levels of brain-derived neurotrophic factor and glial-derived neurotrophic factor in the nigrostriatal pathway. Therefore, we maintained the animals on alternate-day fasting for 2 weeks and injected MPTP (30 mg/kg/day, intraperitoneally [i.p.]) for 5 days. We observed that alternate-day fasting attenuated MPTP-induced dopaminergic neuronal loss and astroglial activation in the substantia nigra and the striatum. Moreover, neurochemical analysis using high-performance liquid chromatography showed that alternate-day fasting reduced MPTP-induced depletion of striatal dopamine. Consistent with these results, behavioral tests showed that fasting suppressed the motor impairment caused by MPTP. Furthermore, fasting increased the phosphorylation of phosphatidylinositol-3-kinase and protein kinase B, which are downstream signaling molecules of neurotrophic factors. Fasting also increased the phosphorylation of extracellular signal-regulated protein kinase and cAMP response element-binding protein, further supporting the involvement of neurotrophic factors in the observed neuroprotective effects. Hence, our results demonstrated the dopaminergic neuroprotection of intermittent fasting in an MPTP mouse model of Parkinson's disease, supporting the idea that fasting could be an instrumental tool for preventing neurodegeneration in the brain.

Keywords:  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Fasting; Parkinson's disease; brain-derived neurotrophic factor; glial-derived neurotrophic factor

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109212
Front Behav Neurosci. 2022 ;16 957702

Alterations of mitochondrial dynamics in serotonin transporter knockout rats: A possible role in the fear extinction recall mechanisms.

Paola Brivio, Maria Teresa Gallo, Peter Karel, Giulia Cogi, Fabio Fumagalli, Judith R Homberg, Francesca Calabrese.

  Stress-related mental disorders encompass a plethora of pathologies that share the exposure to a negative environment as trigger for their development. The vulnerability to the effects of a negative environment is not equal to all but differs between individuals based on the genetic background makeup. Here, to study the molecular mechanisms potentially underlying increased threat anticipation, we employed an animal model showing this symptom (5-HTT knockout rats) which we exposed to Pavlovian fear conditioning (FC). We investigated the role of mitochondria, taking advantage of the recent evidence showing that the dynamic of these organelles is dysregulated after stress exposure. Behavioral experiments revealed that, during the second day of extinction of the FC paradigm, 5-HTT knockout (5-HTT-/-) animals showed a lack of fear extinction recall. From a mechanistic standpoint, we carried out our molecular analyses on the amygdala and prefrontal cortex, given their role in the management of the fear response due to their tight connection. We demonstrated that mitochondrial dynamics are impaired in the amygdala and prefrontal cortex of 5-HTT-/- rats. The dissection of the potential contributing factors revealed a critical role in the mechanisms regulating fission and fusion that are dysregulated in transgenic animals. Furthermore, mitochondrial oxidative phosphorylation, mitochondrial biogenesis, and the production of antioxidant enzymes were altered in these brain regions in 5-HTT-/- rats. In summary, our data suggest that increased extracellular 5-HT levels cause an unbalance of mitochondrial functionality that could contribute to the reduced extinction recall of 5-HTT-/- rats, pointing out the role of mitochondrial dynamics in the etiology of psychiatric disorders. Our findings, also, provide some interesting insights into the targeted development of drugs to treat such disorders.

Keywords:  5-HTT–/–; fission; fusion; mitochondria; stress-related disorders

DOI:  https://doi.org/10.3389/fnbeh.2022.957702
Alzheimers Dement. 2022 Nov 17.

APOE ε4 carrier status and sex differentiate rates of cognitive decline in early- and late-onset Alzheimer's disease.

Angelina J Polsinelli, Paige E Logan, Kathleen A Lane, Mohit K Manchella, Sára Nemes, Apoorva Bharthur Sanjay, Sujuan Gao, Liana G Apostolova.

   BACKGROUND: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on rates of cognitive decline in early- (EO) and late- (LO) onset Alzheimer's disease (AD).
METHOD: We ran mixed-effects models with longitudinal cognitive measures as dependent variables, and sex, APOE ε4 carrier status, and interaction terms as predictor variables in 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center.
RESULTS: APOE ε4 carriers showed accelerated cognitive decline relative to non-carriers in both EOAD and LOAD, although the patterns of specific cognitive domains that were affected differed. Female participants showed accelerated cognitive decline relative to male participants in EOAD only. The effect of APOE ε4 was greater in EOAD for executive functioning (p < 0.0001) and greater in LOAD for language (p < 0.0001).
CONCLUSION: We found APOE ε4 effects on cognitive decline in both EOAD and LOAD and female sex in EOAD only. The specific patterns and magnitude of decline are distinct between the two disease variants.
HIGHLIGHTS: Apolipoprotein E (APOE) ε4 carrier status and sex differentiate rates of cognitive decline in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD). APOE ε4 in EOAD accelerated decline in memory, executive, and processing speed domains. Female sex in EOAD accelerated decline in language, memory, and global cognition. The effect of APOE ε4 was stronger for language in LOAD and for executive function in EOAD. Sex effects on language and executive function decline differed between EOAD and LOAD.

Keywords:  APOE ε4; cognitive decline; early-onset Alzheimer's disease; late-onset Alzheimer's disease; sex differences

DOI:  https://doi.org/10.1002/alz.12831
Elife. 2022 Nov 14. pii: e75039. [Epub ahead of print]11

Structural and functional insights of the human peroxisomal ABC transporter ALDP.

Yutian Jia, Yanming Zhang, Wenhao Wang, Jianlin Lei, Zhengxin Ying, Guanghui Yang.

  Adrenoleukodystrophy protein (ALDP) is responsible for the transport of very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations have been identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural and biochemical characterization. Here we report the cryo-electron microscopy (cryo-EM) structure of human ALDP with nominal resolution at 3.4 Å. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette (ABC) transporters, ALDP has two substrate binding cavities formed by the transmembrane domains (TMD). Such structural organization may be suitable for the coordination of VLCFAs. Based on the structure, we performed integrative analysis of the cellular trafficking, protein thermostability, ATP hydrolysis and the transport activity of representative mutations. These results provide a framework for understanding the working mechanism of ALDP and pathogenic roles of disease-associated mutations.

Keywords:  molecular biophysics; structural biology

DOI:  https://doi.org/10.7554/eLife.75039
Science. 2022 11 04. 378(6619): 488-492

Atlas-based data integration for mapping the connections and architecture of the brain.

Trygve B Leergaard, Jan G Bjaalie.

Detailed knowledge about the neural connections among regions of the brain is key for advancing our understanding of normal brain function and changes that occur with aging and disease. Researchers use a range of experimental techniques to map connections at different levels of granularity in rodent animal models, but the results are often challenging to compare and integrate. Three-dimensional reference atlases of the brain provide new opportunities for cumulating, integrating, and reinterpreting research findings across studies. Here, we review approaches for integrating data describing neural connections and other modalities in rodent brain atlases and discuss how atlas-based workflows can facilitate brainwide analyses of neural network organization in relation to other facets of neuroarchitecture.

DOI: https://doi.org/10.1126/science.abq2594
Korean J Neurotrauma. 2022 Oct;18(2): 188-197

Effect of MCI-186 on Lipid Peroxidation in Experimental Traumatic Brain Damage in Rats.

Murat Baloglu, Metin Ant Atasoy.

   Objective: Brain damage occurs in many clinical conditions, including trauma, ischemia, and hypertension. Reactive oxygen products and lipid peroxidation are responsible for the brain damage that occurs in these clinical conditions. We investigated whether MCI-186 (3-methyl-1-phenyl-2-pyrazoline-5-one), a free radical binding agent on lipid peroxidation, affects malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase (GPx) levels in traumatic brain damage.
Methods: The traumatic brain damage model, modified by Feeney, was performed on 28 male Wistar rats separated into 4 groups. The MDA, GSH, and GPx levels in the brain tissues of each group were studied.
Results: MDA levels in the traumatized group were significantly higher than those in the sham and MCI-186 groups (p<0.05), while GSH levels were significantly higher in the sham group than in the trauma and solvent groups (p<0.05). No significant difference was observed between the sham and MCI-186 groups (p>0.05). Although the average GPx level was higher in the sham and MCI-186 groups, no significant difference was found between groups.
Conclusion: Reactive oxidation products significantly decreased in the MCI-186 group. Thus, MCI-186 can be used as a free radical-binding agent in traumatic brain damage.

Keywords:  Antioxidant; Free radical; Lipid peroxidation; MCI-186; Traumatic brain injury

DOI:  https://doi.org/10.13004/kjnt.2022.18.e30
Nature. 2022 Nov 16.

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.

Joel W Blanchard, Leyla Anne Akay, Jose Davila-Velderrain, Djuna von Maydell, Hansruedi Mathys, Shawn M Davidson, Audrey Effenberger, Chih-Yu Chen, Kristal Maner-Smith, Ihab Hajjar, Eric A Ortlund, Michael Bula, Emre Agbas, Ayesha Ng, Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta Lin, Tak Ko, Lea R'Bibo, William T Ralvenius, David A Bennett, Hugh P Cam, Manolis Kellis, Li-Huei Tsai.

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.

DOI: https://doi.org/10.1038/s41586-022-05439-w