bims-medebr 2026-07-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–07–26
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Maternal dietary n-3 PUFA deficiency leads to sex-specific alterations in placental and cerebral fatty acid profiles and in oxylipin profiles in the developing mouse brain.
Circular RNA circDNAJC5 Regulates Ultrafine Particle-Disrupted Microglial Lipid Metabolism via the Sphingolipid Signaling Pathway.
Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.
Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.
Higher fasting brain glucose is associated with lower gray matter volume in healthy adults.
Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1.
Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice.
Mapping Brain Spatial Metabolic Atlas Reveals Anesthesia-Induced Region-Specific Alterations.
Connexins in metabolic control: linking brain cellular communication to systemic homeostasis.
Cdk7 Regulates Myelin Sheath Morphology and Lipid Homeostasis in Schwann Cells.
Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
Chronic glucocorticoid exposure disrupts lactate homeostasis and hippocampal neurogenesis by reducing cerebrovascular monocarboxylate transporter 1, leading to behavioral abnormalities in mice.
Normal Patterns and Variants in PET Brain Imaging from Childhood to Aging.
D-dopachrome tautomerase promotes astrocytic cholesterol 25-hydroxylase expression through the ERK/NF-κB pathway following rat spinal cord injury.
VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.
Decreased Sphingosine 1-Phosphate Levels in the Prefrontal Cortex of Mice Susceptible to Repeated Social Defeat Stress.
iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury.
Towards spatial lipid profiling by using mass spectrometry: analytical challenges and applications.
Phospholipid flippases ATP8A1 and ATP8A2 regulate GABAA receptor trafficking through distinct mechanisms in hippocampal neurons.
High-fat diet differentially alters hippocampal lipidomic and metabolomic profiles and cognition-related behavior in wild-type and LDL receptor-deficient mice.
Beta-ketothiolase deficiency with progressive basal ganglia and extra basal ganglia involvement: CT-MRI correlation in a pediatric metabolic encephalopathy: A case report.
BCKDK, A Novel Hypoxia-Responsive Kinase That Exacerbates Cerebral Ischemia Injury.

Biochimie. 2026 Jul 21. pii: S0300-9084(26)00170-7. [Epub ahead of print]

Maternal dietary n-3 PUFA deficiency leads to sex-specific alterations in placental and cerebral fatty acid profiles and in oxylipin profiles in the developing mouse brain.

Flore Marchaland, Maud Martinat, Mathieu Di Miceli, Stéphane Grégoire, Moïra Rossitto, Lydie Morel, Agnès Aubert, Alexandra Séré, Jean-Christophe Delpech, Corinne Joffre, Niyazi Acar, Richard P Bazinet, Sophie Layé.

  Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), are essential for optimal neurodevelopment through their effect on neuronal proliferation, neurite outgrowth and synaptogenesis. Emerging evidence highlights that brain PUFAs are metabolized in oxylipins, the bioactive oxidized PUFA metabolites known to regulate inflammatory processes. Recent data highlighted that both PUFA and oxylipin profiles are modulated in the brains of adult male mice by dietary PUFA content. However, little is known on the impact of maternal dietary n-3 PUFA intake during the perinatal period and the neurodevelopmental profile of brain fatty acids and associated oxylipins in mouse offspring, and whether these effects differ between sexes. To address this question, we first measured fatty acid levels in the placenta and embryonic brain of male and female mice at embryonic day (E)17.5 of mothers fed an n-3 PUFA-sufficient diet (based on canola oil, rich in the n-3 precursor alpha-linolenic acid) or an n-3 PUFA-deficient diet (based on sunflower oil, rich in the n-6 precursor linoleic acid) in n-3 PUFAs starting at E0. Then, fatty acids and oxylipins were measured at different post-natal stages, in the brain at postnatal day (P)0 and P7, and in the hippocampus at P14 and P21, in both male and female mouse offspring. Our results show that maternal n-3 PUFA dietary deficiency alters fatty acid profiles as early as E17.5 in both the placenta and the brain. Furthermore, dietary intervention affects both fatty acid and oxylipin profiles throughout postnatal brain development, with notable sex-specific differences. These findings highlight the importance of maternal n-3 PUFA intake during the perinatal period for establishing and maintaining PUFA and oxylipin profiles in the developing brain.

Keywords:  Developing Brain; Hippocampus; Oxylipins; PUFAs; Placenta

DOI:  https://doi.org/10.1016/j.biochi.2026.07.010
Environ Health (Wash). 2026 Jul 17. 4(7): 1454-1468

Circular RNA circDNAJC5 Regulates Ultrafine Particle-Disrupted Microglial Lipid Metabolism via the Sphingolipid Signaling Pathway.

Hui-Xian Zeng, Guoliang Li, Qing-Guo Zeng, Qiong Zhang, Lili Liu, Xiao-Wen Zeng.

  Ultrafine particles (PM0.1) can penetrate the brain and disrupt microglial function. Dysregulated lipid metabolism in activated microglia contributes to the development of Alzheimer's disease (AD), yet the epigenetic mechanisms underlying PM0.1-induced lipid metabolic disruption remain poorly understood. Circular RNAs (circRNAs) are emerging regulators of lipid metabolism, prompting us to investigate their role in PM0.1-exposed microglia. In vitro models of PM0.1-treated microglia (HMC3 and BV2) were established. We identified circDNAJC5, a lipid metabolism-associated circRNA, as significantly downregulated during PM0.1-induced lipid metabolic disruption. circDNAJC5 silencing aggravated lipid dysregulation, whereas its overexpression mitigated PM0.1-induced metabolic alterations. circDNAJC5 functioned as a molecular sponge for miR-98-5p, thereby regulating sphingomyelin synthase 1 (SMS1), a key enzyme in the sphingolipid signaling pathway. circDNAJC5 downregulation and lipid metabolic abnormalities were further validated in the brains of PM-exposed mice and AD mouse models, as well as in the blood of elderly individuals with cognitive impairment and hyperlipidemia. These findings highlight an epigenetic mechanism linking environmental exposure to microglial lipid metabolism and suggest circDNAJC5 as a potential biomarker for neurodegenerative and metabolic disorders.

Keywords:  Alzheimer’s disease; Circular RNA; Lipid metabolism; Microglia; Ultrafine particles

DOI:  https://doi.org/10.1021/envhealth.5c00701
Biochem Pharmacol. 2026 Jul 20. pii: S0006-2952(26)00614-3. [Epub ahead of print]253(Pt 1): 118275

Decoding lactate signals in Alzheimer's disease: redox control, receptor pharmacology, lactylation chemistry, and neuroglial vulnerability.

Wajid Zaman, Asma Ayaz, Aziz Ullah.

  Alzheimer's disease (AD) develops within a metabolically heterogeneous brain in which lactate functions as an oxidative substrate, a redox-coupled metabolite, a proton-linked transport signal, a receptor ligand, and a precursor of lysine lactylation. These roles are often considered independently, obscuring why lactate supports neuronal function in some settings yet accompanies persistent inflammation and neurodegeneration in others. This review introduces a lactate signal-decoding framework that emphasizes cellular interpretation rather than concentration alone. The framework integrates the lactate/pyruvate ratio, the cytosolic reduced-to-oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) state, lactate dehydrogenase (LDH) isoenzyme context, proton-coupled monocarboxylate transport, extracellular pH, hydroxycarboxylic acid receptor 1 (HCAR1) signaling, and enzymatic or non-enzymatic lactylation. We compare neuronal, astrocytic, microglial, and neurovascular responses and examine how aging, apolipoprotein E ε4 (APOE4), amyloid pathology, hypoperfusion, sleep disruption, and systemic metabolic disease reshape them. Particular attention is given to the chemistry and analytical validation of histone and non-histone lactylation; the proposed interaction of tau lactylation with other post-translational modifications; and links to proteostasis, iron homeostasis, and mitochondrial quality control. As a hypothesis-generating model, AD progression may involve loss of coordination among lactate transport, oxidation, receptor signaling, pH control, and covalent modification. This framework prioritizes restoration of metabolic coordination over indiscriminate lactate suppression and identifies biomarker and experimental requirements for clinical translation.

Keywords:  Alzheimer’s disease; HCAR1; Lactate signaling; Lactylation; Monocarboxylate transporters; Neuroglia; Redox state; Tau

DOI:  https://doi.org/10.1016/j.bcp.2026.118275
Front Nutr. 2026 ;13 1886340

Nutritional substrates and microglial metabolic fitness in brain aging and Alzheimer's disease: from lipid handling to TREM2-linked translation.

Ze Li, QiuLi Ming, LinPeng Fu, JingShuang Yang, YiLin Lv, BingQian Chen, ZhaoFeng Lu.

  Alzheimer's disease is increasingly viewed as a disorder in which age-related disturbances in microglial metabolism and the handling of nutritional substrates contribute to progressive loss of protective function. This review examines how lipids and ketone bodies shape microglial metabolic fitness in the aging brain and in Alzheimer's disease, and how these effects intersect with triggering receptor expressed on myeloid cells 2 (TREM2) signaling and translational biomarkers. Available evidence indicates that early compensatory glycolysis may give way to chronic bioenergetic failure, while cholesterol and lipoprotein trafficking, lipid droplet accumulation, ketone-body signaling, and TREM2-associated lysosomal pathways influence plaque engagement, phagocytosis, and inflammatory responses. The review also considers how apolipoprotein E genotype, brain region, sex, disease stage, and model system condition translation from experimental models to human disease. Fluid, imaging, and tissue readouts are therefore discussed as stage- and context-dependent proxies rather than fixed signatures. Overall, nutritional strategies and microglia-targeted interventions are most likely to be informative when aligned with disease stage and biological context.

Keywords:  Alzheimer's disease; TREM2; brain aging; immunometabolism; ketone bodies; lipids; microglia

DOI:  https://doi.org/10.3389/fnut.2026.1886340
J Cereb Blood Flow Metab. 2026 Jul 19. 271678X261444882

Higher fasting brain glucose is associated with lower gray matter volume in healthy adults.

Helena van Nieuwenhuizen, Botond B Antal, Antoine Hone-Blanchet, Andrew Lithen, Liam McMahon, Bruce G Jenkins, Eva-Maria Ratai, Lilianne R Mujica-Parodi.

  Glucose hypometabolism is implicated in age-related neurodegeneration, with peripheral markers such as hyperglycemia and insulin resistance linked to increased dementia risk and brain atrophy. However, the degree to which peripheral and cerebral glucose dysregulation are coupled remains unclear. To address this, we used ultra-high-field 1H MRS to directly quantify fasting brain glucose concentrations in the posterior cingulate cortex of 47 healthy adults from across the lifespan, with concurrent structural MRI and fasting blood glucose measurements. We found that both fasting blood and brain glucose increase with age but follow distinct trajectories: peripheral glucose rises significantly by midlife (40-60 years) and then plateaus, whereas cerebral glucose remains stable until older age (60-80 years) before increasing. Furthermore, brain glucose, but not blood glucose, independently predicts gray matter loss and partially mediates age-related atrophy, with effects strongest in subcortical, GLUT4-expressing regions. Our results provide direct in vivo evidence that higher fasting brain glucose levels are associated with age-related gray matter loss, and suggest a delayed trajectory compared to peripheral glucose elevation, consistent with cerebral metabolic prioritization. Brain glucose measured by MRS represents a promising biomarker of metabolic dysfunction that may enable early detection of neuronal vulnerability and inform interventions targeting brain-specific glucose metabolism.

Keywords:  Aging; MRS; atrophy; glucose; metabolism

DOI:  https://doi.org/10.1177/0271678X261444882
Biochem Pharmacol. 2026 Jul 24. pii: S0006-2952(26)00626-X. [Epub ahead of print] 118287

Mitochondria-targeted reactive species scavenger JP4-039 protects against disturbances of redox homeostasis, mitochondrial quality control, and glucose metabolism in brains of glutaryl-CoA dehydrogenase-deficient mice: A potential new therapeutic strategy for glutaric acidemia type 1.

Renata de Britto, Leonardo de Moura Alvorcem, Manuela Bianchin Marcuzzo, Rafael T Ribeiro, Carolina Soares, Adriana Fernanda K Vizuete, Larissa D Bobermin, Gianina Teribele Venturin, Samuel Greggio, Eduardo R Zimmer, André Quincozes-Santos, Diogo Onofre de Souza, Carlos-Alberto Gonçalves, Peter Wipf, Jerry Vockley, Bianca Seminotti, Moacir Wajner, Guilhian Leipnitz.

  Glutaric aciduria type 1 (GA1) is a cerebral organic aciduria caused by deficient activity of glutaryl-CoA dehydrogenase (GCDH). Patients present with acute striatal degeneration and develop progressive cortical leukodystrophy whose pathophysiology is only partially known. As treatment for GA1 is limited, we evaluated the impact of JP4-039, a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger, on redox homeostasis, mitochondrial quality control, and glucose metabolism in the cortical and striatal brain tissues of GCDH-deficient (Gcdh-/-) mice. Both tissues exhibited increases in lipid peroxidation, ROS levels, and the activities of superoxide dismutase, catalase, and glutathione S-transferase. Furthermore, glutathione reductase activity was increased, and glutathione peroxidase was reduced in the striatum, while Nrf2 mRNA levels were elevated in the cortex. Notably, most of these altered endpoints of redox homeostasis were prevented by treatment with JP4-039. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) expression was reduced in the cortex of Gcdh-/- mice, whereas voltage-dependent anion channel (VDAC) and dynamin-related protein 1 (DRP1) expression were increased in the striatum, signaling a disturbance of mitochondrial quality control. JP4-039 mitigated the DRP1 change. The cerebral cortex displayed reduced glucose metabolism, increased lactate levels, and elevated activities of hexokinase, pyruvate kinase, and lactate dehydrogenase (LDH), which JP4-039 mitigated. GLUT3 expression was reduced in the cerebral cortex, but JP4-039 did not change this effect. Our data suggest that redox imbalance and dysregulated mitochondrial quality control and of the glycolytic pathway contribute to the pathophysiology of GA1, and that JP4-039 may offer therapeutic benefit.

Keywords:  Cerebral cortex; Gcdh(-/-) mice; Glucose metabolism; Glutaric aciduria type 1; JP4-039; Mitochondrial quality control; Oxidative stress; Striatum

DOI:  https://doi.org/10.1016/j.bcp.2026.118287
Neurochem Res. 2026 Jul 20. pii: 221. [Epub ahead of print]51(4):

Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice.

Chun-Hsien Hsu, Pei-Wen Chu, Yi-Ying Chen, Min-Hao Ho, En-Chih Liao, Shau-Kwaun Chen.

  Although dyslipidemia and lipid accumulation are established risk factors for numerous neurological diseases, including stroke and neurodegenerative disorders, whether dyslipidemia directly causes neuronal death or acts as a secondary factor remains debatable. To answer this question, ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects. In this study, we examined neurological phenotype and mitochondrial and metabolic alterations in ApoE-knockout mice, which exhibited elevated serum cholesterol and triglyceride levels from an early age. These mutant mice exhibited mild cognitive phenotypes, suggesting that the functions of the cerebral cortex were affected by lipid dysregulation. Decreased electron transport chain complex IV activity indicated compromised mitochondrial function in 1-year-old mutant mice. Increased oxidative stress in cortical tissues, and downregulated expression of the key antioxidative genes indicated increased oxidative stress and mitochondrial damage in the mutant mice. Decreased mitochondrial mass was also observed, possibly due to the increase of mitophagy. However, no extensive cell death or significant reduction in cortical neuronal count was detected although the neurites degenerated in 1-year-old mutant mice. Upregulation of the Pgc1a gene, a master regulator of mitochondrial biogenesis, suggested the presence of protective mechanisms in the brain. Collectively, these findings, together with the phenotypes developed in Ldlr-/- mutant mice, suggest that hyperlipidemia alone may be insufficient to induce significant neurodegeneration. There should be additional factors that play a crucial role in the pathogenesis of these diseases.

Keywords:  ApoE; Dyslipidemia; Mitochondria; Neurodegeneration

DOI:  https://doi.org/10.1007/s11064-026-04842-3
Neurosci Bull. 2026 Jul 18.

Mapping Brain Spatial Metabolic Atlas Reveals Anesthesia-Induced Region-Specific Alterations.

Wei Feng, Lijuan Pang, Chun-Jie Liu, Jiuming He, Lisi Wang, Zhenyu Xu, Yinglong Zeng, Zengqiang Yuan, Chao Zhang.

  The brain supports consciousness through regional heterogeneity. However, the spatial complexity of its metabolome under anesthesia remains unclear. In this study, we established a spatial metabolomic atlas of the mouse brain under wakefulness, inhalation anesthesia, and injectable anesthesia. In total, 727 metabolites were identified and spatially mapped across 11 representative brain regions. We found that anesthesia significantly altered the brain metabolic landscape in a spatially dependent manner, particularly affecting lipid metabolism, amino acid pathways, and neurotransmitter-related metabolites. Furthermore, we monitored the cortical microvascular blood flow and blood oxygen levels during anesthesia. We observed that different anesthesia modalities induced distinct changes in cortical arteriovenous microvascular hemodynamics, suggesting a potential association between metabolic alterations and cerebrovascular regulation. We developed an open-access online database, the mouse brain spatial metabolome atlas ( https://mbsma.liulab.cloud/#/dashboard ), to facilitate access to and analysis of the dataset. Our study reveals anesthesia-induced spatial metabolic reprogramming in the brain, providing insights into neural metabolism and cerebrovascular dynamics, with implications for perioperative brain protection and safer anesthesia strategies.

Keywords:  Anesthesia; Brain; Imaging; Mass spectrometry; Metabolism

DOI:  https://doi.org/10.1007/s12264-026-01675-6
Life Med. 2026 Aug;5(4): lnag018

Connexins in metabolic control: linking brain cellular communication to systemic homeostasis.

Yiyi Zhu, Hui Chen, Dan Li, Alexei Verkhratsky, Chenju Yi.

Connexins, a family of transmembrane proteins, are essential for intercellular communication in the mammalian central nervous system, particularly through their assembly into gap junction channels. This review explores the central role of connexin-mediated signalling in hypothalamic regulation of nutrient metabolism and energy homeostasis, together with the function of connexins in peripheral metabolic organs. Focusing on connexins Cx43 and Cx30, we discuss their specific expression within hypothalamic neuroglial populations, including astrocytes and tanycytes, and their involvement in glucose sensing, metabolic signalling, and neuroendocrine regulation. Functional studies demonstrate that hypothalamic Cx43 is dynamically regulated by metabolic status, while its knockdown impairs glucose-stimulated insulin secretion and systemic energy balance. Tanycytes, interconnected into a Cx43-dependent network, play a critical role in relaying metabolic cues from cerebrospinal fluid and blood to hypothalamic neurons, thereby orchestrating adaptive responses to glycaemic changes. The review further details how the disruption of connexin-mediated coupling in tanycytes leads to impaired glucose sensing, altered neuronal activity, and systemic metabolic disorders. Beyond the hypothalamus, this review also summarizes how connexins in peripheral metabolic organs contribute to metabolic homeostasis, inflammatory regulation, and disease progression. Collectively, these discoveries highlight the fundamental importance of connexins in integrating metabolic signals and maintaining systemic homeostasis.

DOI: https://doi.org/10.1093/lifemedi/lnag018
Glia. 2026 Sep;74(9): e70194

Cdk7 Regulates Myelin Sheath Morphology and Lipid Homeostasis in Schwann Cells.

Nathalie Schumacher, Alexandra Pieltain, Pierre Tocquin, Nicolas Thelen, Arnaud Lavergne, Nathalie Masar, Romano Terrasi, Romane Leloup, Giulio Muccioli, Philippe Gailly, Peter Arthur-Farraj, Renaud Vandenbosch, Rachelle Franzen.

  Schwann cells (SC) are responsible for myelination in the peripheral nervous system (PNS). Myelin allows saltatory transmission of action potentials along axons and functionally relies on its unique constitution. We previously reported that Cdk7, a regulator of cell cycle progression and transcription, regulates myelin gene expression in oligodendrocytes and contributes to myelin maintenance in the central nervous system. Using mice with conditional Cdk7 knock-out in SCs, we provide evidence that Cdk7 is dispensable for myelin initiation but needed for the correct myelin thickness of larger caliber fibers in young mice, as well as for myelin elongation and rapid nerve conduction throughout age. We report that Cdk7 loss results in disturbed myelin stoichiometry, with significant dysregulation of lipid-related genes in SCs and a reduction in myelin protein zero. Finally, we demonstrate that Rxrγ, a nuclear receptor involved in lipid metabolism, is significantly downregulated in the absence of Cdk7. However, although Cdk7 regulates myelin segment length, our results indicate that this effect occurs independently of Rxrγ in myelinating dorsal root ganglion explants.

Keywords:  Cdk7; Schwann cells; lipids; myelin

DOI:  https://doi.org/10.1002/glia.70194
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600571123

Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.

Lin Li, Wenzheng Zou, Yuqing Lv, Yingfei Lu, Jiaqi Liang, Shukui Zhang, Baoyang Hu, Jianwei Jiao.

  Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.

Keywords:  ether lipids; mitochondria; neurogenesis; peroxisome

DOI:  https://doi.org/10.1073/pnas.2600571123
J Pharmacol Sci. 2026 Sep;pii: S1347-8613(26)00039-3. [Epub ahead of print]162(1): 80-88

Chronic glucocorticoid exposure disrupts lactate homeostasis and hippocampal neurogenesis by reducing cerebrovascular monocarboxylate transporter 1, leading to behavioral abnormalities in mice.

Ayami Kita-Shirakura, Kaede Ishihara, Nagisa Kimura, Momoka Tanida, Ryota Araki, Takeshi Yabe.

  Prolonged glucocorticoid elevation is strongly associated with brain dysfunction and the pathogenesis of stress-related disorders, including several psychiatric disorders. Elevated lactate levels have been reported in the brains of patients with psychiatric disorders and animal models of chronic stress and psychiatric disorders. Prolonged glucocorticoid elevation may disrupt brain lactate homeostasis, but the mechanisms through which this occurs and the pathological significance of the disruption are incompletely understood. Here, we show that chronic corticosterone (CORT) treatment increases lactate in the hippocampus and reduces monocarboxylate transporter 1 (MCT1) expression in hippocampal cerebrovascular endothelial cells. Cerebrovascular-specific overexpression of MCT1 reduced hippocampal lactate accumulation and ameliorated impaired hippocampal neurogenesis, depression-like behavior, and cognitive impairment in chronically CORT-treated mice. Conversely, knockdown of cerebrovascular MCT1 expression increased lactate accumulation in the hippocampus and caused impaired hippocampal neurogenesis and cognitive impairment. These findings suggest that chronic glucocorticoid elevation induces lactate accumulation via dysregulation of cerebrovascular lactate transport, thereby impairing neurogenesis and inducing behavioral abnormalities. This mechanism may contribute to stress-related brain dysfunction and the pathogenesis of psychiatric disorders.

Keywords:  Cognitive impairment; Depression; Lactate; Monocarboxylate transporter 1; Neurogenesis

DOI:  https://doi.org/10.1016/j.jphs.2026.07.001
PET Clin. 2026 Jul 21. pii: S1556-8598(26)00035-0. [Epub ahead of print]

Normal Patterns and Variants in PET Brain Imaging from Childhood to Aging.

Sahar Darabi Monadi, Thomas J Werner, Abass Alavi, Andrew B Newberg.

  Precise interpretation of brain PET imaging in both clinical and research settings depends on a well-defined understanding of normal variation, which is complicated by the evolving metabolic pattern of brain activity over the life span as well as the dynamic nature of human mental states. This article reviews important technical and neurophysiological factors that influence what constitutes a normal brain PET scan. It highlights the role of different radiopharmaceuticals in measuring cerebral blood flow, glucose metabolism, and neurotransmitter activity, while emphasizing that baseline cognitive, sensory, and emotional conditions-as well as age-related neurologic changes-significantly affect imaging outcomes.

Keywords:  Aging and cognition; Brain function; Cerebral glucose metabolism (CMRGlc); FDG (18F-fluorodeoxyglucose); Functional imaging; Neuropsychiatric disorders; Normal variation; Positron emission tomography (PET)

DOI:  https://doi.org/10.1016/j.cpet.2026.04.003
Sci Rep. 2026 Jul 21.

D-dopachrome tautomerase promotes astrocytic cholesterol 25-hydroxylase expression through the ERK/NF-κB pathway following rat spinal cord injury.

Huiyuan Ji, Hui Li, Dongyan Zhu, Liang Wang, Yuejiao Cao, Jiajia Zhai, Dehui Xu, Bingqiang He, Weiguan Chen.

  Astrocytes act as crucial cellular centres of cholesterol synthesis and metabolism and help maintain homeostasis in the healthy CNS. Spinal cord injury (SCI) results in abnormalities in astrocytic cholesterol metabolism and excessive oxysterol accumulation, contributing to the activation of inflammation. However, the relevant regulatory mechanism involved in aberrant cholesterol metabolism by astrocytes has not been fully elucidated. In the present study, we demonstrated that SCI-induced D-DT protein levels increased synchronously with CH25H expression. Administration of the D-DT inhibitor 4-CPPC markedly decreased CH25H expression in astrocytes following SCI. D-DT facilitates CH25H production in astrocytes by activating the intracellular ERK/NF-κB pathway through binding to the CD74 receptor. Conditioned culture medium from astrocytes following the knockdown of astrocyte CH25H expression by siRNA reduced microglial migration. The inhibition of D-DT or CH25H activity reduces microglia/macrophage accumulation at the lesion site and improves motor functional recovery following SCI. Our results reveal a novel function of D-DT-mediated astrocytic CH25H activation, which modulates pathological microenvironments through the activation of inflammation. These data may provide a potential therapeutic strategy for CNS inflammation-associated diseases.

Keywords:   d-DT; CH25H; Cholesterol metabolism; Inflammation; Spinal cord injury

DOI:  https://doi.org/10.1038/s41598-026-63510-2
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2603069123

VAMP7-dependent mitochondria-lysosome contacts contribute to glial mitochondrial dynamics and dopaminergic neuron survival.

Honglei Wang, Mengxiao Wang, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Linfang Wang, Shuanglong Yi, Shiping Zhang, Yufeng Pan, Margaret S Ho.

  Although disrupted mitochondrial dynamics in neurons are closely linked to neurodegenerative diseases, far less is known about how mitochondrial dynamics are regulated in glia or whether glial mitochondrial dysfunction contributes to neurodegeneration. Here, we show that the R-SNARE protein VAMP7 regulates the untethering of mitochondria-lysosome contacts (MLCs) in adult fly glia. Glial-specific knockdown of VAMP7 leads to prolonged MLCs and mitochondrial elongation associated with altered fission/fusion dynamics. These VAMP7-deficient mitochondria exhibit hyperpolarized membrane potential, leading to increased reactive oxygen species production, lipid droplet accumulation, and dopaminergic neurodegeneration. Mechanistically, VAMP7 interacts with the GTPase-activating protein TBC1D15-17 to promote Rab7 GTP hydrolysis. Without VAMP7, TBC1D15-17 remains bound to Rab7 but fails to activate its hydrolysis, resulting in elevated GTP-bound Rab7 and impaired MLCs untethering. Consistently, expression of GTP-locked Rab7Q67L or GTPase-activating protein-dead TBC1D15-17ΔGAP phenocopies the mitochondrial defects, while GDP-bound Rab7T22N or wild-type TBC1D15-17 restores the MLC dynamics. Considering that SNARE proteins mediate membrane fusion, our results demonstrate a role for VAMP7 in glial mitochondrial dynamics via organelle contacts, impacting neuron survival in a non-cell-autonomous manner.

Keywords:  VAMP7; glia; mitochondrial dynamics

DOI:  https://doi.org/10.1073/pnas.2603069123
ACS Chem Neurosci. 2026 Jul 21.

Decreased Sphingosine 1-Phosphate Levels in the Prefrontal Cortex of Mice Susceptible to Repeated Social Defeat Stress.

Katsuya Morito, Suzumi Kimura, Saki Fujisawa, Yuki Nishimura, Kentaro Takayama.

  Repeated psychological stress is a major risk factor for psychiatric disorders. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is known to contribute to regulating central nervous system functions. However, the relationship between the onset of psychological stress-induced behavioral disorders and S1P metabolism in the brain remains poorly understood. Because prefrontal cortex (PFC) and hippocampus are key brain regions involved in psychological stress responses, we investigated whether repeated social defeat stress (SDS) alters S1P metabolism in these regions. The S1P levels in the PFC, but not in the hippocampus, of mice susceptible to 4-day SDS were markedly lower than those in the control mice and were positively correlated with sociability. Additionally, mRNA expressions of an S1P-degrading enzyme Plpp3 and an inflammatory mediator Hmgb1 were increased in the PFC of 4-day SDS-susceptible mice. These results suggest that impaired S1P signaling in the PFC is associated with the onset of psychosocial stress-induced social avoidance.

Keywords:  bioactive sphingolipid; lipid phosphate phosphatase 3; prefrontal cortex; psychosocial stress; sphingosine 1-phosphate

DOI:  https://doi.org/10.1021/acschemneuro.6c00163
J Neuroinflammation. 2026 Jul 20.

iPLA2β-dependent phospholipid remodeling drives ZIKV-induced neuroinflammation and neurological injury.

Li Jiao, Wenxin Shao, Ying Xie, Sirong Li, Jiahong Gao, Jianyu Xu, Rui Tong, Dehong Li, Qiangming Sun.

Zika virus (ZIKV) infection of the developing brain induces neuroinflammatory responses that can restrict viral replication but may also contribute to neurological injury when dysregulated. Although neuronal phospholipid homeostasis is critical for membrane integrity and synaptic function, how ZIKV infection reprograms lipid metabolism to drive neuropathogenesis remains unclear. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a key mediator of ZIKV-induced neuronal lipid remodeling. iPLA2β is rapidly upregulated in neurons and in the neonatal brain following infection, and its expression is promoted by the viral envelope protein, which interacts with iPLA2β in neurons. Genetic ablation of iPLA2β reduces viral burden in the developing brain and in primary neurons and disrupts ZIKV-induced phospholipid remodeling, characterized by altered arachidonic acid-containing phospholipids and depletion of docosahexaenoic acid-enriched species. Importantly, sustained iPLA2β activity promotes phospholipid remodeling that supports efficient ZIKV replication, thereby increasing viral burden and contributing to a pro-inflammatory lipid environment. This is associated with increased prostaglandin E₂ production, glial activation, and neuronal loss. Both genetic and pharmacological inhibition of iPLA2β partially restores phospholipid homeostasis and reduces viral burden, accompanied by attenuation of neuroinflammatory responses. Functionally, targeting iPLA2β improves survival and neurobehavioral outcomes and mitigates long-term cognitive deficits following neonatal ZIKV infection. Collectively, these findings support iPLA2β-dependent phospholipid remodeling as a host process that facilitates ZIKV replication and links infection to neuroinflammation and neurological injury, highlighting iPLA2β as a potential therapeutic target in ZIKV-associated neuropathogenesis.

DOI: https://doi.org/10.1186/s12974-026-03973-2
Anal Bioanal Chem. 2026 Jul 23.

Towards spatial lipid profiling by using mass spectrometry: analytical challenges and applications.

Yaowei Liu, Yihua Ou, Hemi Luan, Tiangang Luan.

  Lipidomics, as a crucial branch of metabolomics, is dedicated to systematically analyzing the composition, structure, function, and dynamic changes of lipids in organisms, playing a pivotal role in elucidating disease mechanisms and discovering biomarkers. Conventional lipidomics methods based on liquid chromatography-mass spectrometry (LC-MS) require tissue homogenization, which obscures the spatial distribution of lipids and precludes the analysis of their heterogeneity within complex tissue microenvironments. In recent years, the development of spatial omics technologies such as mass spectrometry imaging (MSI) and laser capture microdissection (LCM) has provided powerful tools for the in situ and visual investigation of lipid spatial distribution. This paper systematically reviews the main analytical strategies in lipidomics, focusing on the technical principles, advances, and recent applications of spatial multi-omics integration. It further discusses the challenges faced by spatial lipidomics in terms of quantitative accuracy, isomer identification, and spatial localization precision, and provides an outlook on future technological developments. Spatial lipidomics breaks through the bottleneck of losing spatial information in traditional methods, and opens up a new path for further exploration of disease mechanisms and the discovery of new biomarkers in the spatial dimension.

Keywords:  Laser capture microdissection; Lipid metabolism; Mass spectrometry imaging; Spatial lipidomics; Spatial multi-omics

DOI:  https://doi.org/10.1007/s00216-026-06684-y
iScience. 2026 Jul 17. 29(7): 116626

Phospholipid flippases ATP8A1 and ATP8A2 regulate GABAA receptor trafficking through distinct mechanisms in hippocampal neurons.

Muneyuki Kawase, Shu Tokunaga, Yuta Umemura, Hossam H Shawki, Jumpei Omi, Ayana Hoshiai, Tomoha Ohshima, Tsuzumi Nakajima, Takao Kohno, Takashi Sakurai, Junken Aoki, Hisashi Oishi, Mitsuharu Hattori.

  Phospholipid asymmetry in cellular membranes is maintained by flippases. ATP8A1 and ATP8A2 are the principal flippases of phosphatidylserine (PS) in the mammalian nervous system; however, their specific physiological roles and potential functional redundancy remain incompletely characterized. Here, we show that ATP8A1/ATP8A2 double-knockout mice displayed more severe growth retardation than ATP8A2 knockout mice, indicating that ATP8A1 and ATP8A2 play redundant roles. In hippocampal neurons, ATP8A2 was highly enriched at inhibitory post-synapses. Surface biotinylation assays revealed increased surface GABAA receptor levels of hippocampal neurons deficient for ATP8A1 or ATP8A2. Mechanistically, our data support a model in which ATP8A2, but not ATP8A1, regulates local membrane lipid asymmetry, thereby facilitating dynamin2 recruitment and promoting GABAA receptor endocytosis. Collectively, ATP8A1 and ATP8A2 share overlapping roles in postnatal growth, while they contribute to neural function by modulating inhibitory synaptic transmission through distinct mechanisms.

Keywords:  GABAA receptor; Phospholipid flippase; dynamin; inhibitory synapse; phosphatidylserine

DOI:  https://doi.org/10.1016/j.isci.2026.116626
Neurosci Lett. 2026 Jul 23. pii: S0304-3940(26)00184-9. [Epub ahead of print] 138684

High-fat diet differentially alters hippocampal lipidomic and metabolomic profiles and cognition-related behavior in wild-type and LDL receptor-deficient mice.

Weiwei Liao, Jing Ren, Yi Rong, Chun Xie, Xifei Yang.

  Obesity and dyslipidemia are linked to cognitive decline, yet the role of LDL receptor (LDLr) deficiency in cognitive susceptibility to high-fat diet (HFD) remains unclear. This study examined the effects of HFD on cognitive function and hippocampal lipidomic and metabolomic profiles in wild-type (WT) and LDLr⁻/⁻ mice. Male mice of both genotypes were fed a control diet or HFD for 12 weeks and assessed for body weight, serum lipid profiles, anxiety-like behavior, spatial and recognition memory, and hippocampal lipidomic/metabolomic alterations using untargeted LC-MS/MS. HFD increased body weight and aggravated circulating lipid abnormalities, most prominently in LDLr⁻/⁻ mice. LDLr deficiency was associated with anxiety-like behavior and impairments in spatial and recognition memory, whereas HFD impaired recognition memory in WT mice but did not further worsen most behavioral outcomes in LDLr⁻/⁻ mice. Hippocampal lipidomics revealed genotype- and diet-dependent remodeling of sphingolipid and glycerophospholipid metabolism, with prominent changes in phosphatidylinositol, sterol lipid, phosphatidylethanolamine-related lipids, and phosphatidylethanol. Metabolomics indicated that LDLr deficiency was a major contributor to hippocampal metabolic reprogramming involving SLC-mediated transport and alanine/aspartate/glutamate metabolism, with additional HFD-associated alterations in glutamate-related pathways and oxidative phosphorylation. Integrated analysis linked energy-related metabolites with phospholipid remodeling and nucleotide sugar derivatives with sphingomyelins. These findings suggest that LDLr deficiency establishes a hippocampal lipid-metabolic vulnerability associated with cognitive impairment, while HFD primarily intensifies systemic dyslipidemia and hippocampal molecular remodeling.

Keywords:  Cognitive function; High-fat diet; Hippocampus; LDLr deficiency; Lipidomics; Metabolomics

DOI:  https://doi.org/10.1016/j.neulet.2026.138684
Radiol Case Rep. 2026 Oct;21(10): 4705-4714

Beta-ketothiolase deficiency with progressive basal ganglia and extra basal ganglia involvement: CT-MRI correlation in a pediatric metabolic encephalopathy: A case report.

Berihu Gebre, Yirgalem Gereziher, Dejen Gebrewahd, Catherine Alcober.

  Beta-ketothiolase deficiency (BKTD), also called mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is a rare autosomal recessive inborn error of metabolism affecting isoleucine catabolism and ketone body utilization. Although recurrent ketoacidotic crises are the hallmark of the disease, neurological complications-particularly basal ganglia injury-are increasingly recognized. We report a 2-year-old girl with known BKTD who presented with severe euglycemic ketoacidosis and acute encephalopathy. Initial CT showed symmetric hypodensity confined to the bilateral globus pallidi. Follow-up CT during ongoing metabolic instability demonstrated interval progression to involve the bilateral putamina and cerebral peduncles. MRI, obtained after referral, revealed nonenhancing T2/FLAIR hyperintense, T1 hypointense globus pallidus lesions without diffusion restriction but with punctate SWI hypointensities consistent with microcystic cavitary degeneration and microhemorrhage. There were additional diffusion-restricting lesions in the bilateral cerebral peduncles, small nonrestricting white matter foci in the frontal and right parietal lobes, and generalized cerebral atrophy. A baseline MRI 17 months earlier had been normal. This case illustrates the evolution from acute pallidal injury to irreversible basal ganglia necrosis with microhemorrhage and concurrent acute/subacute tract involvement, and highlights how CT and MRI together can characterize the spectrum of BKTD-related brain injury.

Keywords:  BKTD; Basal ganglia; Beta-ketothiolase deficiency; Cerebral peduncle; Globus pallidus; Inborn error of metabolism; SWI

DOI:  https://doi.org/10.1016/j.radcr.2026.06.125
Stroke. 2026 Jul 23.

BCKDK, A Novel Hypoxia-Responsive Kinase That Exacerbates Cerebral Ischemia Injury.

Boya Liao, Fang Zhang, Chang Han, Xinyao Yi, Ziyi Zhang, Leigang Jin, Fei Meng, Stanley Sau-Ching Wong, Ruby L C Hoo, Leiluo Geng, Wei Jia.

   BACKGROUND: Alterations in circulating amino acid profiles have been observed in ischemic stroke patients; however, whether cerebral ischemia disrupts amino acid metabolism within brain tissue and whether this disruption contributes to cellular stress and cerebral injury remain unknown. This hypothesis-testing study investigates disrupted BCAA (branched-chain amino acid) catabolism as a key mechanism of ischemic brain damage and evaluates BCKDK (branched-chain α-keto acid dehydrogenase kinase) as a novel therapeutic target.
METHODS: Mouse primary cortical neurons subjected to oxygen-glucose deprivation and brain tissue from a mouse acute ischemic stroke model were used as experimental systems. Untargeted metabolomics and metabolic flux analysis were used to characterize BCAA metabolism in both models. In vivo pharmacological inhibition or in vitro knockdown of BCKDK was performed using BT2 treatment or RNA interference. Primary outcome variables included infarct volume, BCKDH (branched-chain α-keto acid dehydrogenase) enzyme activity, neuronal viability, and markers of energy metabolism and glutamate excitotoxicity. Between-group differences were evaluated using 1-way ANOVA; data are presented as mean ± SD with 95% CIs and corresponding P values.
RESULTS: Metabolomics analysis of oxygen-glucose deprivation-exposed primary neurons revealed impaired BCAA catabolism and significant BCAA accumulation compared with normoxic controls. In ischemic mouse brain tissue, BCKDH activity was significantly suppressed, and BCKDK expression was markedly upregulated relative to sham-operated animals. Both pharmacological and genetic suppression of BCKDK substantially reduced cerebral ischemic injury, as evidenced by decreased infarct volume and improved neuronal survival (95% CI and P values per comparison). Mechanistically, ischemia-induced BCKDK expression via HIF-1α (hypoxia-inducible factor 1α)-mediated transcriptional activation, which inhibited BCAA conversion to tricarboxylic acid cycle substrates, thereby potentiating energy deficiency and glutamate excitotoxicity.
CONCLUSIONS: These data identify BCKDK as a novel hypoxia-responsive factor whose upregulation drives disrupted BCAA catabolism as a key mechanism of ischemic neuronal injury. BCKDK represents a promising therapeutic target for cerebral ischemia, directly supported by both in vitro and in vivo experimental evidence presented here.

Keywords:  animals; brain; hypoxia; neurons; oxygen

DOI:  https://doi.org/10.1161/STROKEAHA.125.053856