bims-medebr 2024-07-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–07–21
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University

Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice.
Deuterium Metabolic Imaging of Alzheimer Disease at 3-T Magnetic Field Strength: A Pilot Case-Control Study.
The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.
Synaptic mitochondria glycation contributes to mitochondrial stress and cognitive dysfunction.
Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture.
Role of cell metabolism in the pathophysiology of brain size-associated neurodevelopmental disorders.
Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders.
BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.
Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function.
Metabolism changes caused by glucose in normal and cancer human brain cell lines by Raman imaging and chemometric methods.
Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.
FABP3 Induces Mitochondrial Autophagy to Promote Neuronal Cell Apoptosis in Brain Ischemia-Reperfusion Injury.
Extracellular vesicles released from microglia after palmitate exposure impact brain function.
Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.
How membrane phospholipids containing long chain polyunsaturated fatty acids and their oxidation products orchestrate lipid raft dynamics to control inflammation.
SH-SY5Y cells undergo changes in peroxisomal metabolism when exposed to decanoic acid.
Predicting lipid sorting in curved membranes.

Peptides. 2024 Jul 11. pii: S0196-9781(24)00124-4. [Epub ahead of print]179 171271

Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice.

Shaobin Yang, Xiaoqian Zhao, Yimeng Zhang, Qi Tang, Yanhong Li, Yaqin Du, Peng Yu.

  Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-β (Aβ), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aβ, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.

Keywords:  Alzheimer's disease; Astrocyte; Glucose metabolism; Mitochondrial dysfunction; Tirzepatide

DOI:  https://doi.org/10.1016/j.peptides.2024.171271
Radiology. 2024 Jul;312(1): e232407

Deuterium Metabolic Imaging of Alzheimer Disease at 3-T Magnetic Field Strength: A Pilot Case-Control Study.

Alixander S Khan, Katie A Peterson, Orsolya I Vittay, Mary A McLean, Joshua D Kaggie, John T O'Brien, James B Rowe, Ferdia A Gallagher, Tomasz Matys.

Background Impaired glucose metabolism is characteristic of several types of dementia, preceding cognitive symptoms and structural brain changes. Reduced glucose uptake in specific brain regions, detected using fluorine 18 (18F) fluorodeoxyglucose (FDG) PET, is a valuable diagnostic marker in Alzheimer disease (AD). However, the use of 18F-FDG PET in clinical practice may be limited by equipment availability and high cost. Purpose To test the feasibility of using MRI-based deuterium (2H) metabolic imaging (DMI) at a clinical magnetic field strength (3 T) to detect and localize changes in the concentration of glucose and its metabolites in the brains of patients with a clinical diagnosis of AD. Materials and Methods Participants were recruited for this prospective case-control pilot study between March 2021 and February 2023. DMI was performed at 3 T using a custom birdcage head coil following oral administration of deuterium-labeled glucose (0.75 g/kg). Unlocalized whole-brain MR spectroscopy (MRS) and three-dimensional MR spectroscopic imaging (MRSI) (voxel size, 3.2 cm cubic) were performed. Ratios of 2H-glucose, 2H-glutamate and 2H-glutamine (2H-Glx), and 2H-lactate spectroscopic peak signals to 2H-water peak signal were calculated for the whole-brain MR spectra and for individual MRSI voxels. Results A total of 19 participants, including 10 participants with AD (mean age, 68 years ± 5 [SD]; eight males) and nine cognitively healthy control participants (mean age, 70 years ± 6; six males) were evaluated. Whole-brain spectra demonstrated a reduced ratio of 2H-Glx to 2H-glucose peak signals in participants with AD compared with control participants (0.41 ± 0.09 vs 0.58 ± 0.20, respectively; P = .04), suggesting an impairment of oxidative glucose metabolism in AD. However, there was no evidence of localization of these changes to the expected regions of metabolic impairment at MRSI, presumably due to insufficient spatial resolution. Conclusion DMI at 3 T demonstrated impairment of oxidative glucose metabolism in the brains of patients with AD but no evidence of regional signal differences. © RSNA, 2024 Supplemental material is available for this article.

DOI: https://doi.org/10.1148/radiol.232407
bioRxiv. 2024 Jul 03. pii: 2024.07.01.601474. [Epub ahead of print]

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4.

Femke M Feringa, Sascha J Koppes-den Hertog, Lian Wang, Rico J E Derks, Iris Kruijff, Lena Erlebach, Jorin Heijneman, Ricardo Miramontes, Nadine Pömpner, Niek Blomberg, Damien Olivier-Jimenez, Lill Eva Johansen, Alexander J Cammack, Ashling Giblin, Christina E Toomey, Indigo V L Rose, Hebao Yuan, Michael Ward, Adrian M Isaacs, Martin Kampmann, Deborah Kronenberg-Versteeg, Tammaryn Lashley, Leslie M Thompson, Alessandro Ori, Yassene Mohammed, Martin Giera, Rik van der Kant.

Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

DOI: https://doi.org/10.1101/2024.07.01.601474
Brain. 2024 Jul 13. pii: awae229. [Epub ahead of print]

Synaptic mitochondria glycation contributes to mitochondrial stress and cognitive dysfunction.

Sourav Samanta, Firoz Akhter, Renhao Xue, Alexandre A Sosunov, Long Wu, Doris Chen, Ottavio Arancio, Shi Fang Yan, Shirley ShiDu Yan.

  Mitochondrial and synaptic dysfunction are pathological features of brain aging and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigate the mechanisms of advanced glycation endproducts (AGEs)-mediated mitochondrial and synaptic stress and evaluate the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analyzed alterations in accumulation/buildup of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrate for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGEs-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in aging brain. Importantly, clearance of AGEs-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification/of AGEs, reduces synaptic mitochondrial AGEs accumulation and improves mitochondrial and cognitive function in aging and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex-vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGEs-induced synaptic plasticity and transmission by fully recovery of decline in LTP or frequency of mEPSC. These studies explore crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain aging and cognitive decline. Synaptic mitochondria are particularly susceptible to AGEs-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGEs accumulation and to improve mitochondrial function and learning and memory.

Keywords:  AGEs metabolism; glyoxalase I; mitochondrial and oxidative stress; synaptic mitochondria toxicity; synaptic transmission/injury

DOI:  https://doi.org/10.1093/brain/awae229
Nat Commun. 2024 Jul 16. 15(1): 5979

Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture.

Alice Braga, Martina Chiacchiaretta, Luc Pellerin, Dong Kong, Philip G Haydon.

Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

DOI: https://doi.org/10.1038/s41467-024-50166-7
Neurobiol Dis. 2024 Jul 17. pii: S0969-9961(24)00207-9. [Epub ahead of print] 106607

Role of cell metabolism in the pathophysiology of brain size-associated neurodevelopmental disorders.

Lei Xing, Wieland B Huttner, Takashi Namba.

Cell metabolism is a key regulator of human neocortex development and evolution. Several lines of evidence indicate that alterations in neural stem/progenitor cell (NPC) metabolism lead to abnormal brain development, particularly brain size-associated neurodevelopmental disorders, such as microcephaly. Abnormal NPC metabolism causes impaired cell proliferation and thus insufficient expansion of NPCs for neurogenesis. Therefore, the production of neurons, which is a major determinant of brain size, is decreased and the size of the brain, especially the size of the neocortex, is significantly reduced. This review discusses recent progress understanding NPC metabolism, focusing in particular on glucose metabolism, fatty acid metabolism and amino acid metabolism (e.g., glutaminolysis and serine metabolism). We provide an overview of the contributions of these metabolic pathways to brain development and evolution, as well as to the etiology of neurodevelopmental disorders. Furthermore, we discuss the advantages and disadvantages of various experimental models to study cell metabolism in the developing brain.

DOI: https://doi.org/10.1016/j.nbd.2024.106607
Neurobiol Dis. 2024 Jul 11. pii: S0969-9961(24)00204-3. [Epub ahead of print]199 106604

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders.

Sara Bonzano, Eleonora Dallorto, Serena Bovetti, Michèle Studer, Silvia De Marchis.

  Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.

Keywords:  Adult neural stem cells; BBSOAS; Dentate gyrus; Mitochondria; Nr2f1

DOI:  https://doi.org/10.1016/j.nbd.2024.106604
Mol Neurobiol. 2024 Jul 19.

BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.

Smijin K Soman, Maryann Swain, Ruben K Dagda.

  Brain-derived neurotrophic factor (BDNF) plays a pivotal role in neuronal development, synaptic plasticity, and overall neuronal health by binding to its receptor, tyrosine receptor kinase B (TrkB). This review delves into the intricate mechanisms through which BDNF-TrkB signaling influences mitochondrial function and potentially influences pathology in neurodegenerative diseases. This review highlights the BDNF-TrkB signaling pathway which regulates mitochondrial bioenergetics, biogenesis, and dynamics, mitochondrial processes vital for synaptic transmission and plasticity. Furthermore, we explore how the BDNF-TrkB-PKA signaling in the cytosol and in mitochondria affects mitochondrial transport and distribution and mitochondrial content, which is crucial for supporting the energy demands of synapses. The dysregulation of this signaling pathway is linked to various neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by mitochondrial dysfunction and reduced BDNF expression. By examining seminal studies that have characterized this signaling pathway in health and disease, the present review underscores the potential of enhancing BDNF-TrkB signaling to mitigate mitochondrial dysfunction in neurodegenerative diseases, offering insights into therapeutic strategies to enhance neuronal resilience and function.

Keywords:  Alzheimer’s disease; BDNF; Mitochondria; Neurodegeneration; Parkinson’s disease; TrkB

DOI:  https://doi.org/10.1007/s12035-024-04357-4
Transl Psychiatry. 2024 Jul 16. 14(1): 289

Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function.

Edith M Schneider Gasser, Ron Schaer, Flavia S Mueller, Alexandra C Bernhardt, Han-Yu Lin, Christian Arias-Reyes, Ulrike Weber-Stadlbauer.

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

DOI: https://doi.org/10.1038/s41398-024-03010-x
Sci Rep. 2024 Jul 18. 14(1): 16626

Metabolism changes caused by glucose in normal and cancer human brain cell lines by Raman imaging and chemometric methods.

Monika Kopec, Karolina Beton-Mysur, Jakub Surmacki, Halina Abramczyk.

  Glucose is the main source of energy for the human brain. This paper presents a non-invasive technique to study metabolic changes caused by glucose in human brain cell lines. In this paper we present the spectroscopic characterization of human normal brain (NHA; astrocytes) and human cancer brain (CRL-1718; astrocytoma and U-87 MG; glioblastoma) control cell lines and cell lines upon supplementation with glucose. Based on Raman techniques we have identified biomarkers that can monitor metabolic changes in lipid droplets, mitochondria and nucleus caused by glucose. We have studied the vibrations at 750 cm-1, 1444 cm-1, 1584 cm-1 and 1656 cm-1 as a function of malignancy grade. We have compared the concentration of cytochrome, lipids and proteins in the grade of cancer aggressiveness in normal and cancer human brain cell lines. Chemometric analysis has shown that control normal, control cancer brain cell lines and normal and cancer cell lines after supplementation with glucose can be distinguished based on their unique vibrational properties. PLSDA (Partial Least Squares Discriminant Analysis) and ANOVA tests have confirmed the main role of cytochromes, proteins and lipids in differentiation of control human brain cells and cells upon supplementation with glucose. We have shown that Raman techniques combined with chemometric analysis provide additional insight to monitor the biology of astrocytes, astrocytoma and glioblastoma after glucose supplementation.

Keywords:  Biomarkers; Brain cancer; Glucose; PLS-DA; Raman imaging; Raman spectroscopy

DOI:  https://doi.org/10.1038/s41598-024-67718-y
medRxiv. 2024 Jul 04. pii: 2024.07.03.24309787. [Epub ahead of print]

Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.

Camila Armirola-Ricaurte, Laura Morant, Isabelle Adant, Sherifa Ahmed Hamed, Menelaos Pipis, Stephanie Efthymiou, Silvia Amor-Barris, Derek Atkinson, Liedewei Van de Vondel, Aleksandra Tomic, Els de Vriendt, Stephan Zuchner, Bart Ghesquiere, Michael Hanna, Henry Houlden, Michael P Lunn, Mary M Reilly, Vedrana Milic Rasic, Albena Jordanova.

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to report COX18 as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane. Exome sequencing was performed in four affected individuals. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in a Drosophila melanogaster knockdown model. Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G in COX18 in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants in COX18 . All affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of the COX18 homolog in Drosophila melanogaster displayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons. Our study presents genetic and functional evidence that supports COX18 as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.

DOI: https://doi.org/10.1101/2024.07.03.24309787
Neurotox Res. 2024 Jul 15. 42(4): 35

FABP3 Induces Mitochondrial Autophagy to Promote Neuronal Cell Apoptosis in Brain Ischemia-Reperfusion Injury.

Fang-Fang Zhong, Bo Wei, Guo-Xiang Bao, Yi-Ping Lou, Ming-Er Wei, Xin-Yue Wang, Xiao Xiao, Jin-Jin Tian.

  This study elucidates the molecular mechanisms by which FABP3 regulates neuronal apoptosis via mitochondrial autophagy in the context of cerebral ischemia-reperfusion (I/R). Employing a transient mouse model of middle cerebral artery occlusion (MCAO) established using the filament method, brain tissue samples were procured from I/R mice. High-throughput transcriptome sequencing on the Illumina CN500 platform was performed to identify differentially expressed mRNAs. Critical genes were selected by intersecting I/R-related genes from the GeneCards database with the differentially expressed mRNAs. The in vivo mechanism was explored by infecting I/R mice with lentivirus. Brain tissue injury, infarct volume ratio in the ischemic penumbra, neurologic deficits, behavioral abilities, neuronal apoptosis, apoptotic factors, inflammatory factors, and lipid peroxidation markers were assessed using H&E staining, TTC staining, Longa scoring, rotation experiments, immunofluorescence staining, and Western blot. For in vitro validation, an OGD/R model was established using primary neuron cells. Cell viability, apoptosis rate, mitochondrial oxidative stress, morphology, autophagosome formation, membrane potential, LC3 protein levels, and colocalization of autophagosomes and mitochondria were evaluated using MTT assay, LDH release assay, flow cytometry, ROS/MDA/GSH-Px measurement, transmission electron microscopy, MitoTracker staining, JC-1 method, Western blot, and immunofluorescence staining. FABP3 was identified as a critical gene in I/R through integrated transcriptome sequencing and bioinformatics analysis. In vivo experiments revealed that FABP3 silencing mitigated brain tissue damage, reduced infarct volume ratio, improved neurologic deficits, restored behavioral abilities, and attenuated neuronal apoptosis, inflammation, and mitochondrial oxidative stress in I/R mice. In vitro experiments demonstrated that FABP3 silencing restored OGD/R cell viability, reduced neuronal apoptosis, and decreased mitochondrial oxidative stress. Moreover, FABP3 induced mitochondrial autophagy through ROS, which was inhibited by the free radical scavenger NAC. Blocking mitochondrial autophagy with sh-ATG5 lentivirus confirmed that FABP3 induces mitochondrial dysfunction and neuronal apoptosis by activating mitochondrial autophagy. In conclusion, FABP3 activates mitochondrial autophagy through ROS, leading to mitochondrial dysfunction and neuronal apoptosis, thereby promoting cerebral ischemia-reperfusion injury.

Keywords:  Cerebral ischemia-reperfusion; FABP3; High-throughput transcriptome sequencing; Mitochondrial autophagy; Mitochondrial dysfunction; Neuronal apoptosis; Oxidative stress; ROS

DOI:  https://doi.org/10.1007/s12640-024-00712-4
J Neuroinflammation. 2024 Jul 16. 21(1): 173

Extracellular vesicles released from microglia after palmitate exposure impact brain function.

Gabriela C De Paula, Blanca I Aldana, Roberta Battistella, Rosalía Fernández-Calle, Andreas Bjure, Iben Lundgaard, Tomas Deierborg, João M N Duarte.

  Dietary patterns that include an excess of foods rich in saturated fat are associated with brain dysfunction. Although microgliosis has been proposed to play a key role in the development of brain dysfunction in diet-induced obesity (DIO), neuroinflammation with cytokine over-expression is not always observed. Thus, mechanisms by which microglia contribute to brain impairment in DIO are uncertain. Using the BV2 cell model, we investigated the gliosis profile of microglia exposed to palmitate (200 µmol/L), a saturated fatty acid abundant in high-fat diet and in the brain of obese individuals. We observed that microglia respond to a 24-hour palmitate exposure with increased proliferation, and with a metabolic network rearrangement that favors energy production from glycolysis rather than oxidative metabolism, despite stimulated mitochondria biogenesis. In addition, while palmitate did not induce increased cytokine expression, it modified the protein cargo of released extracellular vesicles (EVs). When administered intra-cerebroventricularly to mice, EVs secreted from palmitate-exposed microglia in vitro led to memory impairment, depression-like behavior, and glucose intolerance, when compared to mice receiving EVs from vehicle-treated microglia. We conclude that microglia exposed to palmitate can mediate brain dysfunction through the cargo of shed EVs.

Keywords:  Energy metabolism; Glycolysis; LPS; Neuroinflammation; Obesity

DOI:  https://doi.org/10.1186/s12974-024-03168-7
Cell Rep. 2024 Jul 11. pii: S2211-1247(24)00817-9. [Epub ahead of print]43(7): 114488

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.

Juan F Codocedo, Claudia Mera-Reina, Peter Bor-Chian Lin, Paul B Fallen, Shweta S Puntambekar, Brad T Casali, Nur Jury-Garfe, Pablo Martinez, Cristian A Lasagna-Reeves, Gary E Landreth.

  Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Keywords:  Alzheimer’s disease; CP: Metabolism; CP: Neuroscience; NF-κB; amyloid; hexokinase 2; inflammation; lonidamine; microglia; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2024.114488
J Nutr. 2024 Jul 16. pii: S0022-3166(24)00396-1. [Epub ahead of print]

How membrane phospholipids containing long chain polyunsaturated fatty acids and their oxidation products orchestrate lipid raft dynamics to control inflammation.

Rafia Virk, Katie Cook, Andres Cavazos, Stephen R Wassall, Kymberly M Gowdy, Saame Raza Shaikh.

  Long chain polyunsaturated fatty acids (LC-PUFA) influence varying aspects of inflammation. One mechanism by which they regulate inflammation is by controlling the size and molecular composition of lipid rafts. Lipid rafts are sphingolipid/cholesterol-enriched plasma membrane microdomains that compartmentalize signaling proteins and thereby control downstream inflammatory gene expression and cytokine production. This review summarizes developments in our understanding of how LC-PUFA acyl chains of phospholipids, in addition to oxidized derivatives of LC-PUFAs such as oxidized 1-palmitoyl-2-arachidonyl-phosphatidylcholine (oxPAPC), manipulate formation of lipid rafts and thereby inflammation. We reviewed the literature, largely from the past two decades, on the impact of LC-PUFA acyl chains and oxidized products of LC-PUFAs on lipid raft biophysical organization of myeloid and lymphoid cells. The majority of the studies are based on rodent or cellular experiments with supporting mechanistic studies using biomimetic membranes and molecular dynamic simulations. These studies have focused largely on the LC-PUFA docosahexaenoic acid, with some studies addressing eicosapentaenoic acid. A few studies have investigated the role of oxidized phospholipids on rafts. The biophysical literature suggests a model in which n-3 LC-PUFAs, in addition to oxPAPC, localize predominately to non-raft regions and impart a disordering effect in this environment. Rafts become larger due to the ensuing increase in the difference in order between raft and non-rafts. Biochemical studies suggest some n-3 LC PUFAs can be found within rafts. This deviation from homeostasis is a potential trigger for controlling aspects of innate and adaptive immunity. Overall, select LC-PUFA acyl chains and oxidized acyl chains of phospholipids control lipid raft dynamics and downstream inflammation. Gaps in knowledge remain, particularly on underlying molecular mechanisms by which plasma membrane receptor organization is controlled in response to oxidized LC-PUFA acyl chains of membrane phospholipids. Validation in humans is also an area for future study.

Keywords:  docosahexaenoic acid; eicosapentaenoic acid; immune cells; oxidized phospholipids; plasma membrane; rafts

DOI:  https://doi.org/10.1016/j.tjnut.2024.07.015
J Neurochem. 2024 Jul 17.

SH-SY5Y cells undergo changes in peroxisomal metabolism when exposed to decanoic acid.

Tomas Baldwin, Peter Clayton, Tricia Rutherford, Simon Heales, Simon Eaton.

  Medium-chain fatty acids (MCFAs), particularly decanoic acid (C10) and octanoic acid (C8), have garnered attention in recent years for their potential antiepileptic properties. A previous study from our laboratory demonstrated that C10 targets the PPARγ nuclear receptor, increasing the activity of the antioxidant enzyme catalase and thereby possibly modulating peroxisomal content. Here, we examined markers of peroxisomal content and activity in response to C10 and C8 exposure in neuronal-like SH-SY5Y cells. SH-SY5Y were treated with 250 mM C10 or C8 for a period of 6 days. Following this, biochemical markers of peroxisomal content and function were assessed, including acyl-coA oxidase activity, peroxisomal gene expression and peroxisomal VLCFA β-oxidation. Our findings revealed that C10 treatment augments acyl-CoA oxidase 1 (ACOx1) activity by 129% in comparison to control cells. An exploration into genes related to peroxisomal biosynthesis showed 23% increased expression of PEX11α upon C10 exposure, implying peroxisomal proliferation. Furthermore, it was observed that C10 exposure not only elevated ACOx1 activity but also enhanced peroxisomal β-oxidation of docosanoic acid (C22). Our findings bolster the premise that C10 functions as a peroxisome proliferator, influencing peroxisomal content and function. Further investigations are required to fully understand the mechanistic details as to how this may be beneficial in epilepsy and the potential implications with regards to peroxisomal disease.

Keywords:  C10; C8; MCT diet; metabolism; peroxisome; seizures

DOI:  https://doi.org/10.1111/jnc.16185
Methods Enzymol. 2024 ;pii: S0076-6879(24)00117-4. [Epub ahead of print]701 287-307

Predicting lipid sorting in curved membranes.

Jackson Crowley, Cécile Hilpert, Luca Monticelli.

  Most biological membranes are curved, and both lipids and proteins play a role in generating curvature. For any given membrane shape and composition, it is not trivial to determine whether lipids are laterally distributed in a homogeneous or inhomogeneous way, and whether the inter-leaflet distribution is symmetric or not. Here we present a simple computational tool that allows to predict the preference of any lipid type for membranes with positive vs. negative curvature, for any given value of curvature. The tool is based on molecular dynamics simulations of tubular membranes with hydrophilic pores. The pores allow spontaneous, barrierless flip-flop of most lipids, while also preventing differences in pressure between the inner and outer water compartments and minimizing membrane asymmetric stresses. Specifically, we provide scripts to build and analyze the simulations. We test the tool by performing simulations on simple binary lipid mixtures, and we show that, as expected, lipids with negative intrinsic curvature distribute to the tubule inner leaflet, the more so when the radius of the tubular membrane is small. Compared to other existing computational methods, relying on membrane buckles and tethers, our method is based on spontaneous inter-leaflet transport of lipids, and therefore allows to explore lipid distribution in asymmetric membranes. The method can easily be adapted to work with any molecular dynamics code and any force field.

Keywords:  Biological membrane; Computer simulation; Lipid bilayer; Lipid flip- flop; Lipid membrane; Lipid sorting; Membrane curvature; Molecular dynamics

DOI:  https://doi.org/10.1016/bs.mie.2024.03.022