bims-medebr 2026-05-17 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–05–17
24 papers selected by
Regina F. Fernández, Johns Hopkins University

Polar lipids, omega-3 polyunsaturated fatty acids homeostasis, and brain aging: Mechanisms, dietary sources, and neuroprotection.
Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.
SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response.
Brain metabolomic profiling reveals ischemia-dominant disruption of metabolic pathways and tissue homeostasis in neonatal hypoxic-ischemic brain injury.
Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.
Low 5HT1B and 5HT4 Receptor Neurotransmission as a Potential Link Between Cholesterol Metabolism and Suicide Risk.
Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.
Restoring mitochondrial health after blast-induced traumatic brain injury: modifiable factors and therapeutic opportunities.
Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.
Female metabolic resilience and male-biased protein quality defects under hypoxia in human brain organoids.
1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.
170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.
Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.
Fructose Intake Is Associated with Brain Metabolic Reprogramming and Exacerbation of Alzheimer-like Alterations in APP/PS1 Mice.
Emerging Roles of Adenosine Metabolism in Astrocytes During Brain Injury.
An improved method for high-purity isolation of oligodendrocytes from neonatal and adult mouse brain.
Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.
Ceftriaxone has a similar effect on astrocytic and neuronal GLT-1 distribution after mild traumatic brain injury.
Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.
Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways.
Telomerase mRNA-Lipid nanoparticles attenuate neuroinflammation after traumatic brain injury in mice.
Reverse electron transfer at mitochondrial complex I restrains dopaminergic neuron activity to promote early-life sleep in Drosophila.
Oleic and omega-3 fatty acids buffer neuroinflammation in a scopolamine model with Alzheimer's-like features via target-level interactions.

Nutr Res. 2026 Apr 21. pii: S0271-5317(26)00044-8. [Epub ahead of print]150 127-138

Polar lipids, omega-3 polyunsaturated fatty acids homeostasis, and brain aging: Mechanisms, dietary sources, and neuroprotection.

Francesco Visioli, João Tomé-Carneiro.

  The relationship between lipid metabolism and neurodegeneration is a critical determinant of brain aging with therapeutic implications. This review focuses on how polar lipids and omega-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), contribute to membrane organization, signaling, neuroinflammation resolution, and cognitive resilience during aging. The mammalian brain, containing over 50% lipids by dry weight, is exceptionally enriched in DHA, which preferentially accumulates in cognitive-critical regions including the hippocampus and prefrontal cortex. Age-related decline in brain PUFA content is a consistent finding across species and is linked to lower synaptic density, neuronal loss, and cognitive impairment. This decline results from converging mechanisms including impaired transport across the blood-brain barrier, oxidative damage, altered lipid remodeling, and reduced inflammatory resolution. We also discuss how dietary intake, endogenous PUFA biosynthesis, sex, obesity, and hepatic metabolic dysfunction may modify brain PUFA availability. Clinical evidence suggests that omega-3 interventions may provide selective cognitive benefits, particularly for executive function and in genetically susceptible populations such as APOE4 carriers, although effects differ according to dose, formulation, and baseline status. Complex lipid sources including milk fat globule membrane may offer advantages beyond simple fatty acid supplementation by improving the delivery of bioactive polar lipids. Overall, the field is moving toward mechanism-informed and precision nutrition strategies to preserve brain health across the lifespan.

Keywords:  Brain aging; Docosahexaenoic acid (DHA); Milk fat globule membrane (MFGM); Neurodegeneration; Polyunsaturated fatty acids (PUFAs); Specialized pro-resolving mediators

DOI:  https://doi.org/10.1016/j.nutres.2026.04.005
Mitochondrion. 2026 May 14. pii: S1567-7249(26)00058-9. [Epub ahead of print] 102168

Quantitative proteomic profiling of neural cells-specific metabolic reprogramming in response to mitochondrial dysfunction using iMPAQT2.

Akito Tani, Mikako Yagi, Natsuki Horiuchi, Kento Nagata, Tomohiro Tanaka, Hiroki Kittaka, Ko Igami, Takeshi Uchiumi.

  Age-related mitochondrial dysfunction is increasingly recognized as a key contributor to neurodegenerative disease pathogenesis. In the central nervous system, neurons, oligodendrocytes, and astrocytes which derived from neural stem cells, fulfill distinct metabolic and functional roles. However, the specific vulnerabilities of these cell types to mitochondrial impairment remain unclear. In this study, we employed the iMPAQT2 proteomics platform to systematically compare the metabolic profiles of neurons, oligodendrocytes, and astrocytes, and to elucidate the molecular consequences of mitochondrial dysfunction induced by chloramphenicol and oligomycin. Our findings indicate that neurons and oligodendrocytes primarily rely on oxidative phosphorylation (OXPHOS) for ATP production, whereas astrocytes predominantly utilize glycolysis. It is noteworthy that oligodendrocytes exhibited enriched pathways for cholesterol synthesis, fatty acid degradation, and heme catabolism-processes that are critical for myelin maintenance. Treatment with the mitochondrial function inhibitors chloramphenicol or oligomycin reduced the expression of OXPHOS enzymes in all cell types. This reduction was particularly pronounced in oligodendrocytes for glycolysis, cholesterol synthesis, heme degradation, and fatty acid degradation. These results suggest that oligodendrocytes are particularly vulnerable to mitochondrial dysfunction, which may play a pivotal role in the pathogenesis of age-related neurodegenerative disorders.

Keywords:  Metabolic enzyme; Mitochondrial dysfunction; Neural cells; Proteomics; iMPAQT2

DOI:  https://doi.org/10.1016/j.mito.2026.102168
J Neuroinflammation. 2026 May 13.

SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.

Hui-Wen Zhang, Xue-Jie Wang, Mao-Mao Chu, Guang-Yuan Xing, Kai Qiu, Yu-Ge Zhang, Wen-Feng Zhang, Yu-Tong Zhang, Xue Liu, Lei Li, Xiao-Wei Lu, Xin-Xin Huang, Lei-Yang Zhang, Zhi-Yuan Zhang.

  Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.

Keywords:  Lipid reprogramming; Microglial immunometabolism; Mitochondrial lipotoxicity; Neuroprotection; SLC27A3; Trilobatin

DOI:  https://doi.org/10.1186/s12974-026-03826-y
J Biomed Sci. 2026 May 13. pii: 50. [Epub ahead of print]33(1):

Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response.

Mingyi Yang, Wei Wang, María Cámara-Quílez, Borghild Hvesser Farsund, Niklas Nonboe Andersen, Karin Garten, Animesh Sharma, Xiaolin Lin, Ingrid Åmellem, Erlend Ravlo, Jing Ye, Magnar Bjørås, Mirta Mittelstedt Leal de Sousa.

   BACKGROUND: CLN3 Batten disease is a severe pediatric neurodegenerative disorder caused by mutations in the CLN3 gene, most commonly a 1 kb deletion encompassing exons 7 and 8. CLN3 deficiency is associated with lysosomal dysfunction, impaired cellular clearance and disrupted metabolism. While neurons are particularly vulnerable in CLN3 Batten disease and have been the primary focus of research, glial cells are increasingly recognized as active contributors to disease pathology. Among them, astrocytes-the most abundant glial cell type in the brain-play critical roles in maintaining neuronal health and homeostasis. However, astrocytes remain understudied in CLN3 patient-derived models.
METHODS: We present the first iPSC-derived astrocyte model from a skin biopsy of a CLN3 patient carrying the common 1 kb deletion. Cellular and molecular features of iPSC and astrocytes derived from both healthy controls and the CLN3 patient were characterized via qPCR, immunocytochemistry and targeted mass spectrometry. In addition, comprehensive omics-based profiling, through transcriptomic and label-free quantitative proteomics, was performed to uncover novel molecular mechanisms and generate hypotheses that can guide future mechanistic and functional studies.
RESULTS: Transcriptomic and proteomic analyses during astrocyte differentiation revealed an upregulation of mitochondrial respiratory chain complexes I and IV-contrasting with the downregulation typically observed in CLN3-deficient neurons. We also identified a metabolic shift favoring the elongation of very-long-chain saturated fatty acids, accompanied by reduced lipid synthesis and enhanced fatty acid oxidation. These metabolic alterations were paralleled by an upregulation of proteins involved in oxidative stress responses, likely reflecting a compensatory adaptation to mitochondrial and lipid metabolic dysregulation. Furthermore, we observed significant changes in chromatin organization during astrocyte differentiation in CLN3 cells, suggesting epigenetic remodeling as a contributing factor to disease pathology.
CONCLUSION: Our findings prompt the hypothesis that mitochondrial dysfunction may precede lysosomal defects in CLN3-deficient astrocytes. Restoring mitochondrial health could improve brain metabolism, inflammation control, neurotransmitter regulation, and neuronal survival, highlighting mitochondria as promising therapeutic targets in CLN3 Batten disease.

Keywords:  CLN3 Batten disease; CLN3 patient-derived astrocytes; Lipid metabolism; Mitochondrial function; Oxidative stress response

DOI:  https://doi.org/10.1186/s12929-026-01253-y
Sci Rep. 2026 May 14.

Brain metabolomic profiling reveals ischemia-dominant disruption of metabolic pathways and tissue homeostasis in neonatal hypoxic-ischemic brain injury.

Nora Wolff, Maria Triantafyllou, Javid Ghaemmaghami, Georgios Sanidas, Chad Everett Byrd, Gabriele Simonti, Susan Aja, Aurelie Roux, Khyzer Aziz, Evan Goldstein, Jiangyang Zhang, Allen Dale Everett, David Graham, Panagiotis Kratimenos, Ioannis Koutroulis, Frances Northington.

  In neonatal hypoxic-ischemic brain injury (HIBI), a common form of perinatal brain damage associated with mortality and neurological disability, the disruption of oxygen and nutrient supply severely impacts brain metabolism. Though therapeutic hypothermia reduces cerebral metabolic rate and improves outcomes, disruption of oxidative metabolism compromising neuronal survival often persists. The complex cerebral metabolic shifts in HIBI remain poorly understood. We directly analyzed the metabolome (LC-MS) of neonatal hypoxia-ischemia (HI)-affected brain tissue to gain further insight into HIBI pathophysiology, isolate the metabolic effects of ischemia and hypoxia, and identify potential therapeutic targets. Postnatal day 10 mice were subjected to five experimental conditions: HI (n = 9) by unilateral carotid artery ligation (UCAL) and hypoxia exposure; contralateral hemispheres; ischemia (UCAL, n = 8); hypoxia (n = 12); and naive (n = 9). Cerebral hemispheres were analyzed 24h post-HI to capture their acute metabolic state. HI resulted in marked alterations in energy production, amino acid and nucleotide metabolism, and pathways governing neuronal homeostasis. Metabolites and pathways linked to NAD⁺ signaling, glutamate regulation, PI3K/AKT signaling, arginine metabolism, neuroinflammation, and vascular regulation were significantly dysregulated. Importantly, these metabolic changes were largely reproduced by ischemia alone, revealing an ischemia-dominant metabolic phenotype. Overall, brain metabolomic profiling identified ischemia as a primary driver of metabolic dysfunction in neonatal HIBI and highlighted specific metabolic pathways involved in bioenergetic deficit, imbalance of neurodegenerative-neuroprotective mechanisms, inflammation, and vascular function, as candidate targets for future therapeutic strategies aimed at limiting secondary brain injury and mitigating neurodevelopmental sequelae.

Keywords:  Arginine; Hypoxic-ischemic encephalopathy; N-acetylaspartic acid; NAD+ signaling; Neurocritical care; Perinatal arterial ischemic stroke

DOI:  https://doi.org/10.1038/s41598-026-51705-6
Nutrients. 2026 Apr 28. pii: 1392. [Epub ahead of print]18(9):

Long-Chain Fatty Acids as Drivers of Neuroinflammation in Neurodegeneration: Mechanistic Links to Lipid Peroxidation, Ferroptosis, and Mitochondrial Dysfunction.

Rafail C Christodoulou, Laura Lorentzen, Daniel Eller, Evros Vassiliou.

  Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis.

Keywords:  astrogliosis; immunometabolism; lipid peroxidation; long-chain fatty acids; microglia; neurodegeneration; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.3390/nu18091392
J Neurochem. 2026 May;170(5): e70466

Low 5HT1B and 5HT4 Receptor Neurotransmission as a Potential Link Between Cholesterol Metabolism and Suicide Risk.

Hans O Kalkman, Lukasz Smigielski.

  Elevated levels of the inflammatory cytokine IL-6 and decreased levels of cholesterol in blood and brain tissue have been reported in studies of individuals who attempted or completed suicide. The mechanisms underlying these effects remain unclear. In this review, we discuss a potential mechanistic link between these observations involving lipid raft function and serotonergic signaling. Reduced cholesterol availability may affect lipid raft function and could, potentially through reduced levels of the lipid raft protein S100A10 (p11), result in diminished cell-surface expression of the serotonin receptors 5-HT1B and 5-HT4. Both receptors have been implicated in the suppression of impulsive and aggressive behavior. Lipid rafts are also organizing platforms for GABA, glutamate, and serotonin transporters. Reduced serotonin reuptake could contribute to the often-reported decrease in the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in suicidal individuals. Inflammatory cytokines, including IL-6, may further influence serotonergic signaling by increasing expression of the enzyme indoleamine-2,3-dioxygenase (IDO), which enhances tryptophan degradation through the kynurenine pathway. Reduced tryptophan availability may limit serotonin synthesis and thereby decrease activation of the 5-HT1B and 5-HT4 receptors. These observations suggest that the combined effects of low cholesterol, elevated IL-6 signaling, and reduced tryptophan availability may increase impulsivity and thereby heighten vulnerability to suicidal behavior. This framework accommodates findings from genetic and biomarker studies in suicidal patients. Owing to its effect on lipid raft organization, the fish-oil component docosahexaenoic acid (DHA) might modulate these processes and potentially reduce suicide risk in individuals with low cholesterol levels.

Keywords:  IDO; IL‐6; S100A10; ceramide; cholesterol; impulsivity; lipid raft; tryptophan

DOI:  https://doi.org/10.1111/jnc.70466
bioRxiv. 2026 Feb 27. pii: 2026.02.25.708044. [Epub ahead of print]

Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement.

Sebastian F Salathe, Benjamin A Kugler, Edziu Franczak, Xin C Davis, Frederick B Boakye, Julie Allen, Kyle L Fulghum, Eric D Queathem, E Matthew Morris, Patrycja Puchalska, Peter A Crawford, John P Thyfault.

Ketogenesis and ketone body metabolism are linked to brain health benefits, including delaying age-related cognitive decline and neurodegeneration. Exercise, particularly when combined with an overnight fast, stimulates ketogenesis and ketone body turnover as well as improves brain metabolism and cognition. Yet, whether ketone metabolism is obligatory for this response is unknown. Here, we use chronic exercise via voluntary wheel running plus time-restricted feeding (VWR+TRF, fasting from ZT10.5-18.5) to explore whether ketone bodies are a potential mediator of exercise-induced brain health benefits in middle-aged mice. To independently distinguish the roles of neuronal ketone body metabolism vs. hepatic ketone body production, we studied middle-age female neuronal-specific SCOT knockout mice and female hepatocyte-specific HMGCS2 knockout mice, respectively. VWR+TRF was compared to sedentary ad-libitum fed (SED+AL) mice to assess the impact on whole-body metabolism (indirect calorimetry), cognition (Barnes Maze and Y-Maze), and molecular adaptations in the hippocampus (proteomics). VWR+TRF robustly upregulated systemic lipid oxidation in all mice, regardless of genotype, during the first 6.5 hours of the dark period. In female SCOT-Neuron-KO mice, we show impaired responses to VWR+TRF in indices of short- and long-term memory. Proteomic analysis of isolated hippocampi revealed that SCOT-Neuron-KO mice failed to globally upregulate key facilitators of synaptic function, including leucine-rich repeated transmembrane proteins, neurexins, and neuroligins. In female HMGCS2-Liver-KO mice, impaired responses to VWR+TRF in indices of short-term memory were paired with an upregulation in ketogenesis machinery in the hippocampal proteome, suggesting potential in vivo evidence of cerebral ketogenesis, a mechanism mitigating an otherwise more pronounced behavioral phenotype. Together, these findings suggest that neuronal ketone body utilization is essential, and hepatic ketone production is contributory, to the full cognitive and synaptic adaptations to exercise plus time-restricted feeding, supporting ketone metabolism as a key mechanistic link between metabolic state and brain health in midlife.

DOI: https://doi.org/10.64898/2026.02.25.708044
NPJ Metab Health Dis. 2026 May 13. pii: 18. [Epub ahead of print]4(1):

Restoring mitochondrial health after blast-induced traumatic brain injury: modifiable factors and therapeutic opportunities.

Cortney J Laye, W Brad Hubbard.

Blast-induced traumatic brain injury (blast TBI) causes diffuse neuropathology, blood-brain barrier disruption, and complex neurological sequelae. Mitochondrial dysfunction is increasingly recognized as a contributor to secondary injury cascades and has been associated with bioenergetic impairment, alterations in mitochondrial dynamics, oxidative stress, and apoptotic signaling following blast exposure. Primary data from our recent study demonstrates acute TCA cycle impairment and supports a framework of glycolytic shift in the brain alongside a bottleneck of key TCA cycle intermediates. This review also examines current literature on mitochondrial pathophysiology across neurons, astrocytes, and endothelial cells after blast TBI. We highlight cumulative data detailing disruptions in mitochondrial quality control, including fission-fusion imbalance, and altered mitophagy, as well as bioenergetic dysfunction, calcium dysregulation, enzymatic alterations, and oxidative damage. The influence of lifestyle and environmental modifiers on brain mitochondrial health and how it can alter long-term outcomes after blast TBI are also discussed. We further discuss therapeutic strategies, including mild mitochondrial uncouplers, modulators of mitochondrial dynamics, and mitochondrial transplantation, aimed at preserving mitochondrial integrity and function. Collectively, these findings demonstrate that mitochondrial dysfunction is an important component of blast TBI pathophysiology and supports continued investigation of approaches that integrate modifying factors and therapeutic strategies to improve outcomes after blast TBI.

DOI: https://doi.org/10.1038/s44324-026-00111-7
Epilepsia. 2026 May 14.

Pyruvate dehydrogenase autoantibodies in autoantibody-negative patients with seizures are associated with reduced pyruvate dehydrogenase activity.

Annika Breuer, Chiara A Hummel, Tobias Baumgartner, Juliane L Berns, Afaf Milad Said, Isabel Bünger, Susanne Schoch, Gábor Zsurka, Harald Prüss, Wolfram S Kunz, Rainer Surges, Albert J Becker, Julika Pitsch.

   OBJECTIVE: We investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures, who were negative for known antineuronal autoantibodies.
METHODS: We screened serum samples from 387 patients autoantibody-negative for known antineuronal autoantibodies with psychiatric disturbances and/or epileptic seizures, including patients with temporal lobe epilepsy of unknown etiology. Various techniques, including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and in vitro assays assessing neuronal autoantibody uptake, neuronal viability, pyruvate dehydrogenase (PDH) enzyme activity, and mitochondrial DNA levels in biofluids were applied.
RESULTS: Mass spectrometry detected all three subunits of the intramitochondrial PDHc-pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, and dihydrolipoyl dehydrogenase-as targets of antibodies present in serum samples from three index patients suspicious for AIE with psychiatric symptoms or seizures. The presence of the anti-PDHc autoantibodies was confirmed by immunoblotting in 12 of 387 patients. Exposure of cultured primary neurons to commercial anti-PDH antibodies resulted in neuronal uptake and loss of neuronal viability. Patient-derived autoantibodies also impaired PDH enzyme activity in vitro. Additionally, cell-free mitochondrial DNA fragment levels were elevated in the serum and cerebrospinal fluid of PDH-positive patients compared to controls.
SIGNIFICANCE: Anti-PDH autoantibodies were detected in patients suspicious for AIE with seizures and/or psychiatric symptoms as core manifestation in the absence of known antineuronal autoantibodies. These autoantibodies bind neuronal structures and reduce PDH enzyme activity under experimental conditions, supporting mechanistic plausibility of a functional role in disease.

Keywords:  antimitochondrial autoantibodies; enzyme activity; mitochondria; psychiatric symptoms; seizures

DOI:  https://doi.org/10.1002/epi.70282
iScience. 2026 May 15. 29(5): 115714

Female metabolic resilience and male-biased protein quality defects under hypoxia in human brain organoids.

Romane Gaston-Breton, Amal Bouzid, Ekaterina Antipushina, Narciso Costa, Balazs Sarkadi, Agota Apati, Rania Harati, Maxim Sharaev, Jean Armengaud, Clémence Disdier, Rifat Hamoudi, Aloïse Mabondzo.

  Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and long-term neurological impairment caused by reduced oxygen and blood supply to the brain. Although sex differences influence HIE outcomes, the underlying cellular and molecular mechanisms remain poorly understood. Human cerebral organoids (hCOs) provide a relevant model to investigate hypoxic responses with a focus on sexual dimorphism. We generated hCOs at different maturation stages (2, 4, and 6 months) and selected the optimal stage to study hypoxic injury during brain development. Proteomic analyses revealed maturation-dependent features, including neurogenesis, astrogliogenesis, and cell growth. Hypoxic stress was associated with mitochondrial dysfunction and altered energy metabolism in both sexes. Female-derived hCOs showed enhanced metabolic adaptation, whereas male-derived hCOs exhibited alterations in protein quality control pathways. Overall, this study highlights sex as an important biological variable in hypoxic brain injury and provides insights relevant to HIE pathophysiology, while suggesting potential biomarkers for therapeutic development.

Keywords:  developmental neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.115714
Transl Psychiatry. 2026 May 14.

1-deoxysphinganine promoted microglial glycolytic reprogramming and neuroinflammation in alzheimer's disease.

Tao Ye, Xinhuang Lv, Zheyu Fang, Qiyao Li, Feichi Chen, Yiyao Dong, Kun Xiang, Yao Yang, Conghui Dai, Quang Le Do, Jing Sun, Kuan-Pin Su, Jiaming Liu.

Recent evidence suggests that microglial activation, driven by a metabolic shift towards glycolysis, was involved in the pathogenesis of Alzheimer's disease (AD). Although sphingolipid (SL) dysregulation has been linked to AD, the role of 1-deoxysphinganine (deoxySO), an atypical and neurotoxic SL, on microglial glycolytic reprogramming remains unclear. We measured serum deoxySO levels in AD patients and evaluated their association with cognitive performance. In APP/PS1 mice, we examined cerebral deoxySO level and the effects of deoxySO supplementation on cognitive function, neuropathology, and microglial activation. In vitro, BV2 microglia were used to assess inflammatory and metabolic changes via qPCR, western blot, ELISA, and RNA-seq analyses. The serum deoxySO levels were significantly elevated in AD patients, which was positively correlated with cognitive impairment. APP/PS1 mice exhibited increased cerebral deoxySO level, and supplementation with deoxySO could exacerbate cognitive deficits and Aβ plaque accumulation. Moreover, deoxySO supplementation increased microglial activation and enhanced inflammation in vivo and in vitro AD models. qPCR analysis identified disease-associated microglia (DAM) as a key deoxySO-responsive subpopulation, while RNA-seq revealed significant enrichment of genes related to glycolytic metabolism and inflammatory responses. Subsequently, qPCR confirmed that deoxySO promoted glycolytic metabolic reprogramming, which promoted DAM activation, thereby aggravating AD pathology. These findings identify deoxySO as a critical metabolic driver that links to microglial glycolytic activation and neuroinflammation, suggesting that targeting deoxySO-mediated metabolic pathways may offer a novel therapeutic strategy for AD.

DOI: https://doi.org/10.1038/s41398-026-04093-4
J Clin Pharmacol. 2026 May;66(5): e70209

170 Years of Mitochondrial Research and the Emergence of Mitochondrial Medicine.

Volkmar Weissig.

  One hundred and sixty-eight years lie between the first description of mitochondria as "pale roundish granules" and their eventual recognition as the "chief executive organelle" of the cell. Booming mitochondrial research during the last three decades has revealed that being the "powerhouse of the cell" is just one of many fundamental roles mitochondria play for cellular life. Mitochondria are at the crossroads of complex metabolic pathways; they regulate cellular signaling and innate immunity, and they determine whether a cell should divide, differentiate, or die. Human disorders caused by malfunctioning mitochondria have been described starting at the beginning of the 1960s, nowadays, it seems widely accepted that there are hardly any human diseases anymore that are not associated with dysfunctioning mitochondria. Even the process of aging seems to be controlled by this powerful organelle. This review is written for Pharmacologists, Physicians, and Healthcare Providers who are not familiar with mitochondrial biology and with the tremendous insights gained during the last three decades into the vital roles this cell organelle plays for life and death. It is aimed at raising awareness of still underappreciated mitochondrial diseases, which represent the largest group of inborn errors of metabolism.

Keywords:  aging; apoptosis; cellular signaling; drug development; energy metabolism; immunity; mitochondria; mitochondrial diseases

DOI:  https://doi.org/10.1002/jcph.70209
Curr Neuropharmacol. 2026 May 07.

Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.

Mohsin A Khan, Zaw A Khan, Fouzia Shoeb, Zainab Siddiqui, Gauri Pandey, Ghizal Fatima, Rizwan H Khan, Mohmmad M Khan.

  Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.

Keywords:  Alzheimer's disease; cognitive dysfunction.; de novo lipogenesis; de novo lipogenesis inhibitors; neurodegeneration; neurogenesis disruption

DOI:  https://doi.org/10.2174/011570159X423516260216052123
Int J Mol Sci. 2026 May 04. pii: 4113. [Epub ahead of print]27(9):

Fructose Intake Is Associated with Brain Metabolic Reprogramming and Exacerbation of Alzheimer-like Alterations in APP/PS1 Mice.

Paulina Ormazabal, Patricio Órdenes-Constenla, Camila Gherardelli, Marianela Bastías-Pérez, José Brito-Valenzuela, Marcelo Flores-Opazo, Nibaldo C Inestrosa, Pedro Cisternas.

  Emerging evidence implicates metabolic dysfunction as a key contributor to Alzheimer's disease (AD) pathogenesis. Fructose, a major component of modern diets, promotes systemic metabolic alterations; however, its direct impact on AD-related brain dysfunction remains poorly defined. Here, we investigated the effects of short-term fructose consumption on systemic metabolism, brain glucose handling, and cognitive performance in APP/PS1 transgenic mice. Six-month-old asymptomatic male mice received 15% fructose in drinking water for eight weeks, while controls received plain water. Fructose-fed APP/PS1 mice developed metabolic alterations consistent with early metabolic syndrome, including increased fasting glucose and dyslipidemia. These changes were accompanied by reduced cerebral glucose utilization, increased Aβ42 accumulation, and impaired cognitive performance. In parallel, fructose intake enhanced neuroinflammatory markers, suggesting a coordinated disruption of metabolic and inflammatory pathways in the brain. Collectively, these findings support the idea that fructose consumption may exacerbate Alzheimer-like alterations linking systemic metabolic dysfunction to impaired brain glucose metabolism and neuroinflammation. This study provides mechanistic evidence supporting a role for dietary fructose as a modifiable risk factor in AD vulnerability.

Keywords:  Alzheimer’s disease; cognitive decline; fructose; glucose metabolism; metabolic syndrome

DOI:  https://doi.org/10.3390/ijms27094113
CNS Neurosci Ther. 2026 May;32(5): e70889

Emerging Roles of Adenosine Metabolism in Astrocytes During Brain Injury.

Shu Zhu, Shanshan Zhong, Xiaoru Lin, Chuansheng Zhao, Yugang Li.

OBJECTIVE: Adenosine is a key metabolic and neuroregulatory factor in the brain, and an adenosine-rich immunosuppressive microenvironment is formed post-stroke, making the adenosine pathway a crucial therapeutic target for improving stroke immunotherapy efficacy. This study aims to address the knowledge gaps hindering adenosine therapy translation, summarize the integrated network of extracellular and intracellular adenosine metabolism, and highlight the dynamic changes of adenosine metabolism in astrocytes and the potential of purine-converting enzymes as therapeutic targets for cerebral ischemic stroke.
METHODS: We conducted a comprehensive summary and analysis of existing research progress over the past two decades, focusing on adenosine metabolic networks (extracellular and intracellular), adenosine metabolic enzymes, subcellular compartmental metabolic pathways, dynamic changes of adenosine metabolism in astrocytes during brain injury, and the role of purine-converting enzymes in cerebral ischemic stroke. We also reviewed the limitations of current adenosine-related therapies (e.g., P2Y12-targeted drugs) and existing knowledge gaps.
RESULTS: Post-stroke, dying and stressed neuronal cells increase ATP release, which is converted to adenosine by extracellular enzymes, forming an adenosine-rich immunosuppressive microenvironment. P2Y receptors (a type of ADP receptor) have been extensively studied as vital drug targets for ischemic stroke, but treatments such as Ticagrelor (targeting P2Y12) are associated with severe bleeding. Key knowledge gaps include the lack of cell type-specific regulation of the adenosine pathway in the brain and insufficient consideration of cell compartmentalized adenosine metabolism. Additionally, astrocyte adenosine metabolism undergoes dynamic changes during brain injury, and purine-converting enzymes exhibit potential as novel therapeutic targets for cerebral ischemic stroke.
CONCLUSIONS: Adenosine metabolism forms an integrated complex network involving extracellular and intracellular processes, with distinct metabolic enzymes and subcellular compartmental pathways. Dynamic changes of adenosine metabolism in astrocytes and purine-converting enzymes are critical for the development of adenosine-based therapies for cerebral ischemic stroke. Addressing existing knowledge gaps (e.g., cell type-specific regulation and compartmentalized metabolism) is essential to overcome current clinical trial difficulties and promote the translation of adenosine therapy for stroke.

DOI: https://doi.org/10.1002/cns.70889
iScience. 2026 May 15. 29(5): 115841

An improved method for high-purity isolation of oligodendrocytes from neonatal and adult mouse brain.

Peiyi Guo, Elisabet Mandon, Jie Wang, Morgan Mooney, Keith Reddig, Paula Vo, Madison C Jerome, Anoushka Lotun, Jessica B Spinelli, Guangping Gao, Dominic J Gessler.

  Oligodendrocytes are central to myelination and are key targets in myelin disease research and gene therapy. We optimized magnetic isolation of O4+ oligodendrocytes from adult mouse brain and PDGFRα+ oligodendrocyte precursor cells from neonatal brain, and evaluated purity, viability, maturation, metabolism, and rAAV transduction. The protocol yielded highly enriched adult O4+ cells and neonatal OPCs with preserved viability, structural integrity, and developmental potential. Isolated adult cells maintained oxidative and glycolytic activity, incorporated glucose carbon into central metabolic pathways, and supported the quantification of oligodendrocyte-directed rAAV9-phMBP-EGFP transduction. Neonatal PDGFRα+ cells proliferated and differentiated into MBP- and QKI7-positive oligodendrocytes. This approach provides a practical platform for studying oligodendrocyte biology and evaluating therapeutic vectors and other interventions in myelin disorders.

Keywords:  biological sciences research methodologies; cell biology; neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.115841
JIMD Rep. 2026 May;67 e70093

Progressive White Matter Changes in Mitochondrial Disease: A Quantitative MRI Study.

Nora Mickelsson, Jussi Hirvonen, Mika H Martikainen.

  Primary mitochondrial diseases frequently affect the central nervous system, yet the extent, distribution and progression of white matter hyperintensities (WMHs) remain insufficiently characterised, particularly in terms of quantitative volumetrics and longitudinal progression. Although WMHs are typically attributed to cerebral small-vessel disease, mitochondrial disorders may cause white matter injury through distinct vascular and metabolic mechanisms. We conducted a retrospective single-centre study at Turku University Hospital including 36 patients with mitochondrial disease, each with at least one brain MRI (73 images). Longitudinal data were available for 15 patients. Three-dimensional T1-weighted and FLAIR images (1.5/3 T) were analysed with the FDA-cleared cNeuro tool to obtain intracranial volume-normalised WMH and lesion volumes and an automated global Fazekas score. At baseline (median age 49 years), WMHs were present in all supratentorial regions. Over time, WMH volumes increased significantly in periventricular, deep and juxtacortical regions, while lesion progression was predominantly periventricular. Fazekas scores remained generally low and stable. In follow-up imaging, women and patients carrying the m.3243A>G variant showed a greater burden of WMHs and lesions, compared with men and those with other mitochondrial diagnoses. WMH load did not differ according to history of stroke-like episodes. Mitochondrial disease is associated with early and progressive WMH accumulation, particularly in individuals with the m.3243A>G variant, and the pattern exceeds what would be expected from conventional vascular risk factors alone. These findings support a disease-specific mechanism of white matter vulnerability and highlight the importance of quantitative MRI for monitoring progression in mitochondrial disease.

Keywords:  disease progression; longitudinal imaging; mitochondrial disease; quantitative MRI; small‐vessel pathology; white matter hyperintensities

DOI:  https://doi.org/10.1002/jmd2.70093
Biochem Biophys Res Commun. 2026 May 08. pii: S0006-291X(26)00659-5. [Epub ahead of print]822 153895

Ceftriaxone has a similar effect on astrocytic and neuronal GLT-1 distribution after mild traumatic brain injury.

Yana Naumenko, Borys Olifirov, Irada Yuryshynets, Tetyana Pivneva.

  Traumatic brain injury (TBI) is a significant health problem around the world. Even mild TBI (mTBI) can cause long-term neurodegenerative consequences such as Alzheimer's disease. Excitotoxicity plays a vital role in neuronal death after TBI, and Glutamate Transporter 1 (GLT-1) may be a therapeutic target for reducing TBI outcomes. It has been found that ceftriaxone (a beta-lactam antibiotic) can reduce TBI symptoms, including astrocyte reactivity and inflammation, and may also affect GLT-1 expression. The primary objective of this study is to investigate how ceftriaxone affects GLT-1 in neurons and astrocytes. mTBI was modelled in male albino mice using a modified Marmarou's weight-drop method. Ceftriaxone (250 mg/kg) was administered intraperitoneally for 3 and 5 days after injury. We immunolabeled coronal brain slices to detect GLT-1 expression and distribution, using antibodies to Glial Fibrillary Acidic Protein (GFAP - astrocytic marker), NeuN (neuronal marker), and GLT-1. The presence of fluorescently labelled areas and the ratio of fluorophores within each area were examined using an image processing plugin that identifies regions with substantial staining in confocal microscopy images. In this article, we address the dynamics of changes in fluorescence intensity and area for the regions we describe as GFAP, NeuN, and GLT-1. We found that GLT-1 dynamics change in both neurons and astrocytes following mTBI, but ceftriaxone affects these changes. In our opinion, due to the displacement of glutamate transporter clusters in cells, they cannot properly fulfil their function of limiting excitability produced by trauma.

Keywords:  Ceftriaxone; Glial reactivity; Glutamate transporter 1; Hippocampus; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.bbrc.2026.153895
Curr Neuropharmacol. 2026 May 08.

Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.

Sanjana Gupta, P Mohamed Nihal, Talha Jawaid, Astik Manju Ashesh, Manish R Bhise, Manoj Rawat, Sathiyanarayanan Lohidasan, Pranay Wal, Ajay Kumar, Dileep Kumar, Amin Gasmi.

  Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.

Keywords:  Alzheimer’s disease; antioxidants; calcium dyshomeostasis; mitochondrial dysfunction; mitochondrial targeted therapies; mitophagy; neurodegeneration; neuroprotection; oxidative stress.

DOI:  https://doi.org/10.2174/011570159X419571260226033536
Front Immunol. 2026 ;17 1783755

Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways.

Aojie Lian, Mei He, Hong Zhang, Yingmei Yang.

  Microglia are increasingly implicated in autism spectrum disorder (ASD), but their role remains difficult to define because the available evidence is heterogeneous in cohort composition, developmental stage, sampled brain region, and experimental modality. This Review summarizes current evidence on three related aspects of ASD-relevant microglial biology: microglial heterogeneity, immunometabolic regulation, and synapse-related pathways. Human postmortem studies, bulk transcriptomics, single-cell and spatial atlases, methylomic deconvolution, and in vivo neuroimmune imaging collectively support the presence of immune- and glia-associated alterations in at least a subset of ASD brains, but these findings do not support a single ASD-wide microglial phenotype. Instead, current evidence is more consistent with region-, stage-, sex-, and context-dependent microglial variation that should be interpreted together with neuronal, astrocytic, vascular, and broader tissue-level changes. We further review how lipid handling, mitochondrial function, phagocytic-lysosomal load, and bioactive lipid signaling may influence microglial competence in ASD-relevant settings, while noting that much of the detailed mechanistic immunometabolism literature still derives from aging and neurodegeneration. At the microglia-synapse interface, complement deposition, phosphatidylserine exposure, anti-engulfment checkpoints, and astrocyte-microglia crosstalk provide more informative mechanistic entry points than broad activation terminology. Across studies, the major challenge is not whether microglia are involved in ASD, but how to distinguish primary pathogenic effects from secondary adaptation, and how to relate molecular signatures to excessive, insufficient, or mistargeted synaptic remodeling. Overall, the literature supports a more precise interpretation of ASD-related microglial biology based on developmental timing, cellular context, and mechanism-linked readouts rather than non-specific inflammatory labels alone.

Keywords:  TSPO PET; astrocyte-microglia crosstalk; autism spectrum disorder; complement; developmental timing; immunometabolism; microglia; synaptic pruning

DOI:  https://doi.org/10.3389/fimmu.2026.1783755
Neurotherapeutics. 2026 May 08. pii: S1878-7479(26)00087-5. [Epub ahead of print]23(3): e00917

Telomerase mRNA-Lipid nanoparticles attenuate neuroinflammation after traumatic brain injury in mice.

Goknur Kara, Morgan Holcomb, Anjana Tiwari, Hannah Flinn, Trinity Eimer, Austin Marshall, Marissa Burke, Peter Park, Karem A Court, John P Cooke, Biana Godin, Sonia Villapol.

  Traumatic brain injury (TBI) is a leading cause of chronic neurological disability, yet no disease-modifying therapy exists. Emerging evidence indicates that TBI activates cellular aging programs, including telomere erosion and persistent inflammation, that contribute to progressive neurodegeneration. Telomerase reverse transcriptase (TERT) maintains telomere homeostasis and provides cytoprotective effects in the central nervous system but it has not been therapeutically targeted after TBI. Here, we developed an mRNA nanotherapy consisting of mouse TERT mRNA encapsulated in lipid nanoparticles (mTERT-LNPs) and evaluated it in a mouse model of moderate TBI. We first established that TBI transiently disrupts TERT biology, with reduced cortical TERT mRNA and shortened telomeres at 3 days post-injury (dpi), followed by partial recovery by 14 dpi. mTERT-LNPs were well tolerated in vitro and in vivo. Following intravenous delivery in the acute post-injury window, LNPs localized to the injured brain and displayed expected peripheral biodistribution. A single systemic dose increased cortical TERT mRNA and protein and partially restored telomere length at 3 dpi. TERT mRNA delivery significantly reduced Iba1+ microglial activation and suppressed pro-inflammatory cytokines. Systemically, mTERT-LNPs lowered serum C-reactive protein indicating reduced peripheral inflammation, without adverse effects on peripheral organs. Several outcomes showed sex-dependent patterns. Collectively, these data provide the first in vivo evidence that telomerase therapy can modulate telomere biology and neuroinflammation after TBI, supporting mRNA-LNP-mediated TERT restoration as a scalable, mechanistically grounded strategy for disease modification in TBI and related disorders.

Keywords:  Cytokines; Microglial activation; Neuroinflammation; Telomerase reverse transcriptase (TERT); Traumatic brain injury (TBI); mRNA–lipid nanoparticles (mRNA-LNPs)

DOI:  https://doi.org/10.1016/j.neurot.2026.e00917
bioRxiv. 2026 Feb 23. pii: 2026.02.22.707308. [Epub ahead of print]

Reverse electron transfer at mitochondrial complex I restrains dopaminergic neuron activity to promote early-life sleep in Drosophila.

Jeffrey B Rosa, Hayle H Kim, Jenny Luong, Jianing Yang, Peyton Yee, Allen Yan, Anyara Rodriguez, Matthew S Kayser.

Sleep architecture and depth undergo profound changes across early life. In many species, including Drosophila melanogaster , juvenile animals exhibit elevated sleep drive and deeper sleep states relative to adults, a process linked to reduced activity of wake-promoting dopaminergic neurons (DANs). To identify cell-intrinsic mechanisms regulating developmental sleep, we profiled gene expression in juvenile and mature DANs and performed a targeted RNAi screen of genes with higher juvenile expression. From this screen, we found that the magnitude of mitochondrial complex I (MCI) disruption produced distinct behavioral outcomes. Severe MCI loss-of-function caused locomotor deficits due to mitochondrial dysfunction and reduced neuronal activity. Surprisingly, partial MCI inhibition preserved mitochondrial integrity but resulted in sleep loss, with a most pronounced impact on juvenile adult sleep fragmentation and depth. We demonstrate that dopaminergic neuron activity in juvenile flies is sensitive to the Coenzyme Q redox state with a low CoQ/CoQH2 promoting sleep depth by restraining DAN activity. Our results are consistent with a model in which the reverse transfer of electrons from CoQH2 to NAD+ at MCI limits DAN activity. By dissociating changes in CoQ redox state from catastrophic mitochondrial failure, this work indicates that sleep phenotypes may serve as sensitive indicators of emerging mitochondrial dysfunction, with implications for understanding the developmental origins of neurodegenerative vulnerability.

DOI: https://doi.org/10.64898/2026.02.22.707308
Food Funct. 2026 May 14.

Oleic and omega-3 fatty acids buffer neuroinflammation in a scopolamine model with Alzheimer's-like features via target-level interactions.

Marlua Albertuni, Maria Torrecillas-Lopez, Teresa Gonzalez-de la Rosa, Luna Barrera-Chamorro, Elvira Marquez-Paradas, Jose L Del Rio-Vazquez, Maria D Navarro-Hortal, Carmen M Claro-Cala, Sergio Montserrat-de la Paz.

Diet quality, beyond total fat, may shape the immune tone of the brain in Alzheimer's-relevant contexts. We examined whether the fatty acid profile and food matrix of high-fat diets (HFD) modulate hippocampal neuroinflammation in vivo and explored target-level mechanisms with molecular docking. Male B6129SF2/J mice received a standard diet (SD) or HFD enriched with extra-virgin olive oil (EVOO), refined olive oil (ROO), refined palm oil (RPO), or ω3 long-chain polyunsaturated fatty acids (ω3-LCPUFA). During the final week, scopolamine induced acute cholinergic dysfunction. Neuroinflammation was assessed in the dentate gyrus by IHC (Iba-1, COX-2, and TNF-α) and by IF of astrocytes (GFAP intensity and morphology). Docking was employed to evaluate interactions of oleic and palmitic acids, EPA, and DHA with AChE, COX-2, BACE1, and TREM2. All HFD groups attenuated scopolamine-induced increases in Iba-1, COX-2 and TNF-α compared with the SD-scopolamine group, with limited separation among lipid classes under this acute stressor. By contrast, astroglial readouts showed a clear hierarchy: EVOO-HFD produced the lowest GFAP signal and the most ramified morphology, followed closely by ω3-LCPUFA, with ROO being intermediate and SFA being the least favourable. Docking supported a mechanistic framework: EPA/DHA displayed stronger predicted engagement than oleate/palmitate at COX-2 and BACE1, while long-chain fatty acids occupied the AChE peripheral site and a lipid/apoE-responsive surface on TREM2. In conclusion, PUFA-rich feeding, and notably that with the EVOO matrix, preferentially buffers hippocampal neuroinflammation in a scopolamine-induced Alzheimer's-like model. These findings support a composition, binding, and function framework and strengthen the translational rationale for precision nutrition strategies prioritizing ω3-LCPUFA and high-quality olive oils.

DOI: https://doi.org/10.1039/d6fo00279j