bims-medebr 2023-12-24 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–12–24
28 papers selected by
Regina F. Fernández, Johns Hopkins University

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.
Intracellular cholesterol visualization in brain tissue using D4H∗.
Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics.
Lactate Mediates High-Intensity Interval Training-Induced Promotion of Hippocampal Mitochondrial Function through the GPR81-ERK1/2 Pathway.
Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.
Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer's Disease.
Extracellular vesicle-associated cholesterol supports the regenerative functions of macrophages in the brain.
Metabolic Determinants of Cerebellar Circuit Formation and Maintenance.
Filipin complex-reactive brain lesions: a cautionary tale.
Cholesterol is more readily oxidized than phospholipid linoleates in cell membranes to produce cholesterol hydroperoxides.
Metabolic transitions regulate global protein fatty acylation.
Neuron-specific loss of Ppp6c induces neonatal death and decreases the number of cortical neurons and interneurons.
Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex.
BACH1 changes microglial metabolism and affects astrogenesis during mouse brain development.
HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND).
ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.
Palmitoylation of the Glucagon-like Peptide-1 Receptor Modulates Cholesterol Interactions at the Receptor-Lipid Microenvironment.
Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress.
Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.
Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL): Report of a new family and a novel DARS2 mutation.
Important roles of linoleic acid and α-linolenic acid in regulating cognitive impairment and neuropsychiatric issues in metabolic-related dementia.
Global quantitative proteomic analysis of aged mouse hippocampus.
Butyrate suppresses experimental necrotizing enterocolitis-induced brain injury in mice.
Generation of a Dcx-CreERT2 knock-in mouse for genetic manipulation of newborn neurons.
Protein kinase D (PKD) on the crossroad of lipid absorption, synthesis and utilization.
ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells.
Dopamine transporter membrane mobility is bidirectionally regulated by phosphorylation and palmitoylation.
Central activation of the fatty acid sensor GPR120 suppresses microglia reactivity and alleviates sickness- and anxiety-like behaviors.

Mol Psychiatry. 2023 Dec 22.

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism.

Keiji Kawatani, Marie-Louise Holm, Skylar C Starling, Yuka A Martens, Jing Zhao, Wenyan Lu, Yingxue Ren, Zonghua Li, Peizhou Jiang, Yangying Jiang, Samantha K Baker, Ni Wang, Bhaskar Roy, Tammee M Parsons, Ralph B Perkerson, Hanmei Bao, Xianlin Han, Guojun Bu, Takahisa Kanekiyo.

ABCA7 loss-of-function variants are associated with increased risk of Alzheimer's disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency-induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids. Furthermore, ABCA7-deficient iPSC-derived neurons showed compromised mitochondrial respiration and excess ROS generation, as well as enlarged mitochondrial morphology compared to the isogenic controls. ABCA7 deficiency also decreased spontaneous synaptic firing and network formation in iPSC-derived neurons, in which the effects were rescued by supplementation with phosphatidylglycerol or NAD+ precursor, nicotinamide mononucleotide. Importantly, effects of ABCA7 deficiency on mitochondria morphology and synapses were recapitulated in synaptosomes isolated from the brain of neuron-specific Abca7 knockout mice. Together, our results provide evidence that ABCA7 loss-of-function contributes to AD risk by modulating mitochondria lipid metabolism.

DOI: https://doi.org/10.1038/s41380-023-02372-w
STAR Protoc. 2023 Dec 13. pii: S2666-1667(23)00746-3. [Epub ahead of print]5(1): 102779

Intracellular cholesterol visualization in brain tissue using D4H∗.

Sherida M de Leeuw, Tal Nuriel.

  Studying cholesterol biology in the brain has been greatly hindered by the lack of adequate cholesterol visualization techniques. Here, we present a protocol for using a high-affinity cholesterol probe D4H∗-mCherry as a histology reagent in mouse or human brain tissue. We describe steps for D4H∗ tissue treatment and crosslinking leading to stable labeling of intracellular membrane cholesterol. Furthermore, co-labeling with Rab5 endosomal marker and optimized buffers to reduce background enable punctate cholesterol visualization within the organelle membranes.

Keywords:  Antibody; Microscopy; Molecular/Chemical Probes

DOI:  https://doi.org/10.1016/j.xpro.2023.102779
Redox Biol. 2023 Dec 12. pii: S2213-2317(23)00397-X. [Epub ahead of print]69 102996

Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics.

Xiaolin Han, Shan Huang, Ziyun Zhuang, Xiaochen Zhang, Min Xie, Nengjun Lou, Mengyu Hua, Xianghua Zhuang, Shuyan Yu, Shihong Chen.

  Diabetic encephalopathy (DE) is a common central nervous system complication of diabetes mellitus without effective therapy currently. Recent studies have highlighted synaptic mitochondrial damages as a possible pathological basis for DE, but the underlying mechanisms remain unclear. Our previous work has revealed that phosphatidate phosphatase Lipin1, a critical enzyme involved with phospholipid synthesis, is closely related to the pathogenesis of DE. Here, we demonstrate that Lipin1 is significantly down-regulated in rat hippocampus of DE. Knock-down of Lipin1 within hippocampus of normal rats induces dysregulation of homeostasis in synaptic mitochondrial dynamics with an increase of mitochondrial fission and a decrease of fusion, then causes synaptic mitochondrial dysfunction, synaptic plasticity deficits as well as cognitive impairments, similar to that observed in response to chronic hyperglycemia exposure. In contrast, an up-regulation of Lipin1 within hippocampus in the DE model ameliorates this cascade of dysfunction. We also find that the effect of Lipin1 that regulating mitochondrial dynamics results from maintaining appropriate phospholipid components in the mitochondrial membrane. In conclusion, alterations in hippocampal Lipin1 contribute to hippocampal synaptic mitochondrial dysfunction and cognitive deficits observed in DE. Targeting Lipin1 might be a potential therapeutic strategy for the clinical treatment of DE.

Keywords:  Cognitive dysfunction; Diabetic encephalopathy; Lipin1; Phospholipids; Synaptic mitochondrial dynamics; Synaptic plasticity

DOI:  https://doi.org/10.1016/j.redox.2023.102996
Antioxidants (Basel). 2023 Dec 07. pii: 2087. [Epub ahead of print]12(12):

Lactate Mediates High-Intensity Interval Training-Induced Promotion of Hippocampal Mitochondrial Function through the GPR81-ERK1/2 Pathway.

Qinghui Shang, Xuepeng Bian, Lutao Zhu, Jun Liu, Min Wu, Shujie Lou.

  Mitochondrial biogenesis and fusion are essential for maintaining healthy mitochondria and ATP production. High-intensity interval training (HIIT) can enhance mitochondrial function in mouse hippocampi, but its underlying mechanism is not completely understood. Lactate generated during HIIT may mediate the beneficial effects of HIIT on neuroplasticity by activating the lactate receptor GPR81. Furthermore, growing evidence shows that lactate contributes to mitochondrial function. Given that mitochondrial function is crucial for cerebral physiological processes, the current study aimed to determine the mechanism of HIIT in hippocampal mitochondrial function. In vivo, GPR81 was knocked down in the hippocampi of mice via the injection of adeno-associated virus (AAV) vectors. The GPR81-knockdown mice were subjected to HIIT. The results demonstrated that HIIT increased mitochondria numbers, ATP production, and oxidative phosphorylation (OXPHOS) in the hippocampi of mice. In addition, HIIT induced mitochondrial biogenesis, fusion, synaptic plasticity, and ERK1/2 phosphorylation but not in GPR81-knockdown mice. In vitro, Neuro-2A cells were treated with L-lactate, a GPR81 agonist, and an ERK1/2 inhibitor. The results showed that both L-lactate and the GPR81 agonist increased mitochondrial biogenesis, fusion, ATP levels, OXPHOS, mitochondrial membrane potential, and synaptic plasticity. However, the inhibition of ERK1/2 phosphorylation blunted L-lactate or the GPR81 agonist-induced promotion of mitochondrial function and synaptic plasticity. In conclusion, our findings suggest that lactate mediates HIIT-induced promotion of mitochondrial function through the GPR81-ERK1/2 pathway.

Keywords:  ERK1/2; GPR81; high-intensity interval training; lactate; mitochondria

DOI:  https://doi.org/10.3390/antiox12122087
Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00449-7. [Epub ahead of print]

Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism.

Riley J Wedan, Jacob Z Longenecker, Sara M Nowinski.

  Contrary to their well-known functions in nutrient breakdown, mitochondria are also important biosynthetic hubs and express an evolutionarily conserved mitochondrial fatty acid synthesis (mtFAS) pathway. mtFAS builds lipoic acid and longer saturated fatty acids, but its exact products, their ultimate destination in cells, and the cellular significance of the pathway are all active research questions. Moreover, why mitochondria need mtFAS despite their well-defined ability to import fatty acids is still unclear. The identification of patients with inborn errors of metabolism in mtFAS genes has sparked fresh research interest in the pathway. New mammalian models have provided insights into how mtFAS coordinates many aspects of oxidative mitochondrial metabolism and raise questions about its role in diseases such as obesity, diabetes, and heart failure. In this review, we discuss the products of mtFAS, their function, and the consequences of mtFAS impairment across models and in metabolic disease.

Keywords:  fatty acids; inborn errors of metabolism; lipid metabolism; lipids; mitochondria; mitochondrial fatty acid synthesis; mouse models; mtFAS

DOI:  https://doi.org/10.1016/j.cmet.2023.11.017
Int J Mol Sci. 2023 Dec 18. pii: 17604. [Epub ahead of print]24(24):

Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer's Disease.

Xue-Ying He, Jannusz Frackowiak, Carl Dobkin, William Ted Brown, Song-Yu Yang.

  Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10) is the HSD17B10 gene product playing an appreciable role in cognitive functions. It is the main hub of exercise-upregulated mitochondrial proteins and is involved in a variety of metabolic pathways including neurosteroid metabolism to regulate allopregnanolone homeostasis. Deacetylation of 17β-HSD10 by sirtuins helps regulate its catalytic activities. 17β-HSD10 may also play a critical role in the control of mitochondrial structure, morphology and dynamics by acting as a member of the Parkin/PINK1 pathway, and by binding to cyclophilin D to open mitochondrial permeability pore. 17β-HSD10 also serves as a component of RNase P necessary for mitochondrial tRNA maturation. This dehydrogenase can bind with the Aβ peptide thereby enhancing neurotoxicity to brain cells. Even in the absence of Aβ, its quantitative and qualitative variations can result in neurodegeneration. Since elevated levels of 17β-HSD10 were found in brain cells of Alzheimer's disease (AD) patients and mouse AD models, it is considered to be a key factor in AD pathogenesis. Since data underlying Aβ-binding-alcohol dehydrogenase (ABAD) were not secured from reported experiments, ABAD appears to be a fabricated alternative term for the HSD17B10 gene product. Results of this study would encourage researchers to solve the question why elevated levels of 17β-HSD10 are present in brains of AD patients and mouse AD models. Searching specific inhibitors of 17β-HSD10 may find candidates to reduce senile neurodegeneration and open new approaches for the treatment of AD.

Keywords:  17β-HSD10; ABAD; Alzheimer’s disease; mitochondria; multifunctional protein; neurosteroid metabolism

DOI:  https://doi.org/10.3390/ijms242417604
J Extracell Vesicles. 2023 Dec;12(12): e12394

Extracellular vesicle-associated cholesterol supports the regenerative functions of macrophages in the brain.

Sam Vanherle, Jeroen Guns, Melanie Loix, Fleur Mingneau, Tess Dierckx, Flore Wouters, Koen Kuipers, Tim Vangansewinkel, Esther Wolfs, Paula Pincela Lins, Annelies Bronckaers, Ivo Lambrichts, Jonas Dehairs, Johannes V Swinnen, Sanne G S Verberk, Mansour Haidar, Jerome J A Hendriks, Jeroen F J Bogie.

  Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation predominantly through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance support the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.

Keywords:  cholesterol; extracellular vesicle; oligodendrocyte precursor cell differentiation; remyelination; repair-associated macrophage

DOI:  https://doi.org/10.1002/jev2.12394
Cerebellum. 2023 Dec 20.

Metabolic Determinants of Cerebellar Circuit Formation and Maintenance.

Manuel Gonzalez-Rodriguez, Isaac Marin-Valencia.

  Cells configure their metabolism in a synchronized and timely manner to meet their energy demands throughout development and adulthood. Transitions of developmental stages are coupled to metabolic shifts, such that glycolysis is highly active during cell proliferation, whereas oxidative phosphorylation prevails in postmitotic states. In the cerebellum, metabolic transitions are remarkable given its protracted developmental timelines. Such distinctive feature, along with its high neuronal density and metabolic demands, make the cerebellum highly vulnerable to metabolic insults. Despite the expansion of metabolomic approaches to uncover biological mechanisms, little is known about the role of metabolism on cerebellar development and maintenance. To illuminate the intricate connections between metabolism, physiology, and cerebellar disorders, we examined here the impact of metabolism on cerebellar growth, maturation, and adulthood through the lens of inborn errors of metabolism.

Keywords:  Ataxia; Cerebellum; Inborn errors of metabolism; Metabolism; Neurodegeneration; Neurodevelopment

DOI:  https://doi.org/10.1007/s12311-023-01641-2
Neuropathol Appl Neurobiol. 2023 Dec 19. e12950

Filipin complex-reactive brain lesions: a cautionary tale.

Adeline A Lau, Paul J Trim, Barbara M King, Sofia Hassiotis, Ya Hui Hung, Ashley I Bush, Marten F Snel, Kim M Hemsley.

   OBJECTIVE: Filipin complex is an autooxidation-prone fluorescent histochemical stain used in the diagnosis of Niemann-Pick Disease Type C (NP-C), a neurodegenerative lysosomal storage disorder. It is also widely used by researchers examining the distribution and accumulation of unesterified cholesterol in cell and animal models of neurodegenerative diseases including NP-C and Sanfilippo syndrome (mucopolysaccharidosis IIIA; MPS IIIA). Recently, it has been suggested to be useful in studying Alzheimer's and Huntington's disease. Given filipin's susceptibility to photobleaching, we sought to establish a quantitative biochemical method for free cholesterol measurement.
METHODS: Brain tissue from mice with MPS IIIA was stained with filipin. Total and free cholesterol in brain homogenates was measured using a commercially available kit and a quantitative LC-MS/MS assay was developed. Gangliosides GM1, GM2 and GM3 were also quantified using LC-MS/MS.
RESULTS: As anticipated, the MPS IIIA mouse brain displayed large numbers of filipin-positive intra-cytoplasmic inclusions, presumptively endo-lysosomes. Challenging the prevailing dogma, however, we found no difference in the amount of free cholesterol in MPS IIIA mouse brain homogenates cf. control tissue, using either the fluorometric kit or LC-MS/MS assay. Filipin has previously been reported to bind to GM1 ganglioside, however, this lipid does not accumulate in MPS IIIA cells/tissues. Using a fluorometric assay, we demonstrate for the first time that filipin cross-reacts with both GM2 and GM3 gangliosides, explaining the filipin-reactive inclusions observed in MPS IIIA brain cells.
CONCLUSION: Filipin is not specific for free cholesterol, and positive staining in any setting should be interpreted with caution.

Keywords:  Filipin complex; Niemann-Pick C; cholesterol; ganglioside; lysosomal; mouse; mucopolysaccharidosis

DOI:  https://doi.org/10.1111/nan.12950
Free Radic Biol Med. 2023 Dec 13. pii: S0891-5849(23)01156-5. [Epub ahead of print]211 89-95

Cholesterol is more readily oxidized than phospholipid linoleates in cell membranes to produce cholesterol hydroperoxides.

Yoshiro Saito, Noriko Noguchi, Etsuo Niki.

  Cholesterol is an essential component of cell membranes and serves as an important precursor of steroidal hormones and bile acids, but elevated levels of cholesterol and its oxidation products have been accepted as a risk factor for maintenance of health. The free and ester forms of cholesterol and fatty acids are the two major biological lipids. The aim of this hypothesis paper is to address the long-standing dogma that cholesterol is less susceptible to free radical peroxidation than polyunsaturated fatty acids (PUFAs). It has been observed that cholesterol is peroxidized much slower than PUFAs in plasma but that, contrary to expectations from chemical reactivity toward peroxyl radicals, cholesterol appears to be more readily autoxidized than linoleates in cell membranes. The levels of oxidation products of cholesterol and linoleates observed in humans support this notion. It is speculated that this discrepancy is ascribed to the fact that cholesterol and phospholipids bearing PUFAs are localized apart in raft and non-raft domains of cell membranes respectively and that the antioxidant vitamin E distributed predominantly in the non-raft domains cannot suppress the oxidation of cholesterol lying in raft domains which are relatively deficient in antioxidant.

Keywords:  Cholesterol; Free radical peroxidation; Hydroperoxide; Lipid raft; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.011
J Biol Chem. 2023 Dec 13. pii: S0021-9258(23)02591-7. [Epub ahead of print] 105563

Metabolic transitions regulate global protein fatty acylation.

Manasi Talwadekar, Subhash Khatri, Chinthapalli Balaji, Arnab Chakraborty, Nandini-Pal Basak, Siddhesh Kamat, Ullas Kolthur-Seetharam.

  Intermediary metabolites and flux through various pathways have emerged as key determinants of post-translational modifications. Independently, dynamic fluctuations in their concentrations are known to drive cellular energetics in a bi-directional manner. Notably, intracellular fatty acid pools that drastically change during fed and fasted states act as precursors for both ATP production and fatty acylation of proteins. Protein fatty acylation is well regarded for its role in regulating structure and functions of diverse proteins, however the effect of intracellular concentrations of fatty acids on protein modification is less understood. In this regard, we unequivocally demonstrate that metabolic contexts, viz. fed and fasted states, dictate the extent of global fatty acylation. Moreover, we show that presence or absence of glucose, that influences cellular and mitochondrial uptake/utilization of fatty acids, affects palmitoylation and oleoylation, which is consistent with their intracellular abundance in fed and fasted states. Employing complementary approaches including click-chemistry, lipidomics and imaging, we show the top-down control of cellular metabolic state. Importantly, our results establish the crucial role of mitochondria and retrograde signaling components like SIRT4, AMPK and mTOR in orchestrating protein fatty acylation at a whole cell level. Specifically, pharmacogenetic perturbations that alter either mitochondrial functions and/or retrograde signaling affect protein fatty acylation. Besides illustrating the cross-talk between carbohydrate and lipid metabolism in mediating bulk post-translational modification, our findings also highlight the involvement of mitochondrial energetics.

Keywords:  Acylation; acyl exchange; free fatty acids; oleate; palmitate; sirtuins

DOI:  https://doi.org/10.1016/j.jbc.2023.105563
Biochem Biophys Res Commun. 2023 Dec 05. pii: S0006-291X(23)01447-X. [Epub ahead of print]693 149353

Neuron-specific loss of Ppp6c induces neonatal death and decreases the number of cortical neurons and interneurons.

Miki Matsuoka, Daisuke Sakai, Hiroshi Shima, Toshio Watanabe.

Protein phosphatase 6 (PP6) is a Ser/Thr protein phosphatase with the catalytic subunit Ppp6c. Recent cell-level studies have revealed that Ppp6c knockdown suppresses neurite outgrowth, suggesting that Ppp6c is involved in the development of the nervous system. We found that the function of PP6 in neurons is essential for mouse survival after birth, as all neural-stem-cell-specific KO (Ppp6cNKO) and neuron-specific KO mice died within 2 days of birth. By contrast, approximately 40 % of oligodendrocyte-specific KO mice died within 2 days of birth, whereas others survived until weaning or later, suggesting that the lethality of PP6 loss differs between neurons and oligodendrocytes. Furthermore, the fetal brain of Ppp6cNKO mice exhibited decreased numbers of neurons in layers V-VI and interneurons in layer I of the neocortex. These results suggest for the first time that Ppp6c is essential for neonatal survival and proper development of neurons and interneurons in the neocortex.

DOI: https://doi.org/10.1016/j.bbrc.2023.149353
Nat Commun. 2023 Dec 16. 14(1): 8380

Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex.

Alexander Popov, Nadezda Brazhe, Kseniia Morozova, Konstantin Yashin, Maxim Bychkov, Olga Nosova, Oksana Sutyagina, Alexey Brazhe, Evgenia Parshina, Li Li, Igor Medyanik, Dmitry E Korzhevskii, Zakhar Shenkarev, Ekaterina Lyukmanova, Alexei Verkhratsky, Alexey Semyanov.

How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in the neocortical tissue of younger (22-50 years) and older (51-72 years) adults. Aging decreases the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The protein-to-lipid ratio decreases in astrocytes and increases in neurons. Aged astrocytes show morphological atrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Atrophy correlates with the loss of gap junction coupling between astrocytes and increased input resistance. Aging is accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling is observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of cortical astrocytes, but not neurons.

DOI: https://doi.org/10.1038/s41467-023-44192-0
Dev Cell. 2023 Dec 07. pii: S1534-5807(23)00616-0. [Epub ahead of print]

BACH1 changes microglial metabolism and affects astrogenesis during mouse brain development.

Yanyan Wang, Wenwen Wang, Libo Su, Fen Ji, Mengtian Zhang, Yanzhen Xie, Tianyu Zhang, Jianwei Jiao.

  Microglia are highly heterogeneous as resident immune cells in the central nervous system. Although the proinflammatory phenotype of microglia is driven by the metabolic transformation in the disease state, the mechanism of metabolic reprogramming in microglia and whether it affects surrounding astrocyte progenitors have not been well elucidated. Here, we illustrate the communication between microglial metabolism and astrogenesis during embryonic development. The transcription factor BTB and CNC homology 1 (Bach1) reduces lactate production by inhibiting two key enzymes, HK2 and GAPDH, during glycolysis. Metabolic perturbation of microglia reduces lactate-dependent histone modification enrichment at the Lrrc15 promoter. The microglia-derived LRRC15 interacts with CD248 to participate in the JAK/STAT pathway and influence astrogenesis. In addition, Bach1cKO-Cx3 mice exhibit abnormal neuronal differentiation and anxiety-like behaviors. Altogether, this work suggests that the maintenance of microglia metabolic homeostasis during early brain development is closely related to astrogenesis, providing insights into astrogenesis and related diseases.

Keywords:  BACH1; LRRC15; astrogenesis; histone lactylation; microglia metabolism

DOI:  https://doi.org/10.1016/j.devcel.2023.11.018
Int J Mol Sci. 2023 Dec 17. pii: 17566. [Epub ahead of print]24(24):

HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND).

Izchel Figarola-Centurión, Martha Escoto-Delgadillo, Gracia Viviana González-Enríquez, Juan Ernesto Gutiérrez-Sevilla, Eduardo Vázquez-Valls, Jhonathan Cárdenas-Bedoya, Blanca Miriam Torres-Mendoza.

  During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague-Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.

Keywords:  HAND; HIV; Pink1; Ppargc1a; Sirt3; Tert; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy; telomeric dysfunction

DOI:  https://doi.org/10.3390/ijms242417566
Neurobiol Dis. 2023 Dec 16. pii: S0969-9961(23)00402-3. [Epub ahead of print]190 106386

ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.

Wardiya Afshar-Saber, Nicole A Teaney, Kellen D Winden, Hellen Jumo, Xutong Shi, Gabrielle McGinty, Jed Hubbs, Cidi Chen, Itay Tokatly Latzer, Federico Gasparoli, Darius Ebrahimi-Fakhari, Elizabeth D Buttermore, Jean-Baptiste Roullet, Phillip L Pearl, Mustafa Sahin.

  Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.

Keywords:  Autism spectrum disorder; Epilepsy; GABA metabolism; Mitochondrion; Stem cell derived neurons

DOI:  https://doi.org/10.1016/j.nbd.2023.106386
J Phys Chem B. 2023 Dec 19.

Palmitoylation of the Glucagon-like Peptide-1 Receptor Modulates Cholesterol Interactions at the Receptor-Lipid Microenvironment.

Amit Naglekar, Amitabha Chattopadhyay, Durba Sengupta.

The G protein-coupled receptor (GPCR) superfamily of cell surface receptors has been shown to be functionally modulated by post-translational modifications. The glucagon-like peptide receptor-1 (GLP-1R), which is a drug target in diabetes and obesity, undergoes agonist-dependent palmitoyl tail conjugation. The palmitoylation in the C-terminal domain of GLP-1R has been suggested to modulate the receptor-lipid microenvironment. In this work, we have performed coarse-grain molecular dynamics simulations of palmitoylated and nonpalmitoylated GLP-1R to analyze the differential receptor-lipid interactions. Interestingly, the placement and dynamics of the C-terminal domain of GLP-1R are found to be directly dependent on the palmitoyl tail. We observe that both cholesterol and phospholipids interact with the receptor but display differential interactions in the presence and absence of the palmitoyl tail. We characterize important cholesterol-binding sites and validate sites that have been previously reported in experimentally resolved structures of the receptor. We show that the receptor acts like a conduit for cholesterol flip-flop by stabilizing cholesterol in the membrane core. Taken together, our work represents an important step in understanding the molecular effects of lipid modifications in GPCRs.

DOI: https://doi.org/10.1021/acs.jpcb.3c05930
Antioxidants (Basel). 2023 Nov 21. pii: 2021. [Epub ahead of print]12(12):

Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress.

Dongun Lee, Jeong Hee Hong.

  Cholesterol trafficking is initiated by the endocytic pathway and transported from endo/lysosomes to other intracellular organelles. Deficiencies in cholesterol-sensing and binding proteins NPC1 and NPC2 induce accumulation in lysosomes and the malfunction of trafficking to other organelles. Each organelle possesses regulatory factors to induce cholesterol trafficking. The mutation of NPC1 and NPC2 genes induces Niemann-Pick disease type C (NPDC), which is a hereditary disease and causes progressive neurodegeneration, developmental disability, hypotonia, and ataxia. Oxidative stress induces damage in NPDC-related intracellular organelles. Although studies on the relationship between NPDC and oxidation are relatively rare, several studies have reported the therapeutic potential of antioxidants in treating NPDC. Investigating antioxidant drugs to relieve oxidative stress and cholesterol accumulation is suggested to be a powerful tool for developing treatments for NPDC. Understanding NPDC provides challenging issues in understanding the oxidative stress-lysosome metabolism of the lipid axis. Thus, we elucidated the relationship between complexes of intracellular organelles and NPDC to develop our knowledge and suggested potential antioxidant reagents for NPDC therapy.

Keywords:  Niemann-Pick disease type C; cholesterol trafficking; lysosomal proteins; lysosomal storage disorders; oxidative stress

DOI:  https://doi.org/10.3390/antiox12122021
Brain Res. 2023 Dec 16. pii: S0006-8993(23)00495-X. [Epub ahead of print]1825 148724

Upregulation of mitochondrial PGK1 by ROS-TBC1D15 pathway promotes neuronal death after oxygen-glucose deprivation/reoxygenation injury.

Songfeng Chen, Hui Wang, Juan Chen, Jing Cheng, Jingchen Gao, Shujun Chen, Xujin Yao, Jiangdong Sun, Jinyang Ren, Shifang Li, Fengyuan Che, Qi Wan.

  Phosphoglycerate kinase 1 (PGK1) is extensively located in the cytosol and mitochondria. The role of PGK1 in ischemic neuronal injury remains elusive. In the in vitro model of oxygen-glucose deprivation/reoxygenation (OGD/R), we showed that PGK1 expression was increased in cortical neurons. Knockdown of PGK1 led to a reduction of OGD/R-induced neuronal death. The expression of cytosolic PGK1 was reduced, but the levels of mitochondrial PGK1 were increased in OGD/R-insulted neurons. Inhibiting the activity of mitochondrial PGK1 alleviated the neuronal injury after OGD/R insult. We further showed that the protein levels of TBC domain family member 15 (TBC1D15) were decreased in OGD/R-insulted neurons. Knockdown of TBC1D15 led to increased levels of mitochondrial PGK1 after OGD/R insult in cortical neurons. Moreover, increased reactive oxygen species (ROS) resulted in a reduction of TBC1D15 in OGD/R-insulted neurons. These results suggest that the upregulation of mitochondrial PGK1 by ROS-TBC1D15 signaling pathway promotes neuronal death after OGD/R injury. Mitochondrial PGK1 may act as a regulator of neuronal survival and interventions in the PGK1-dependent pathway may be a potential therapeutic strategy.

Keywords:  Mitochondria; Oxygen-glucose deprivation/reoxygenation; Phosphoglycerate Kinase 1; Reactive oxygen species; TBC domain family member 15

DOI:  https://doi.org/10.1016/j.brainres.2023.148724
Mol Genet Metab Rep. 2024 Mar;38 101025

Leukoencephalopathy with Brain stem and Spinal cord involvement and Lactate elevation (LBSL): Report of a new family and a novel DARS2 mutation.

Wei-Lin Huang, Maija R Steenari, Rebekah Barrick, Mariella T Simon, Richard Chang, Shaya S Eftekharian, Alexander Stover, Philip H Schwartz, Alexandra Latini, Jose E Abdenur.

   Background: LBSL is a mitochondrial disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, resulting in a distinctive pattern on brain magnetic resonance imaging (MRI) and spectroscopy. Clinical presentation varies from severe infantile to chronic, slowly progressive neuronal deterioration in adolescents or adults. Most individuals with LBSL are compound heterozygous for one splicing defect in an intron 2 mutational hotspot and a second defect that could be a missense, non-sense, or splice site mutation or deletion resulting in decreased expression of the full-length protein.
Aim: To present a new family with two affected members with LBSL and report a novel DARS2 mutation.
Results: An 8-year-old boy (Patient 1) was referred due to headaches and abnormal MRI, suggestive of LBSL. Genetic testing revealed a previously reported c.492 + 2 T > C mutation in the DARS2 gene. Sanger sequencing uncovered a novel variant c.228-17C > G in the intron 2 hotspot. Family studies found the same genetic changes in an asymptomatic 4-year-old younger brother (Patient 2), who was found on follow-up to have an abnormal MRI. mRNA extracted from patients' fibroblasts showed that the c.228-17C > G mutation caused skipping of exon 3 resulting in lower DARS2 mRNA level. Complete absence of DARS2 protein was also found in both patients.
Summary: We present a new family with two children affected with LBSL and describe a novel mutation in the DARS2 intron 2 hotspot. Despite findings of extensive white matter disease in the brain and spine, the proband in this family presented only with headaches, while the younger sibling, who also had extensive white matter changes, was asymptomatic. Our in-vitro results confirmed skipping of exon 3 in patients and family members carrying the intron 2 variant, which is consistent with previous reported mutations in intron 2 hotspots. DARS2 mRNA and protein levels were also reduced in both patients, further supporting the pathogenicity of the novel variant.

Keywords:  Aminoacyl tRNA synthetase deficiency; Aspartyl tRNA synthetase deficiency; Leukodystrophy; Mitochondrial disorders; Splicing mutations

DOI:  https://doi.org/10.1016/j.ymgmr.2023.101025
Life Sci. 2023 Dec 18. pii: S0024-3205(23)00991-8. [Epub ahead of print]337 122356

Important roles of linoleic acid and α-linolenic acid in regulating cognitive impairment and neuropsychiatric issues in metabolic-related dementia.

Oh Yoen Kim, Juhyun Song.

  Metabolic syndrome (MetS), which is characterized by insulin resistance, high blood glucose, obesity, and dyslipidemia, is known to increase the risk of dementia accompanied by memory loss and depression. The direct pathways and specific mechanisms in the central nervous system (CNS) for addressing fatty acid imbalances in MetS have not yet been fully elucidated. Among polyunsaturated acids, linoleic acid (LA, n6-PUFA) and α-linolenic acid (ALA, n3-PUFA), which are two essential fatty acids that should be provided by food sources (e.g., vegetable oils and seeds), have been reported to regulate various cellular mechanisms including apoptosis, inflammatory responses, mitochondrial biogenesis, and insulin signaling. Furthermore, inadequate intake of LA and ALA is reported to be involved in neuropathology and neuropsychiatric diseases as well as imbalanced metabolic conditions. Herein, we review the roles of LA and ALA on metabolic-related dementia focusing on insulin resistance, dyslipidemia, synaptic plasticity, cognitive function, and neuropsychiatric issues. This review suggests that LA and ALA are important fatty acids for concurrent treatment of both MetS and neurological problems.

Keywords:  Cognitive impairment; Dementia; Linoleic acid (LA); Metabolic syndrome (MetS); α-Linolenic acid (ALA)

DOI:  https://doi.org/10.1016/j.lfs.2023.122356
Proteomics. 2023 Dec 19. e2300276

Global quantitative proteomic analysis of aged mouse hippocampus.

He Huang, Ashley J van Waardenberg, Mark E Graham, Victor Anggono, Jocelyn Widagdo.

  Understanding the molecular changes associated with the aged brain forms the basis for developing potential strategies for slowing cognitive decline associated with normal aging. Focusing on the hippocampus, a critical brain region involved in learning and memory, we employed tandem mass tag methodology to investigate global proteomic changes that occur in advanced-aged (20-month) versus young (3-month) C57BL/6 male mice. Our analysis revealed the upregulation of 236 proteins in the old hippocampal proteome, including those enriched within several age-related processes, such as the adaptive immune response and molecular metabolic pathways, whereas downregulated proteins (88 in total) are mainly involved in axonogenesis and growth cone-related processes. Categorizing proteins by cell-type enrichment in the brain identified a general upregulation of proteins preferentially expressed in microglia, astrocytes, and oligodendrocytes. In contrast, proteins with neuron-specific expression displayed an overall age-related downregulation. By integrating our proteomic with our previously published transcriptomic data, we discovered a mild but significant positive correlation between mRNA and protein expression changes in the aged hippocampus. Therefore, this proteomic data is a valuable additional resource for further understanding age-related molecular mechanisms.

Keywords:  aging; cognitive decline; hippocampus; mass-spectrometry; proteomics

DOI:  https://doi.org/10.1002/pmic.202300276
Front Pediatr. 2023 ;11 1284085

Butyrate suppresses experimental necrotizing enterocolitis-induced brain injury in mice.

Maribel Martinez, Wei Yu, Heather L Menden, Tianhua Lei, Paula Monaghan-Nichols, Venkatesh Sampath.

   Background: Necrotizing enterocolitis (NEC) is a devastating disease in premature infants, and 50% of infants with surgical NEC develop neurodevelopmental defects. The mechanisms by which NEC-induced cytokine release and activation of inflammatory cells in the brain mediate neuronal injury, and whether enteral immunotherapy attenuates NEC-associated brain injury remain understudied. Based on our prior work, which demonstrated that experimental NEC-like intestinal injury is attenuated by the short-chain fatty acid, butyrate, in this study, we hypothesize that NEC-induced brain injury would be suppressed by enteral butyrate supplementation.
Methods: A standardized NEC mouse model [enteral formula feeding, lipopolysaccharide (LPS), and hypoxia] was used. Mice were randomized into the following groups: control, NEC, butyrate pretreated NEC, and butyrate control. NEC scoring (1-4 with 4 representing severe injury) was performed on ileal sections using a validated scoring system. Intestinal and brain lysates were used to assess inflammation, proinflammatory signaling, and apoptosis.
Results: NEC-induced intestinal injury was attenuated by butyrate supplementation. NEC-induced microglial activation in the cerebral cortex and hippocampus was suppressed with butyrate. NEC increased the number of activated microglial cells but decreased the number of oligodendrocytes. Butyrate pretreatment attenuated these changes. Increased activation of proinflammatory Toll-like receptor signaling, cytokine expression, and induction of GFAP and IBA1 in the cerebral cortex observed with NEC was suppressed with butyrate.
Conclusion: Experimental NEC induced inflammation and activation of microglia in several regions of the brain, most prominently in the cortex. NEC-induced neuroinflammation was suppressed with butyrate pretreatment. The addition of short-chain fatty acids to diet may be used to attenuate NEC-induced intestinal injury and neuroinflammation in preterm infants.

Keywords:  NEC; brain injury; butyrate; inflammation; microglia; oligodendrocyte

DOI:  https://doi.org/10.3389/fped.2023.1284085
Genesis. 2023 Dec 16. e23584

Generation of a Dcx-CreERT2 knock-in mouse for genetic manipulation of newborn neurons.

Gabriella A Perez, Kyung-Won Park, Denise Lanza, Jenna Cicardo, M Danish Uddin, Joanna L Jankowsky.

  A wide variety of CreERT2 driver lines are available for genetic manipulation of adult-born neurons in the mouse brain. These tools have been instrumental in studying fate potential, migration, circuit integration, and morphology of the stem cells supporting lifelong neurogenesis. Despite a wealth of tools, genetic manipulation of adult-born neurons for circuit and behavioral studies has been limited by poor specificity of many driver lines targeting early progenitor cells and by the inaccessibility of lines selective for later stages of neuronal maturation. We sought to address these limitations by creating a new CreERT2 driver line targeted to the endogenous mouse doublecortin locus as a marker of fate-specified neuroblasts and immature neurons. Our new model places a T2A-CreERT2 cassette immediately downstream of the Dcx coding sequence on the X chromosome, allowing expression of both Dcx and CreERT2 proteins in the endogenous spatiotemporal pattern for this gene. We demonstrate that the new mouse line drives expression of a Cre-dependent reporter throughout the brain in neonatal mice and in known neurogenic niches of adult animals. The line has been deposited with the Jackson Laboratory and should provide an accessible tool for studies targeting fate-restricted neuronal precursors.

Keywords:  CreER; adult neurogenesis; dentate gyrus; doublecortin; hippocampus; neural progenitor; olfactory bulb; subgranular zone

DOI:  https://doi.org/10.1002/dvg.23584
Biochim Biophys Acta Mol Cell Res. 2023 Dec 15. pii: S0167-4889(23)00226-4. [Epub ahead of print]1871(2): 119653

Protein kinase D (PKD) on the crossroad of lipid absorption, synthesis and utilization.

Magdalena Wit, Andrei Belykh, Grzegorz Sumara.

  Inappropriate lipid levels in the blood, as well as its content and composition in different organs, underlie multiple metabolic disorders including obesity, non-alcoholic fatty liver disease, type 2 diabetes, and atherosclerosis. Multiple processes contribute to the complex metabolism of triglycerides (TGs), fatty acids (FAs), and other lipid species. These consist of digestion and absorption of dietary lipids, de novo FAs synthesis (lipogenesis), uptake of TGs and FAs by peripheral tissues, TGs storage in the intracellular depots as well as lipid utilization for β-oxidation and their conversion to lipid-derivatives. A majority of the enzymatic reactions linked to lipogenesis, TGs synthesis, lipid absorption, and transport are happening at the endoplasmic reticulum, while β-oxidation takes place in mitochondria and peroxisomes. The Golgi apparatus is a central sorting, protein- and lipid-modifying organelle and hence is involved in lipid metabolism as well. However, the impact of the processes taking part in the Golgi apparatus are often overseen. The protein kinase D (PKD) family (composed of three members, PKD1, 2, and 3) is the master regulator of Golgi dynamics. PKDs are also a sensor of different lipid species in distinct cellular compartments. In this review, we discuss the roles of PKD family members in the regulation of lipid metabolism including the processes executed by PKDs at the Golgi apparatus. We also discuss the role of PKDs-dependent signaling in different cellular compartments and organs in the context of the development of metabolic disorders.

Keywords:  Golgi apparatus; Lipid metabolism; Metabolic disease; PKD; Protein kinase D

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119653
Nat Commun. 2023 Dec 20. 14(1): 8463

ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells.

Jiyeon Lee, Haeryung Lee, Hyein Lee, Miram Shin, Min-Gi Shin, Jinsoo Seo, Eun Jeong Lee, Sun Ah Park, Soochul Park.

Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer's disease mouse model results in exacerbated Aβ pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aβ clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aβ clearance across the BBB.

DOI: https://doi.org/10.1038/s41467-023-44319-3
Curr Res Physiol. 2023 ;6 100106

Dopamine transporter membrane mobility is bidirectionally regulated by phosphorylation and palmitoylation.

Madhur Shetty, Danielle E Bolland, Joshua Morrell, Bryon D Grove, James D Foster, Roxanne A Vaughan.

  The primary regulator of dopamine availability in the brain is the dopamine transporter (DAT), a plasma membrane protein that drives reuptake of released dopamine from the extracellular space into the presynaptic neuron. DAT activity is regulated by post-translational modifications that establish clearance capacity through impacts on transport kinetics, and dysregulation of these events may underlie dopaminergic imbalances in mood and psychiatric disorders. Here, using fluorescence recovery after photobleaching, we show that phosphorylation and palmitoylation induce opposing effects on DAT lateral membrane mobility, which may influence functional outcomes by regulating subcellular localization and binding partner interactions. Membrane mobility was also impacted by amphetamine and in polymorphic variant A559V in directions consistent with enhanced phosphorylation. These findings grow the list of DAT properties controlled by these post-translational modifications and highlight their role in establishment of dopaminergic tone in physiological and pathophysiological states.

Keywords:  2-Bromopalmitate; Amphetamine; DHHC2; FRAP; Fluorescence recovery after photobleaching; Mitogen activated protein kinase; Palmitoyl acyl transferase; Protein kinase C

DOI:  https://doi.org/10.1016/j.crphys.2023.100106
J Neuroinflammation. 2023 Dec 19. 20(1): 302

Central activation of the fatty acid sensor GPR120 suppresses microglia reactivity and alleviates sickness- and anxiety-like behaviors.

Shingo Nakajima, Geneviève Demers, Arturo Israel Machuca-Parra, Zahra Dashtehei Pour, Diane Bairamian, Khalil Bouyakdan, Alexandre Fisette, Anita Kabahizi, Josephine Robb, Demetra Rodaros, Cyril Laurent, Guillaume Ferreira, Nathalie Arbour, Thierry Alquier, Stephanie Fulton.

  G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1β and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1β. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions.

Keywords:  Anxiety; Behavioral neuroimmunology; Endotoxemia; Ffar4; Free fatty acid receptor; Locomotion; Neuropharmacology; Nucleus accumbens; Sickness behaviors

DOI:  https://doi.org/10.1186/s12974-023-02978-5