bims-medebr 2025-01-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–01–12
37 papers selected by
Regina F. Fernández, Johns Hopkins University

α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition.
Challenges of Investigating Compartmentalized Brain Energy Metabolism Using Nuclear Magnetic Resonance Spectroscopy in vivo.
Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons.
Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.
Sexual and Metabolic Differences in Hippocampal Evolution: Alzheimer's Disease Implications.
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets.
Impaired Cerebrospinal Fluid Lipoprotein-Mediated Cholesterol Delivery to Neurons in Alzheimer's Disease.
Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.
Update on Fatty Acids and the Brain.
The emerging role of 12/15-lipoxygenase in ischemic stroke.
Treadmill intervention attenuates motor deficit with 6-OHDA-induced Parkinson's disease rat via changes in lipid profiles in brain and muscle.
Glucose metabolism impairment in major depressive disorder.
The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.
The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!
Metabolic reprogramming and astrocytes polarization following ischemic stroke.
Metabolic Dysfunction in Parkinson's Disease: Unraveling the Glucose-Lipid Connection.
Brain magnetic resonance imaging findings in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A case-based review.
MCL-1 regulates cellular transitions during oligodendrocyte development.
Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.
A non-purine inhibitor of xanthine oxidoreductase mitigates adenosine triphosphate degradation under hypoxic conditions in mouse brain.
Comparative lipid profiling reveals the differential response of distinct lipid subclasses in blast and blunt-induced mild traumatic brain injury.
APOE4 alters the lipid droplet proteome and modulates droplet dynamics.
Triacylglycerol mobilization underpins mitochondrial stress recovery.
Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination.
Sexual Dimorphism in Migraine. Focus on Mitochondria.
Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types.
Impact of Omega-3 on Endocannabinoid System Expression and Function, Enhancing Cognition and Behavior in Male Mice.
STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.
Formation of I2+III2 supercomplex rescues respiratory chain defects.
Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.
A creatine efflux transporter in oligodendrocytes.
The Role of Lactate in Ischemic Stroke: As an Energy Source and Signaling Molecule.
Nose-to-brain delivery of DHA-loaded nanoemulsions: A promising approach against Alzheimer's disease.
Comprehensive Approach for Sequential MALDI-MSI Analysis of Lipids, N-Glycans, and Peptides in Fresh-Frozen Rodent Brain Tissues.
Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer's disease in two independent study cohorts.
Consequences of Early Maternal Deprivation on Neuroinflammation and Mitochondrial Dynamics in the Central Nervous System of Male and Female Rats.
Prolonged incubation with Δ9-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices.

Neurochem Res. 2025 Jan 09. 50(1): 76

α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition.

Ângela Beatris Zemniaçak, Rafael Teixeira Ribeiro, Gustavo Machado das Neves, Sâmela de Azevedo Cunha, Tailine Quevedo Tavares, Andrey Vinícios Soares Carvalho, Carlos Alexandre Netto, Roger Frigério Castilho, Moacir Wajner, Alexandre Umpierrez Amaral.

  Brain accumulation of the branched-chain α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) occurs in maple syrup urine disease (MSUD), an inherited intoxicating metabolic disorder caused by defects of the branched-chain α-keto acid dehydrogenase complex. Patients commonly suffer life-threatening acute encephalopathy in the newborn period and develop chronic neurological sequelae of still undefined pathogenesis. Therefore, this work investigated the in vitro influence of pathological concentrations of KIC (5 mM), KMV (1 mM), and KIV (1 mM) on mitochondrial bioenergetics in the cerebral cortex of neonate (one-day-old) rats. KIC, but not KMV and KIV, decreased phosphorylating (stimulated by ADP) and uncoupled (induced by CCCP) mitochondrial respiration supported by pyruvate, malate, and glutamate, indicating metabolic inhibition. These effects were less evident after supplementing the medium with succinate. KIC also mildly increased non-phosphorylating respiration (in the presence of oligomycin) using pyruvate plus malate or glutamate plus malate as substrates, suggesting an uncoupling effect. Moreover, KIC markedly inhibited the activity of α-ketoglutarate dehydrogenase noncompetitively and decreased ATP synthesis. Finally, docking simulations demonstrated that KIC preferentially interacts with E2 and E3 subunits of α-ketoglutarate dehydrogenase at the dihydrolipoamide binding site and into an allosteric site of E1. The present data strongly indicate that KIC compromises mitochondrial bioenergetics in the neonatal rat brain, supporting the hypothesis that disruption of energy homeostasis caused by brain KIC accumulation in the first days of life may be implicated in the neuropathology of MSUD.

Keywords:  Bioenergetics; Brain; Docking simulations; Maple syrup urine disease; α-Ketoisocaproic acid

DOI:  https://doi.org/10.1007/s11064-024-04328-0
Neurochem Res. 2025 Jan 04. 50(1): 73

Challenges of Investigating Compartmentalized Brain Energy Metabolism Using Nuclear Magnetic Resonance Spectroscopy in vivo.

João M N Duarte.

  Brain function requires continuous energy supply. Thus, unraveling brain metabolic regulation is critical not only for our basic understanding of overall brain function, but also for the cellular basis of functional neuroimaging techniques. While it is known that brain energy metabolism is exquisitely compartmentalized between astrocytes and neurons, the metabolic and neuro-energetic basis of brain activity is far from fully understood. 1H nuclear magnetic resonance (NMR) spectroscopy has been widely used to detect variations in metabolite levels, including glutamate and GABA, while 13C NMR spectroscopy has been employed to study metabolic compartmentation and to determine metabolic rates coupled brain activity, focusing mainly on the component corresponding to excitatory glutamatergic neurotransmission. The rates of oxidative metabolism in neurons and astrocytes are both associated with the rate of the glutamate-glutamine cycle between neurons and astrocytes. However, any possible correlation between energy metabolism pathways and the inhibitory GABAergic neurotransmission rate in the living brain remains to be experimentally demonstrated. That is due to low GABA levels, and the consequent challenge of determining GABAergic rates in a non-invasive manner. This brief review surveys the state-of-the-art analyses of energy metabolism in neurons and astrocytes contributing to glutamate and GABA synthesis using 13C NMR spectroscopy in vivo, and identifies limitations that need to be overcome in future studies.

Keywords:  Energy metabolism; GABA; Glutamate; Magnetic resonance; Neurochemicals

DOI:  https://doi.org/10.1007/s11064-024-04324-4
Free Radic Biol Med. 2025 Jan 07. pii: S0891-5849(25)00009-7. [Epub ahead of print]

Coenzyme Q10 deficiency disrupts lipid metabolism by altering cholesterol homeostasis in neurons.

Alba Pesini, Eliana Barriocanal-Casado, Giacomo Monzio Compagnoni, Agustin Hidalgo-Gutierrez, Giussepe Yanez, Mohammed Bakkali, Yashpal S Chhonker, Giulio Kleiner, Delfina Larrea, Saba Tadesse, Luis Carlos Lopez, Daryl J Murry, Alessio Di Fonzo, Estela Area-Gomez, Catarina M Quinzii.

  Coenzyme Q10 (CoQ10) is a critical component of the mitochondrial respiratory chain. CoQ10 deficiencies often cause a variety of clinical syndromes, often involving encephalopathies. The heterogeneity of clinical manifestations implies different pathomechanisms, reflecting CoQ10 involvement in several biological processes. One such process is cholesterol homeostasis, since CoQ10 is synthesized through the mevalonate pathway, which also produces cholesterol. To elucidate the role of lipid dysfunction in the pathogenesis of CoQ10 deficiency, we investigated lipid metabolism in human CoQ10 deficient iPSCs-derived neurons, and in SH-SY5Y neurons after pharmacological manipulation of the mevalonate pathway. We show that CoQ10 deficiency causes alterations in cholesterol homeostasis, fatty acids oxidation, phospholipids and sphingolipids synthesis in neurons. These alterations depend on the molecular defect, and on the residual CoQ10 levels. Our results imply that CoQ10 deficiencies can induce pathology by altering lipid homeostasis and the composition of cellular membranes. These findings provide further understanding of the mechanisms underlying CoQ10 deficiency and point to potential novel therapeutic targets.

Keywords:  COQ2; Cholesterol; Coenzyme Q(10); PDSS2; lipids

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.009
Int J Mol Sci. 2024 Dec 21. pii: 13690. [Epub ahead of print]25(24):

Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles.

Thao N Huynh, Emma N Fikse, Adrianna L De La Torre, Matthew C Havrda, Catherine C Y Chang, Ta Yuan Chang.

  Aging and apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells, including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4-dependent phenotypes. Toll-like receptor 4 (TLR4) is a key macromolecule in inflammation, and its regulation is associated with the cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acyl-CoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. This study found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activates ABCA1, and dampens LPS-dependent NFκB activation. In vivo, two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines, including IL-1β in mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

Keywords:  ACAT inhibitor; ATP binding cassette subfamily A member 1; Alzheimer’s disease; DSPE-PEG2000; F12511; LOAD; NFκB; TLR4; acyl-CoA:cholesterol acyltransferase; apolipoprotein E4 (APOE4); cholesterol; cholesteryl esters; interleukin-1 beta; late-onset Alzheimer’s disease; lipid rafts; microglia; phosphatidylcholine; sterol O-acyltransferase 1

DOI:  https://doi.org/10.3390/ijms252413690
Life (Basel). 2024 Nov 26. pii: 1547. [Epub ahead of print]14(12):

Sexual and Metabolic Differences in Hippocampal Evolution: Alzheimer's Disease Implications.

José Manuel Martínez-Martos, Vanesa Cantón-Habas, Manuel Rich-Ruíz, María José Reyes-Medina, María Jesús Ramírez-Expósito, María Del Pilar Carrera-González.

  Sex differences in brain metabolism and their relationship to neurodegenerative diseases like Alzheimer's are an important emerging topic in neuroscience. Intrinsic anatomic and metabolic differences related to male and female physiology have been described, underscoring the importance of considering biological sex in studying brain metabolism and associated pathologies. The hippocampus is a key structure exhibiting sex differences in volume and connectivity. Adult neurogenesis in the dentate gyrus, dendritic spine density, and electrophysiological plasticity contribute to the hippocampus' remarkable plasticity. Glucose transporters GLUT3 and GLUT4 are expressed in human hippocampal neurons, with proper glucose metabolism being crucial for learning and memory. Sex hormones play a major role, with the aromatase enzyme that generates estradiol increasing in neurons and astrocytes as an endogenous neuroprotective mechanism. Inhibition of aromatase increases gliosis and neurodegeneration after brain injury. Genetic variants of aromatase may confer higher Alzheimer's risk. Estrogen replacement therapy in postmenopausal women prevents hippocampal hypometabolism and preserves memory. Insulin is also a key regulator of hippocampal glucose metabolism and cognitive processes. Dysregulation of the insulin-sensitive glucose transporter GLUT4 may explain the comorbidity between type II diabetes and Alzheimer's. GLUT4 colocalizes with the insulin-regulated aminopeptidase IRAP in neuronal vesicles, suggesting an activity-dependent glucose uptake mechanism. Sex differences in brain metabolism are an important factor in understanding neurodegenerative diseases, and future research must elucidate the underlying mechanisms and potential therapeutic implications of these differences.

Keywords:  Alzheimer’s disease; GLUT4; brain; glucose transporters; hippocampus; insulin regulated aminopeptidase; renin–angiotensin system; sex

DOI:  https://doi.org/10.3390/life14121547
Mol Neurobiol. 2025 Jan 07.

Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets.

Ning-Qi Wang, Pei-Xiang Sun, Qi-Qi Shen, Meng-Yan Deng.

  The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.

Keywords:  AD; Cholesterol homeostasis; HD; LXR; MS; SREBP2

DOI:  https://doi.org/10.1007/s12035-024-04672-w
Res Sq. 2024 Dec 23. pii: rs.3.rs-5682870. [Epub ahead of print]

Impaired Cerebrospinal Fluid Lipoprotein-Mediated Cholesterol Delivery to Neurons in Alzheimer's Disease.

Carla Borràs, Marina Canyelles, David Santos, Noemí Rotllan, Estefanía Núñez, Jesús Vázquez, Daniel Maspoch, Mary Cano-Sarabia, Maria Carmona-Iragui, Sònia Sirisi, Alberto Lleó, Juan Fortea, Daniel Alcolea, Francisco Blanco-Vaca, Joan Carles Escolà-Gil, Mireia Tondo.

In the central nervous system, apolipoprotein (APO) E-containing high-density lipoprotein (HDL)-like particles mediate the transport of glial-derived cholesterol to neurons, which is essential for neuronal membrane remodeling and maintenance of the myelin sheath. Despite this, the role of HDL-like cholesterol trafficking on Alzheimer's disease (AD) pathogenesis remains poorly understood. We aimed to examine cholesterol transport via HDL-like particles in cerebrospinal fluid (CSF) of AD patients compared to control individuals. Additionally, we explored the ability of reconstituted HDL containing different APOE isoforms to regulate cholesterol transport. We evaluated the capacity of CSF HDL-like particles to facilitate radiolabeled unesterified cholesterol efflux from A172 human glioblastoma astrocytes and to deliver cholesterol to SH-SY5Y human neuronal cells. The HDL-like proteome in the AD and control groups was analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Reconstituted HDL nanoparticles were prepared by combining phospholipids and cholesterol with human APOE3 or APOE4, followed by radiolabeling with unesterified cholesterol. Our results showed that cholesterol efflux from astrocytes to CSF were similar between AD patients and controls, both under baseline conditions and after activation of ATP-binding cassette transporters A1 and G1. However, CSF HDL-like particle-mediated neuronal cholesterol uptake was significantly reduced in the AD group. LC-MS/MS analysis identified 775 proteins associated with HDL-like particles in both groups, with no major alterations in proteins linked to cholesterol metabolism. However, 27 proteins involved in non-cholesterol-related processes were differentially expressed. Notably, synthetic reconstituted HDL particles containing APOE4 exhibited reduced capacity to deliver cholesterol to neurons compared to those with APOE3. These findings indicate that CSF HDL-like particles from patients with AD demonstrate impaired cholesterol delivery to neurons. Our study highlights APOE4 as a critical contributor to abnormal neuronal cholesterol uptake in AD pathophysiology.

DOI: https://doi.org/10.21203/rs.3.rs-5682870/v1
Dev Cell. 2025 Jan 02. pii: S1534-5807(24)00760-3. [Epub ahead of print]

Lactate shuttling links histone lactylation to adult hippocampal neurogenesis in mice.

Zhimin Li, Ziqi Liang, Huan Qi, Xing Luo, Min Wang, Zhuo Du, Weixiang Guo.

  Lactate has emerged as a central metabolic fuel and an important signaling molecule. Its availability participates in various brain functions. Although lactate homeostasis is vital for adult hippocampal neurogenesis and cognition, it is still unknown how shuttles lactate across the plasma membrane of neural stem cells (NSCs) to control their activity and neurogenic potential. In this study, we show that monocarboxylate transporter (MCT)1 and MCT2, respectively, control efflux and influx of lactate in the murine NSCs, thereby maintaining intracellular lactate homeostasis. Mechanistically, lactate shuttling links histone lactylation to govern NSC proliferation through MDM2-p53 signaling pathway. Notably, genetic ablation of MCT2 from NSCs or pharmacological inhibition of MDM2-P53 interaction prevents voluntary running-induced NSC proliferation in the murine adult hippocampus. Taken together, our findings demonstrate that lactate shuttling controls histone lactylation, which acts as a nexus for controlling adult hippocampal neurogenesis.

Keywords:  MDM2-p53 pathway; adult neurogenesis; histone lactylation; lactate shuttle; neural stem cells

DOI:  https://doi.org/10.1016/j.devcel.2024.12.021
Nutrients. 2024 Dec 23. pii: 4416. [Epub ahead of print]16(24):

Update on Fatty Acids and the Brain.

Andrew J Sinclair.

The brain is a lipid-rich organ, mainly due to the very high lipid content of myelin, but in addition to this, all the neuronal cell membranes, of which there are over 80 billion in the human brain [...].

DOI: https://doi.org/10.3390/nu16244416
Brain Res Bull. 2025 Jan 07. pii: S0361-9230(25)00006-1. [Epub ahead of print] 111194

The emerging role of 12/15-lipoxygenase in ischemic stroke.

Xuening Wang, Qiuji Shao, Yuan Gao.

  The arachidonic acid metabolic pathway is a classic inflammatory pathway. 12/15-lipoxygenase (LOX), a member of the lipoxygenase family that metabolizes arachidonic acid, has been implicated in the pathogenesis of numerous central nervous system (CNS) diseases. Ischemic stroke is a devastating disease in which the occlusion of cerebral arteries leads to a series of pathophysiological changes in brain tissue, triggering an inflammatory cascade within the brain that results in neuroinflammation. Prior research has shown that 12/15-LOX levels in the brain are elevated following stroke. In this review, we elaborate on the key pathological mechanisms that unfold following ischemic stroke, including neuroinflammation, oxidative stress, neuronal apoptosis, and blood-brain barrier disruption, and present evidence demonstrating that 12/15-LOX inhibition could be used to treat ischemic stroke through various avenues. Furthermore, we list currently available inhibitors of 12/15-LOX and the preclinical or clinical applications, offering novel insights for the early diagnosis, prognosis evaluation, and targeted therapy in neurological diseases.

Keywords:  12/15-LOX; 12/15-LOX inhibitors; ischemic stroke; neuroinflammation

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111194
Aging (Albany NY). 2025 Jan 03. 16

Treadmill intervention attenuates motor deficit with 6-OHDA-induced Parkinson's disease rat via changes in lipid profiles in brain and muscle.

Binar Panunggal, Tu-Hsueh Yeh, Shu-Ping Tsao, Chun-Hsu Pan, Wei-Ting Shih, Ya-Tin Lin, Amelia Faradina, Chia-Lang Fang, Hui-Yu Huang, Shih-Yi Huang.

  One of the key hallmarks of Parkinson's disease is the disruption of lipid homeostasis in the brain, which plays a critical role in neuronal membrane integrity and function. Understanding how treadmill training impacts lipid restructuring and its subsequent influence on motor function could provide a basis for developing targeted non-pharmacological interventions for individuals living with early stage of PD. This study aims to investigate the effects of a treadmill training intervention on motor deficits induced by 6-OHDA in rats model of PD. PD was induced by injecting 6-hydroxy dopamine (6-OHDA) into the medial forebrain bundle (MFB). For 10 weeks, rats underwent treadmill training on a four-lane motorized treadmill. Motor function deficits were evaluated through behavioral tests. Lipidomic analysis was performed through ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS). Treadmill intervention significantly improved motor function and restored altered brain and muscle lipid profiles in PD rats. Among the lipid species identified in PD rats, brain abundance was highest for phosphatidylethanolamine (PE), correlating positively with the beam-walking scores; muscle abundance peaked with lysophosphatidylethanolamine (LysoPE), correlating positively with grip strength scores. In the brain, the levels of diacylglycerol (DG), triacylglycerol (TG), and lysophosphatidylcholine (PC) correlated positively with grip strength and rotarod scores, while only phosphatidylethanolamine (PE) linked to beam-walking scores. In the muscle, the levels of phosphatidylinositol (PI), lysophosphatidylethanolamine (PE), lysophosphatidic acid (PA), ceramide (Cer), and ganglioside were positively correlated with grip strength and rotarod scores. In conclusion, treadmill may protect the cortex, mitigating motor deficits via change lipid profiles in the brain and muscle.

Keywords:  6-hydroxydopamine; Parkinson’s disease; lipidomic; motor function; treadmill

DOI:  https://doi.org/10.18632/aging.206181
Brain Res Bull. 2025 Jan 07. pii: S0361-9230(25)00003-6. [Epub ahead of print] 111191

Glucose metabolism impairment in major depressive disorder.

Fanhao Meng, Jing Wang, Long Wang, Wei Zou.

  Major depressive disorder (MDD) is a common mental disorder with chronic tendencies that seriously affect regular work, life, and study. However, its exact pathogenesis remains unclear. Patients with MDD experience systemic and localized impairments in glucose metabolism throughout the disease course, disrupting various processes such as glucose uptake, glycoprotein transport, glycolysis, the tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). These impairments may result from mechanisms including insulin resistance, hyperglycemia-induced damage, oxidative stress, astrocyte abnormalities, and mitochondrial dysfunction, leading to insufficient energy supply, altered synaptic plasticity, neuronal cell death, and functional and structural damage to reward networks. These mechanical changes contribute to the pathogenesis of MDD and severely interfere with the prognosis. Herein, we summarized the impairment of glucose metabolism and its pathophysiological mechanisms in patients with MDD. In addition, we briefly discussed potential pharmacological interventions for glucose metabolism to alleviate MDD, including glucagon-like peptide-1 receptor agonists, metformin, topical insulin, liraglutide, and pioglitazone, to encourage the development of new therapeutics.

Keywords:  depression brain glucose metabolism inadequate energy supply insulin resistance oxidative stress

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111191
Int J Mol Sci. 2024 Dec 20. pii: 13637. [Epub ahead of print]25(24):

The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment.

Gabriella Testa, Serena Giannelli, Erica Staurenghi, Rebecca Cecci, Lucrezia Floro, Paola Gamba, Barbara Sottero, Gabriella Leonarduzzi.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management.

Keywords:  Alzheimer’s disease; ApoE; LDL receptors; PCSK9; PCSK9 targeting therapies; cholesterol; neuroinflammation; oxidative stress; β-amyloid

DOI:  https://doi.org/10.3390/ijms252413637
J Inherit Metab Dis. 2025 Jan;48(1): e12835

The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat!

Bibiche den Hollander, Eva M M Hoytema van Konijnenburg, Brittany Hewitson, Jan C van der Meijden, Berith M Balfoort, Brad Winter, Annelieke R Müller, Wyeth W Wasserman, Carlos R Ferreira, Clara D van Karnebeek.

  Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. Disorders of fatty acid and ketone body metabolism had the highest treatability (67%), followed by disorders of vitamin and cofactor metabolism (60%), and disorders of lipoprotein metabolism (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes.

Keywords:  ICIMD; IEMbase; IMD; Treatabolome; inborn error of metabolism; treatable IEM

DOI:  https://doi.org/10.1002/jimd.12835
Free Radic Biol Med. 2025 Jan 03. pii: S0891-5849(25)00002-4. [Epub ahead of print]228 197-206

Metabolic reprogramming and astrocytes polarization following ischemic stroke.

Weizhuo Lu, Jiyue Wen.

  Astrocytes are critical for maintaining neuronal activity. Activation of astrocytes, occurs within minutes from ischemic stroke onset due to ischemic causes and subsequent inflammatory damage. Activated astrocytes, also known as reactive astrocytes, are divided into two different phenotypes: A1 (pro-inflammatory) and A2 (anti-inflammatory) astrocytes. A2 astrocytes support neuronal survival and promote tissue healing, while A1 astrocytes have neurotoxic effects. Thus, polarization of reactive astrocyte into A1 or A2 genotype is closely correlated with the development of cerebral ischemia/reperfusion (I/R) injury. Metabolic reprogramming is a process that various metabolic pathways upregulate in cells to balance energy, alter their phenotype, and produce building-block requirements. A1 and A2 astrocytes display different metabolic reprogramming, such as glycolysis, glutamate uptake, and glycogenolysis. Accumulating evidence suggested that manipulation of energy metabolism homeostasis can induce astrocytes to switch from A1 to A2 phenotype. This review disucss the potential factors in affecting astrocytic polarization, emphasizes metabolic reprogramming in reactive astrocytes within the pathophysiological context of cerebral I/R, and explores the relationship between metabolic reprogramming and astrocytic polarization. Importantly, we reveal that regulating metabolic reprogramming in reactive astrocytes may be a potential therapeutic target for cerebral I/R injury.

Keywords:  Glycolysis; Metabolic reprogramming; PPP; Reactive astrocyte

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.002
Biomedicines. 2024 Dec 13. pii: 2841. [Epub ahead of print]12(12):

Metabolic Dysfunction in Parkinson's Disease: Unraveling the Glucose-Lipid Connection.

Jeswinder Sian-Hulsmann, Peter Riederer, Tanja Maria Michel.

  Despite many years of research into the complex neurobiology of Parkinson's disease, the precise aetiology cannot be pinpointed down to one causative agent but rather a multitude of mechanisms. Current treatment options can alleviate symptomsbut only slightly slow down the progression and not cure the disease and its underlying causes. Factors that play a role in causing the debilitating neurodegenerative psycho-motoric symptoms include genetic alterations, oxidative stress, neuroinflammation, general inflammation, neurotoxins, iron toxicity, environmental influences, and mitochondrial dysfunction. Recent findings suggest that the characteristic abnormal protein aggregation of alpha-synuclein and destruction of substantia nigra neurons might be due to mitochondrial dysfunction related to disturbances in lipid and glucose metabolism along with insulin resistance. The latter mechanism of action might be mediated by insulin receptor substrate docking to proteins that are involved in neuronal survival and signaling related to cell destruction. The increased risk of developing Type 2 Diabetes Mellitus endorses a connection between metabolic dysfunction and neurodegeneration. Here, we explore and highlight the potential role of glycolipid cellular insults in the pathophysiology of the disorder, opening up new promising avenues for the treatment of PD. Thus, antidiabetic drugs may be employed as neuromodulators to hinder the progression of the disorder.

Keywords:  Parkinson’s disease; glucose metabolism; lipid metabolism; metabolic dysfunction; mitochondria; multifactorial; neurodegeneration; pathogenesis; protein aggregation; substantia nigra

DOI:  https://doi.org/10.3390/biomedicines12122841
Radiol Case Rep. 2025 Mar;20(3): 1298-1305

Brain magnetic resonance imaging findings in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A case-based review.

Maria Veatriki Christodoulou, Nikoletta Anagnostou, Anastasia K Zikou.

  Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disorder, manifesting with gastrointestinal dysmotility, cachexia, ptosis and peripheral neuropathy. Diffuse leukoencephalopathy in brain MRI is a hallmark of MNGIE. We report a case of a 21-year-old female with MNGIE, presenting with cachexia and chronic diarrhea. Brain MRI revealed lesions in the cerebral deep white matter and the pons, with sparing of the subcortical U-fibers and the cerebral cortex and no apparent involvement of the cerebellum, basal ganglia, and thalamus. A literature review led to the identification of 72 additional cases with MNGIE that underwent brain MRI. Leukoencephalopathy of the cerebral white matter was present in all but 2 patients. The objective of this study is to increase radiologists' awareness of this challenging-to-diagnose disease, as well as to demonstrate the value of advanced MRI techniques in understanding the underlying pathology. The presence of leukoencephalopathy on brain MRI in patients with cachexia and neurological manifestations, should raise the suspicion for MNGIE and trigger further biochemical and genetic testing.

Keywords:  Brain MRI; Leukoencephalopathy; MNGIE; Mitochondrial neurogastrointestinal encephalomyopathy; TYMP mutation

DOI:  https://doi.org/10.1016/j.radcr.2024.11.047
bioRxiv. 2024 Dec 21. pii: 2024.12.20.629796. [Epub ahead of print]

MCL-1 regulates cellular transitions during oligodendrocyte development.

Melanie Gil, Marina R Hanna, Vivian Gama.

Oligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically, myelin sheath formation is an energetically demanding event that requires precision, as alterations may lead to dysmyelination. Recent work has established that fatty acid β-oxidation is required for the function of oligodendrocytes. We have shown that MCL-1, a well-characterized anti-apoptotic protein, is required for the development of oligodendrocytes in vivo . Further, it was recently uncovered that MCL-1 regulates long- chain fatty acid β-oxidation through its interaction with acyl-CoA synthetase long-chain family member 1 (ACSL1), an enzyme responsible for the conversion of long-chain fatty acids into acyl-CoA. Here, we introduce an in vitro system to isolate human stem cell- derived oligodendrocyte progenitor cells and investigate the involvement of MCL-1 during human oligodendrocyte development. Using this system, we pharmacologically inhibited MCL-1 in oligodendrocyte progenitor cells (OPCs) to elucidate the non-apoptotic function of the protein at this developmental stage. Additionally, we used a motor neuron co-culture system to investigate the downstream effects that MCL-1 inhibition has at later developmental stages when oligodendrocytes begin to contact axons and generate myelin basic protein. We demonstrate that the mitochondrial network changes in human oligodendrocyte development resemble those reported in vivo . Our findings point to MCL-1 as a critical factor essential at the OPC stage for proper oligodendrocyte morphogenesis.

DOI: https://doi.org/10.1101/2024.12.20.629796
Neuroscience. 2025 Jan 07. pii: S0306-4522(24)00765-6. [Epub ahead of print]

Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury.

Patricia Cassina, Ernesto Miquel, Laura Martínez-Palma, Adriana Cassina.

  In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.

Keywords:  Aberrant glial cells; Amyotrophic lateral sclerosis; Astrocytes; Chronic pain; Glial metabolism

DOI:  https://doi.org/10.1016/j.neuroscience.2024.12.058
Brain Res. 2025 Jan 02. pii: S0006-8993(25)00002-2. [Epub ahead of print]1849 149444

A non-purine inhibitor of xanthine oxidoreductase mitigates adenosine triphosphate degradation under hypoxic conditions in mouse brain.

Nana Sato, Teruo Kusano, Koji Nagata, Ken Okamoto.

  The brain is an organ that consumes a substantial amount of oxygen, and a reduction in oxygen concentration can rapidly lead to significant and irreversible brain injury. The progression of brain injury during hypoxia involves the depletion of intracellular adenosine triphosphate (ATP) due to decreased oxidative phosphorylation in the inner mitochondrial membrane. Allopurinol is a purine analog inhibitor of xanthine oxidoreductase that protects against hypoxic/ischemic brain injury; however, its underlying mechanism of action remains unclear. In addition, febuxostat is a non-purine xanthine oxidoreductase inhibitor with a different inhibitory mechanism from allopurinol. The impact of febuxostat on brain injury has not been well investigated. Therefore, this study aimed to examine brain ATP and its catabolite levels in the presence or absence of allopurinol and febuxostat under hypoxic conditions by inactivating brain metabolism using focal microwave irradiation. The hypoxic treatment caused a decrease in the adenylate energy charge and ATP levels and an increase in its catabolic products in mouse brains. The febuxostat group showed higher energy charge and ATP levels and lower ATP catabolites than the control group. Notably, despite the comparable suppression of uric acid production in both inhibitor groups, allopurinol treatment was less effective than febuxostat. These results suggest that febuxostat effectively prevents hypoxia-induced ATP degradation in the brain and that its effect is more potent than allopurinol. This study will contribute to developing therapies for improving hypoxia-induced brain dysfunction.

Keywords:  Adenosine triphosphate; Allopurinol; Brain hypoxia; Febuxostat; Non-purine xanthine oxidoreductase inhibitor; Xanthine oxidoreductase

DOI:  https://doi.org/10.1016/j.brainres.2025.149444
Exp Neurol. 2025 Jan 07. pii: S0014-4886(25)00005-6. [Epub ahead of print] 115141

Comparative lipid profiling reveals the differential response of distinct lipid subclasses in blast and blunt-induced mild traumatic brain injury.

Seema Dhariwal, Kiran Maan, Ruchi Baghel, Apoorva Sharma, Megha Kumari, Mohd Aleem, Kailash Manda, Richa Trivedi, Poonam Rana.

  Head trauma from blast exposure is a growing health concern, particularly among active military personnel, and is considered the signature injury of the Gulf War. However, it remains elusive whether fundamental differences exist between blast-related traumatic brain injuries (TBI) and TBI due to other mechanisms. Considering the importance of lipid metabolism associated with neuronal membrane integrity and its compromise during TBI, we sought to find changes in lipidomic profiling during blast or blunt (Stereotaxically Controlled Contusison-SCC)-mediated TBI. In the current study, we have developed the mild TBI (mTBI) model of blast (130 ± 10 kPa) and SCC (1.5 mm dorsal-ventral) on C57BL/6 mice, followed by the serum collection on days 1 and 7. Lipid metabolomics was performed via ultra-high performance liquid chromatography (UHPLC) quadrupole time-of-flight mass spectrometry (qTOF-MS). Additionally, neurobehavioral outcomes were estimated using a revised neurobehavioral severity score for mice (mNSS-R) and an open field test (OFT). The study found that blast-exposed group exhibited more lipid dysregulation, as evidenced by a higher number of significant lipids and associated pathways at both time points. However, the comparative investigation further reveals eight significantly common lipids that can characterize the mTBI regardless of the manner of induction (blast or blunt). Besides, modulated neurobehavioral, locomotor and anxiety functions were also observed post-mTBI. The study illustrates the distinct systemic lipid metabolism intended to preserve the brain's lipid homeostasis post-mTBI. This approach may provide novel insights into lipid metabolism and identification of individual lipid species that aid in understanding the pathophysiology of mTBI.

Keywords:  Blast; Blunt; Lipidomics; Traumatic brain injury; UHPLC-MS and LIPID MAPS®

DOI:  https://doi.org/10.1016/j.expneurol.2025.115141
bioRxiv. 2024 Dec 20. pii: 2024.12.16.628710. [Epub ahead of print]

APOE4 alters the lipid droplet proteome and modulates droplet dynamics.

Cassi M Friday, Isaiah O Stephens, Cathryn T Smith, Sangderk Lee, Diksha Satish, Nicholas A Devanney, Sarah Cohen, Josh M Morganti, Scott M Gordon, Lance A Johnson.

Excess lipid droplet (LD) accumulation is associated with several pathological states, including Alzheimer's disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics contribute to pathophysiology of these disorders remains unclear. Apolipoprotein E (ApoE) is a droplet associated protein with a common risk variant (E4) that confers the largest increase in genetic risk for late-onset AD. E4 is associated with both increased neuroinflammation and excess LD accumulation. In the current study, we sought to quantitatively profile the lipid and protein composition of LDs between the 'neutral' E3 and risk variant E4, to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human E3 or E4 were injected with saline or lipopolysaccharide (LPS), and after 24 hours, hepatic lipid droplets were isolated for proteomic and lipidomic analyses. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with a concomitant increase in phosphatidylcholine species, and overall, the baseline profile of E4 LDs resembled that of the LPS-treated groups. Quantitative proteomics showed that LDs from E4 mice are enriched for proteins involved in protein/vesicle transport but have decreased levels of proteins involved in fatty acid β-oxidation. Interestingly, proteins associated with LDs showed substantial overlap with previously published lists of AD postmortem tissue and microglia 'omics studies, suggesting a potential role for LDs in modulating AD risk or progression. Given this, we exposed primary microglia from the same E3 or E4 mice to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate LD formation and its impact on the cells' immune state. Microglia from E4 mice accumulated more LDs in every condition tested - at baseline and following addition of fatty acids, LPS stimulation, or nN2As. E4 microglia also secreted significantly more cytokines (TNF, IL-1β, IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions, yet showed a blunted response to LPS. In sum, these results suggest that E4 microglia accumulate more LDs compared to E3 microglia and that E4 is associated with a basal LD composition that resembles a pro-inflammatory cell. Together with the high overlap of the LD proteome with established AD-associated datasets, these data further support the idea that alterations in LD dynamics, particularly within microglia, may contribute to the increased risk for AD associated with APOE4 .

DOI: https://doi.org/10.1101/2024.12.16.628710
Nat Cell Biol. 2025 Jan 08.

Triacylglycerol mobilization underpins mitochondrial stress recovery.

Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.

Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41556-024-01586-6
Brain. 2025 Jan 06. pii: awae378. [Epub ahead of print]

Nuclear receptor PPARγ targets GPNMB to promote oligodendrocyte development and remyelination.

Bing Han, Ming-Yue Bao, Qing-Qing Sun, Rui-Ning Wang, Xin Deng, Kun Xing, Feng-Lin Yu, Yan Zhang, Yue-Bo Li, Xiu-Qing Li, Na-Nan Chai, Gai-Xin Ma, Ya-Na Yang, Meng-Yuan Tian, Qian Zhang, Xing Li, Yuan Zhang.

  Myelin injury occurs in brain ageing and in several neurological diseases. Failure of spontaneous remyelination is attributable to insufficient differentiation of oligodendrocyte precursor cells (OPCs) into mature myelin-forming oligodendrocytes in CNS demyelinated lesions. Emerging evidence suggests that peroxisome proliferator-activated receptor γ (PPARγ) is the master gatekeeper of CNS injury and repair and plays an important regulatory role in various neurodegenerative diseases. Although studies demonstrate positive effects of PPARγ in oligodendrocyte ontogeny in vitro, the cell-intrinsic role of PPARγ and the molecular mechanisms involved in the processes of OPC development and CNS remyelination in vivo are poorly understood. Here, we identify PPARγ as an enriched transcription factor in the dysfunctional OPCs accumulated in CNS demyelinated lesions. Its expression increases during OPC differentiation and myelination and is closely related to the process of CNS demyelination/remyelination. Administration of pharmacological agonists of PPARγ not only promotes OPC differentiation and CNS myelination, but also causes a significant increase in remyelination in both cuprizone- and lysophosphatidylcholine-induced demyelination models. In contrast, the attenuation of PPARγ function, either through the specific knockout of PPARγ in oligodendrocytes in vivo or through its inhibition in vitro, leads to decreased OPC maturation, hindered myelin generation and reduced therapeutic efficacy of PPARγ agonists. At a mechanistic level, PPARγ induces myelin repair by directly targeting glycoprotein non-metastatic melanoma protein B (GPNMB), a novel regulator that drives OPCs to differentiate into oligodendrocytes, promotes myelinogenesis in the developing CNS of postnatal mice and enhances remyelination in mice with lysophosphatidylcholine-induced demyelination. In conclusion, our evidence reveals that PPARγ is a positive regulator of endogenous OPC differentiation and CNS myelination/remyelination and suggests that PPARγ and/or its downstream sensor (GPNMB) might be a candidate pharmacological target for regenerative therapy in the CNS.

Keywords:  GPNMB; OPCs; PPARγ; multiple sclerosis; myelination; remyelination

DOI:  https://doi.org/10.1093/brain/awae378
Curr Pain Headache Rep. 2025 Jan 06. 29(1): 11

Sexual Dimorphism in Migraine. Focus on Mitochondria.

Michal Fila, Lukasz Przyslo, Marcin Derwich, Elzbieta Pawlowska, Janusz Blasiak.

   PURPOSE OF REVIEW: Migraine prevalence in females is up to 3 times higher than in males and females show higher frequency, longer duration, and increased severity of headache attacks, but the reason for that difference is not known. This narrative review presents the main aspects of sex dimorphism in migraine prevalence and discusses the role of sex-related differences in mitochondrial homeostasis in that dimorphism. The gender dimension is also shortly addressed.
RECENT FINDINGS: The imbalance between energy production and demand in the brain susceptible to migraine is an important element of migraine pathogenesis. Mitochondria are the main energy source in the brain and mitochondrial impairment is reported in both migraine patients and animal models of human migraine. However, it is not known whether the observed changes are consequences of primary disturbance of mitochondrial homeostasis or are secondary to the migraine-affected hyperexcitable brain. Sex hormones regulate mitochondrial homeostasis, and several reports suggest that the female hormones may act protectively against mitochondrial impairment, contributing to more effective energy production in females, which may be utilized in the mechanisms responsible for migraine progression. Migraine is characterized by several comorbidities that are characterized by sex dimorphism in their prevalence and impairments in mitochondrial functions. Mitochondria may play a major role in sexual dimorphism in migraine through the involvement in energy production, the dependence on sex hormones, and the involvement in sex-dependent comorbidities. Studies on the role of mitochondria in sex dimorphism in migraine may contribute to precise personal therapeutic strategies.

Keywords:  Gender dimension; Migraine comorbidities; Mitochondria; Sex hormones; Sex-dependence of migraine prevalence

DOI:  https://doi.org/10.1007/s11916-024-01317-4
Antioxidants (Basel). 2024 Dec 10. pii: 1502. [Epub ahead of print]13(12):

Multitarget Effects of Nrf2 Signalling in the Brain: Common and Specific Functions in Different Cell Types.

Elisa Navarro, Noemí Esteras.

  Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of cellular defence mechanisms, essential for maintaining the brain's health. Nrf2 supports mitochondrial function and protects against oxidative damage, which is vital for meeting the brain's substantial energy and antioxidant demands. Furthermore, Nrf2 modulates glial inflammatory responses, playing a pivotal role in preventing neuroinflammation. This review explores these multifaceted functions of Nrf2 within the central nervous system, focusing on its activity across various brain cell types, including neurons, astrocytes, microglia, and oligodendrocytes. Due to the brain's vulnerability to oxidative stress and metabolic challenges, Nrf2 is emerging as a key therapeutic target to enhance resilience against oxidative stress, inflammation, mitochondrial dysfunction, and demyelination, which are central to many neurodegenerative diseases.

Keywords:  Nrf2; antioxidants; astrocytes; brain; inflammation; microglia; mitochondria; neurodegeneration; neurons

DOI:  https://doi.org/10.3390/antiox13121502
Nutrients. 2024 Dec 17. pii: 4344. [Epub ahead of print]16(24):

Impact of Omega-3 on Endocannabinoid System Expression and Function, Enhancing Cognition and Behavior in Male Mice.

Maitane Serrano, Miquel Saumell-Esnaola, Garazi Ocerin, Gontzal García Del Caño, Nagore Puente, Joan Sallés, Fernando Rodríguez de Fonseca, Marta Rodríguez-Arias, Inmaculada Gerrikagoitia, Pedro Grandes.

  Background/Objectives: Omega-3 long-chain polyunsaturated fatty acids (PUFAs) support brain cell membrane integrity and help mitigate synaptic plasticity deficits. The endocannabinoid system (ECS) is integral to synaptic plasticity and regulates various brain functions. While PUFAs influence the ECS, the effects of omega-3 on the ECS, cognition, and behavior in a healthy brain remain unclear. Methods and Results: Here, we demonstrate that hippocampal synaptosomes from male mice fed an omega-3-rich diet exhibit increased levels of cannabinoid CB1 receptors (~30%), phospholipase C β1 (PLCβ1, ~30%), monoacylglycerol lipase (MAGL, ~30%), and cannabinoid receptor-interacting protein 1a (Crip1a, ~60%). Conversely, these synaptosomes show decreased levels of diacylglycerol lipase α (DAGLα, ~40%), synaptosomal-associated protein 25kDa (SNAP-25, ~30%), and postsynaptic density protein 95 (PSD-95, ~40%). Omega-3 intake also reduces Gαo and Gαi3 levels, though receptor-stimulated [35S]GTPγS binding remains unaffected. Stimulation of the medial perforant path (MPP) induced long-term potentiation (LTP) in omega-3-fed mice. This LTP was dependent on group I metabotropic glutamate receptors (mGluR), 2 arachidonoylglycerol (2-AG), CB1 receptors, N-type Ca2+ channels, and actin filaments. Behaviorally, omega-3-fed mice displayed reduced exploratory behavior and significantly improved object discrimination in the novel object recognition test (NORT). They also spent more time in open arms and exhibited reduced freezing time in the elevated plus maze (EPM), indicative of reduced anxiety-like behavior. Conclusions: Our findings suggest that omega-3 leverages the ECS to enhance brain function under normal conditions.

Keywords:  CB1 receptor; hippocampus; memory; polyunsaturated fatty acids; synaptic plasticity

DOI:  https://doi.org/10.3390/nu16244344
Front Cell Neurosci. 2024 ;18 1432887

STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.

Mohammad Jodeiri Farshbaf, Taelor A Matos, Kristi Niblo, Yacoub Alokam, Jessica L Ables.

   Introduction: Diabetes is a metabolic disorder of glucose homeostasis that is a significant risk factor for neurodegenerative diseases, such as Alzheimer's disease, as well as mood disorders, which often precede neurodegenerative conditions. We examined the medial habenulainterpeduncular nucleus (MHb-IPN), as this circuit plays crucial roles in mood regulation, has been linked to the development of diabetes after smoking, and is rich in cholinergic neurons, which are affected in other brain areas in Alzheimer's disease.
Methods: This study aimed to investigate the impact of streptozotocin (STZ)-induced hyperglycemia, a type 1 diabetes model, on mitochondrial and lipid homeostasis in 4% paraformaldehyde-fixed sections from the MHb and IPN of C57BL/6 J male mice, using a recently developed automated pipeline for mitochondrial analysis in confocal images. We examined different time points after STZ-induced diabetes onset to determine how the brain responded to chronic hyperglycemia, with the limitation that mitochondria and lipids were not examined with respect to cell type or intracellular location.
Results: Mitochondrial distribution and morphology differentially responded to hyperglycemia depending on time and brain area. Six weeks after STZ treatment, mitochondria in the ventral MHb and dorsal IPN increased in number and exhibited altered morphology, but no changes were observed in the lateral habenula (LHb) or ventral IPN. Strikingly, mitochondrial numbers returned to normal dynamics at 12 weeks. Both blood glucose level and glycated hemoglobin (HbA1C) correlated with mitochondrial dynamics in ventral MHb, whereas only HbA1C correlated in the IPN. We also examined lipid homeostasis using BODIPY staining for neutral lipids in this model given that diabetes is associated with disrupted lipid homeostasis. BODIPY staining intensity was unchanged in the vMHb of STZ-treated mice but increased in the IPN and VTA and decreased in the LHb at 12 weeks. Interestingly, areas that demonstrated changes in mitochondria had little change in lipid staining and vice versa.
Discussion: This study is the first to describe the specific impacts of diabetes on mitochondria in the MHb-IPN circuit and suggests that the cholinergic MHb is uniquely sensitive to diabetesinduced hyperglycemia. Further studies are needed to understand the functional and behavioral implications of these findings.

Keywords:  diabetes; interpeduncular nucleus; lipid; medial habenula; mitochondrial homeostasis

DOI:  https://doi.org/10.3389/fncel.2024.1432887
Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]

Formation of I2+III2 supercomplex rescues respiratory chain defects.

Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.

  Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.

Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex

DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
J Cereb Blood Flow Metab. 2025 Jan 07. 271678X241310729

Glutamine metabolism is systemically different between primary and induced pluripotent stem cell-derived brain microvascular endothelial cells.

Callie M Weber, Bilal Moiz, Marzyeh Kheradmand, Arielle Scott, Claire Kettula, Brooke Wunderler, Viviana Alpízar Vargas, Alisa Morss Clyne.

  Human primary (hpBMEC) and induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (hiBMEC) are interchangeably used in blood-brain barrier models to study neurological diseases and drug delivery. Both hpBMEC and hiBMEC use glutamine as a source of carbon and nitrogen to produce metabolites and build proteins essential to cell function and communication. We used metabolomic, transcriptomic, and computational methods to examine how hpBMEC and hiBMEC metabolize glutamine, which may impact their utility in modeling the blood-brain barrier. We found that glutamine metabolism was systemically different between the two cell types. hpBMEC had a higher metabolic rate and produced more glutamate and GABA, while hiBMEC rerouted glutamine to produce more glutathione, fatty acids, and asparagine. Higher glutathione production in hiBMEC correlated with higher oxidative stress compared to hpBMEC. α-ketoglutarate (α-KG) supplementation increased glutamate secretion from hiBMEC to match that of hpBMEC; however, α-KG also decreased hiBMEC glycolytic rate. These fundamental metabolic differences between BMEC types may impact in vitro blood-brain barrier model function, particularly communication between BMEC and surrounding cells, and emphasize the importance of evaluating the metabolic impacts of iPSC-derived cells in disease models.

Keywords:  Blood-brain barrier; brain microvascular endothelial cells; glutamate metabolism; glutamine metabolism; metabolic flux analysis

DOI:  https://doi.org/10.1177/0271678X241310729
FEBS J. 2025 Jan 10.

A creatine efflux transporter in oligodendrocytes.

Svenja Flögel, Miriam Strater, Dietmar Fischer, Dirk Gründemann.

  Creatine is essential for ATP regeneration in energy-demanding cells. Creatine deficiency results in severe neurodevelopmental impairments. In the brain, creatine is synthesized locally by oligodendrocytes to supply neighboring neurons. Neuronal uptake is mediated by SLC6A8. However, it is still unknown how creatine is released from the producing cells. Here, we investigated the function of the transporter SLC22A15, which exhibits strikingly high amino acid sequence conservation. The release of substrates from 293 cells via heterologously expressed human and rat SLC22A15 was analyzed by mass spectrometry. A number of zwitterions were identified as substrates, with similar efflux transport efficiencies. However, in absolute numbers, the efflux of creatine far outweighed all other substrates. In contrast to the permanent creatine efflux mediated by SLC16A12 and SLC16A9, SLC22A15 was, by default, completely inactive, thereby preventing continuous creatine loss from producing cells. External substrates such as guanidinoacetic acid, GABA, or MPP+ trigger creatine release through a one-to-one exchange. Human and mouse mRNA profiles indicate that SLC22A15 expression is highest in oligodendrocytes and bone marrow. Single-cell RNA sequencing data substantiate the hypothesis that SLC22A15 depends on high intracellular creatine concentrations: high SLC22A15 counts, as in oligodendrocytes and macrophages, correlate with high counts of the creatine synthesis enzymes AGAT and GAMT in both humans and mice, whereas in proximal tubular cells and hepatocytes, AGAT counts are high, but SLC22A15 is absent. Our findings establish SLC22A15 as the pivotal transporter for controlled creatine release from oligodendrocytes, filling a critical gap in understanding creatine metabolism in the brain.

Keywords:  SLC22A15; creatine transporter; macrophage; mass spectrometry; oligodendrocyte

DOI:  https://doi.org/10.1111/febs.17382
Curr Protein Pept Sci. 2025 Jan 02.

The Role of Lactate in Ischemic Stroke: As an Energy Source and Signaling Molecule.

Rui Zhang, Xintong Li, Kemeng Liu, Meng Yang, Peiliang Dong, Hua Han.

  Stroke is an acute cerebrovascular disease that causes brain tissue damage due to sudden blockage or rupture of blood vessels in the brain. According to the latest data from the Global Burden of Disease Study, the number of stroke patients worldwide is estimated to exceed 100 million, and more than 80% of patients suffer from stroke. Ischemic stroke is a type of stroke due to which two-thirds of the patients are disabled or even die, seriously affecting the patient's quality of life. Lactate is an indispensable substance in various physiological and pathological cells and plays a regulatory role in different aspects of energy metabolism and signal transduction. Studies have found that during cerebral ischemia and hypoxia, lactate concentration increases significantly, improving the energy supply to the ischemic area. Based on the scientific concept of lactate travelling through the brain, this article focuses on the important role of lactate as an energy source after ischemic stroke and analyzes the relationship between lactate as a signaling molecule and neuroprotection, angiogenesis, and anti-inflammatory effects. The aim of this study is to outline the molecular mechanisms by which lactate exerts its different effects in ischemic stroke. Some references are provided in this study for the research on lactate therapy for ischemic stroke.

Keywords:  Ischemic stroke; angiogenesis; anti-inflammation.; glycolysis; lactate; neuroprotection

DOI:  https://doi.org/10.2174/0113892037335945241029111720
Int J Pharm. 2025 Jan 07. pii: S0378-5173(24)01359-0. [Epub ahead of print] 125125

Nose-to-brain delivery of DHA-loaded nanoemulsions: A promising approach against Alzheimer's disease.

Léa Otaegui, Théo Urgin, Taghrid Zaiter, Charleine Zussy, Mathieu Vitalis, Yann Pellequer, Niyazi Acar, Claire Vigor, Jean-Marie Galano, Thierry Durand, Laurent Givalois, Arnaud Béduneau, Catherine Desrumaux.

  Reduced docosahexaenoic acid (DHA) concentrations seem to be associated with an increased risk of Alzheimer's disease (AD), and DHA accretion to the brain across the blood-brain-barrier (BBB) can be modulated by various factors. Therefore, there is an urgent need to identify an efficient and non-invasive method to ensure brain DHA enrichment. In the present study, a safe and stable DHA-enriched nanoemulsion, designed to protect DHA against oxidation, was designed and administered intranasally in a transgenic mouse model of AD, the J20 mice. Intranasal treatment with nanoformulated DHA significantly improved well-being and working spatial memory in six-months-old J20 mice. These behavioral effects were associated with a reduction of amyloid deposition, oxidative stress, and neuroinflammation in brain tissues, which may be partially due to DHA-induced inactivation of the pleiotropic kinase GSK3β. In conclusion, intranasal DHA administration exhibited strong therapeutic effects and disease-modifying benefits in the J20 AD model. Given that DHA has already shown safety and tolerability in healthy human subjects, our results further support the need for clinical trials to assess the potential of this approach in Alzheimer's patients.

Keywords:  Alzheimer’s disease; Amyloid plaques; Docosahexaenoic acid; Intranasal administration; Nanoemulsion; Nanovectorization; Neuroinflammation; Omega-3 polyunsaturated fatty acids; Oxidative stress

DOI:  https://doi.org/10.1016/j.ijpharm.2024.125125
Anal Chem. 2025 Jan 09.

Comprehensive Approach for Sequential MALDI-MSI Analysis of Lipids, N-Glycans, and Peptides in Fresh-Frozen Rodent Brain Tissues.

Yea-Rin Lee, Ibrahim Kaya, Elin Wik, Sooraj Baijnath, Henrik Lodén, Anna Nilsson, Xiaoqun Zhang, Dag Sehlin, Stina Syvänen, Per Svenningsson, Per E Andrén.

Multiomics analysis of single tissue sections using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provides comprehensive molecular insights. However, optimizing tissue sample preparation for MALDI-MSI to achieve high sensitivity and reproducibility for various biomolecules, such as lipids, N-glycans, and tryptic peptides, presents a significant challenge. This study introduces a robust and reproducible protocol for the comprehensive sequential analysis of the latter molecules using MALDI-MSI in fresh-frozen rodent brain tissue samples. The optimization process involved testing multiple organic solvents, which identified serial washing in ice-cold methanol, followed by chloroform as optimal for N-glycan analysis. Integrating this optimized protocol into MALDI-MSI workflows enabled comprehensive sequential analysis of lipids (in dual polarity mode), N-glycans, and tryptic peptides within the same tissue sections, enhancing both the efficiency and reliability. Validation across diverse rodent brain tissue samples confirmed the protocol's robustness and versatility. The optimized methodology was subsequently applied to a transgenic Alzheimer's disease (AD) mouse model (tgArcSwe) as a proof of concept. In the AD model, significant molecular alterations were observed in various sphingolipid and glycerophospholipid species, as well as in biantennary and GlcNAc-bisecting N-glycans, particularly in the cerebral cortex. These region-specific alterations are potentially associated with amyloid-beta (Aβ) plaque accumulation, which may contribute to cognitive and memory impairments. The proposed standardized methodology represents a significant advancement in neurobiological research, providing valuable insights into disease mechanisms and laying the foundation for potential preclinical applications. It could aid the development of diagnostic biomarkers and targeted therapies for AD and other neurodegenerative diseases, such as Parkinson's disease.

DOI: https://doi.org/10.1021/acs.analchem.4c05665
Mol Psychiatry. 2025 Jan 07.

Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer's disease in two independent study cohorts.

Benedetta Bigio, Ricardo A S Lima-Filho, Olivia Barnhill, Felipe K Sudo, Claudia Drummond, Naima Assunção, Bart Vanderborght, James Beasley, Sarah Young, Aryeh Korman, Drew R Jones, David L Sultzer, Sergio T Ferreira, Paulo Mattos, Elizabeth Head, Fernanda Tovar-Moll, Fernanda G De Felice, Mychael V Lourenco, Carla Nasca.

A major challenge in the development of more effective therapeutic strategies for Alzheimer's disease (AD) is the identification of molecular mechanisms linked to specific pathophysiological features of the disease. Importantly AD has a two-fold higher incidence in women than men and a protracted prodromal phase characterized by amnestic mild-cognitive impairment (aMCI) suggesting that biological processes occurring early can initiate vulnerability to AD. Here, we used a sample of 125 subjects from two independent study cohorts to determine the levels in plasma (the most accessible specimen) of two essential mitochondrial markers acetyl-L-carnitine (LAC) and its derivative free-carnitine motivated by a mechanistic model in rodents in which targeting mitochondrial metabolism of LAC leads to the amelioration of cognitive function and boosts epigenetic mechanisms of gene expression. We report a sex-specific deficiency in free-carnitine levels in women with aMCI and early-AD compared to cognitively healthy controls; no change was observed in men. We also replicated the prior finding of decreased LAC levels in both women and men with AD, supporting the robustness of the study samples assayed in our new study. The magnitude of the sex-specific free-carnitine deficiency reflected the severity of cognitive dysfunction and held in two study cohorts. Furthermore, patients with the lower free-carnitine levels showed higher β-amyloid(Aβ) accumulation and t-Tau levels assayed in cerebrospinal fluid (CSF). Computational analyses showed that the mitochondrial markers assayed in plasma are at least as accurate as CSF measures to classify disease status. Together with the mechanistic platform in rodents, these translational findings lay the groundwork to create preventive individualized treatments targeting sex-specific changes in mitochondrial metabolism that may be subtle to early cognitive dysfunction of AD risk.

DOI: https://doi.org/10.1038/s41380-024-02862-5
Biology (Basel). 2024 Dec 04. pii: 1011. [Epub ahead of print]13(12):

Consequences of Early Maternal Deprivation on Neuroinflammation and Mitochondrial Dynamics in the Central Nervous System of Male and Female Rats.

Diego San Felipe, Beatriz Martín-Sánchez, Khaoula Zekri-Nechar, Marta Moya, Ricardo Llorente, Jose J Zamorano-León, Eva M Marco, Meritxell López-Gallardo.

  Early life stress (ELS) is associated with an increased risk for neuropsychiatric disorders, and both neuroinflammation and mitochondrial dysfunction seem to be central to mental health. Herein, using an animal model of ELS, a single episode of maternal deprivation (MD, 24 h on pnd 9) extensively documented to elicit behavioural anomalies in male and female Wistar rats, we investigated its consequences in terms of neuroinflammation and mitochondrial dynamics in the prefrontal cortex (PFC) and the hippocampal formation (HCF). MD differentially affected the brain content of cytokines: MD induced a transient increase in pro-inflammatory cytokines (IL-1β and IL-6) in the PFC, as well as in the levels of the anti-inflammatory cytokine IL-10 in the HCF. MD also induced a significant decrease mitochondria citrate synthase activity, but MD did not exert significant changes in mitochondria Complex IV activity, revealing a generalized decrease in mitochondrial density without any change in mitochondrial respiration. In the present study, we demonstrate that MD induces neuroinflammatory processes in specific brain regions. Additional research is needed to better understand the temporal pattern of such changes, their impact on the developing brain, and their participation in the already well-known behavioural consequences of MD.

Keywords:  citrate synthase; complex IV; cytokines; early life stress (ELS); hippocampal formation; inflammatory processes; mitochondria; neonatal; prefrontal cortex; sex dimorphism

DOI:  https://doi.org/10.3390/biology13121011
Biomed Pharmacother. 2025 Jan 08. pii: S0753-3322(24)01684-6. [Epub ahead of print]183 117797

Prolonged incubation with Δ9-tetrahydrocannabinol but not with cannabidiol induces synaptic alterations and mitochondrial impairment in immature and mature rat organotypic hippocampal slices.

Costanza Mazzantini, Lorenzo Curti, Daniele Lana, Alessio Masi, Maria Grazia Giovannini, Giada Magni, Domenico E Pellegrini-Giampietro, Elisa Landucci.

  Cannabis derivatives are among the most widely used psychoactive substances in the world, which leads to growing medical concerns regarding its chronic use and abuse especially among adolescents. Exposure to THC during formative years produces long-term behavioral alterations that share similarities with symptoms of psychiatric and neurodevelopmental disorders. In this study, we have analyzed the functional and molecular mechanisms that might underlie these alterations. Rat organotypic hippocampal slices were cultured for 2 days (immature) or 10 days (mature) in vitro and then exposed for 7 days to THC (1 µM) or CBD (1 µM). At the end of the treatment, slices were analyzed by Western blotting, electrophysiological recordings, RT-PCR, and fluorescence microscopy to explore the molecular and functional changes in the hippocampus. A prolonged (7-day) exposure to THC reduced the expression levels of pre- (synaptophysin, vGlut1) and post-synaptic (PSD95) proteins in both immature and mature slices, whereas CBD significantly increased the expression levels of PSD95 only in immature slices. In addition, THC significantly reduced the passive properties and the intrinsic excitability of membranes and increased sEPSCs in CA1 pyramidal cells of immature but not mature slices. Exposure to both cannabinoids impaired mitochondrial function as detected by the reduction of mRNA expression levels of mitobiogenesis genes such as VDAC1, UCP2, and TFAM. Finally, THC but not CBD caused tissue disorganization and morphological modifications in CA1 pyramidal neurons, astrocytes and microglia in both immature and mature slices. These results are helpful to explain the specific vulnerability of adolescent brain to the effects of psychotropic cannabinoids.

Keywords:  1–7: Synaptophysin; PSD95; UCP2; VDAC1; microglia; sEPSCs

DOI:  https://doi.org/10.1016/j.biopha.2024.117797