bims-medebr 2026-08-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–08–02
thirty-six papers selected by
Regina F. Fernández, Johns Hopkins University

From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.
APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer's disease.
Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.
Energy paradox in REM sleep: balancing supply and consumption in brain metabolism.
Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.
ApoTransferrin Induces Accumulation of Lipid Droplets in Oligodendroglial Cell.
PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.
Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.
Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease.
Spatial MALDI-MSI Reveals a Coordinated Vicious Cycle of Oxidative Membrane Damage and Ceramide-Driven Sphingolipid Dysregulation in the Chronically Neuroinflamed Brain.
Congenital Disorders of Glycosphingolipid Biosynthesis: Ultrarare Severe Syndromes or Relatively Frequent Mild Neurocognitive Illnesses?
Spatially Resolved Free Fatty Acid Profiling Reveals Region- and Age-Dependent Remodeling of Alzheimer's Disease Plaques.
Effects of Hypertonic Lactate Solutions on Intracranial Dynamics, Cerebral Oxygenation, and Metabolism in Patients with Acute Brain Injury: A Scoping Review.
Oligodendroglial TANGO2 Regulates Lipid Metabolism to Control Motor Coordination.
Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury.
Exploring the Metabolic Impact of Traumatic Brain Injury in CCI Mouse Models: A Focus on Early and Prolonged Injury Responses.
Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.
Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.
Omega-3 Fatty Acids and Alzheimer's Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies.
Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.
Regional brain metabolism and metabolic connectivity alterations in corticobasal syndrome assessed with [18F]FDG-PET.
Mitochondrial Dysfunction, Cerebral Metabolic Crisis, and Exploratory Bioenergetic Biomarkers in a Translational Swine Model of Acute Carbon Monoxide Poisoning.
Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
The brain's sweet spot: why microglia can run on fructose metabolism.
Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.
Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.
CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.
Adolescent drinking causes a loss of aspartoacylase-expressing oligodendrocytes and hypomyelination of anterior cingulate and corpus callosum axons in male mice, but not females.
Cholesterol crystal formation and embolism in the central nervous system and their potential role in Alzheimer's disease.
ATP-Red enables single-cell bioenergetic phenotyping by flow cytometry.
The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.
Exosome-mediated delivery of 3-n-butylphthalide rescues microglial energy crisis and ameliorates neuroinflammation in ischemic stroke.
Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.
Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury Through ROS-Dependent Remodeling of Microglial Mitochondrial Dynamics.
Cellular lipid imaging at the ultrastructural level.

Mol Biol Rep. 2026 Jul 29. pii: 1295. [Epub ahead of print]53(1):

From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling.

Muhammad Mateen Tahir, Xiu Liu, Lin-Sheng Yi, Xiao-Qing Hou, Qin Liao, Hua-Li Yu.

   BACKGROUND: The brain contains a large proportion of the body's cholesterol, highlighting its importance in central nervous system function. Cholesterol supports neuronal membrane structure, synapse formation, synaptic vesicle activity, receptor signaling, and myelin integrity. Because the blood-brain barrier limits the entry of peripheral lipoproteins, the brain relies mainly on local cholesterol synthesis, transport, recycling, and turnover.
OBJECTIVE: This review examines the mechanisms that regulate astrocyte-to-neuron cholesterol transfer and explains how defects in SREBP-dependent synthesis, ApoE lipidation, ABC transporter-mediated export, neuronal uptake, intracellular trafficking, and cholesterol turnover contribute to synaptic dysfunction and neurodegeneration.
MECHANISMS: In the adult brain, astrocytes are an important source of cholesterol for neurons. Astrocytic cholesterol synthesis is regulated by sterol regulatory element-binding proteins, which control the expression of key cholesterol-biosynthetic genes. Astrocytes release cholesterol in ApoE-containing lipoprotein particles through ATP-binding cassette transporters. Neurons acquire astrocyte-derived cholesterol through LDLR/LRP1, redistribute it via NPC1/NPC2, and eliminate excess cholesterol as 24 S-hydroxycholesterol through CYP46A1.
CONCLUSION: Disruption of this pathway impairs membrane organization, lipid raft signaling, synaptic function, and neuronal survival. These disturbances are associated with Alzheimer's disease, Huntington's disease, and multiple sclerosis.

Keywords:  ABC transporter; Alzheimer’s disease; Astrocytes; Cholesterol metabolism; Huntington’s disease; Multiple sclerosis; Neurons; SREBP; Therapeutic strategies

DOI:  https://doi.org/10.1007/s11033-026-12488-1
Res Sq. 2026 Jul 15. pii: rs.3.rs-10297182. [Epub ahead of print]

APOE3 Christchurch is associated with sphingolipids recycling and glial lipid remodeling in autosomal dominant Alzheimer's disease.

Iván Daniel Salomón-Cruz, Sara Camila Agudelo-Castrillon, Juan Pablo Barbosa-Carvajal, Laura Alejandra Lozano-Trujillo, Mateo Hoyos Ríos, Lina M Trujillo-Chacón, Andrés Villegas, Edison Osorio, Geysson Javier Fernandez, Estela Area-Gómez, Gloria Patricia Cardona-Gómez.

  Alzheimer's disease is characterized by profound disturbances in brain lipid metabolism, which regulate membrane integrity, connectivity, immune response, and cell survival. However, the mechanisms by which the protective APOE3 Christchurch variant modulates lipid homeostasis in autosomal dominant AD remain poorly understood. Here, we investigated lipid changes in postmortem brains carriers of PSEN1-E280A mutation, including APOE3Ch variant. Using a multimodal approach integrating thin-layer chromatography lipid profiling, enzymatic activity assays, digital PCR, immunofluorescence, flow cytometry, and single-nucleus RNA sequencing, we characterized lipid composition and transcriptional expression in the cerebral cortex. Familial and sporadic AD brains exhibited extensive remodeling of lipid pathways, including depletion of structural phospholipids and marked alterations in sphingolipid metabolism. Notably, APOE3Ch carriers displayed reduced cholesterol and phospholipid content, preservation of ceramide pools, and enrichment of specific ganglioside fractions, accompanied by increased sphingomyelinase activity and coordinated downregulation of genes involved in sphingolipid biosynthesis and remodeling. Single-nucleus transcriptomic analyses further revealed cell-type-specific alterations across glial populations, including reduced pruning of differentiated oligodendrocytes and suppression of lipid metabolic process in astrocytes and microglia. Together, these findings suggest that APOE3Ch promotes a reduced de novo biosynthesis of cholesterol and a distinct sphingolipid metabolic state characterized by enhanced lipid recycling, potentially attenuating lipid-driven neuroinflammatory responses.

Keywords:  Alzheimer’s disease; Post-mortem brain; gangliosides; neutral lipids; phospholipids; salvage pathway; sphingolipids

DOI:  https://doi.org/10.21203/rs.3.rs-10297182/v1
Res Sq. 2026 Jul 22. pii: rs.3.rs-10117408. [Epub ahead of print]

Individualised mapping of living human brain mitochondria by MRI reveals signatures of bioenergetic defects.

Michel Thiebaut de Schotten, Cynthia Liu, Catherine Kelly, Ke Bo, Tor Wager, Eugene Mosharov, Martin Picard.

Mitochondria power brain function and cognition, yet no label-free, non-invasive method has existed to explore their relationship to ageing, disease, and cognition in humans. The MitoBrainMap framework predicts mitochondrial features from magnetic resonance data alone, potentially bridging cellular biology with macroscale brain organization. Here we tested whether it captures meaningful age- and disease-related variation across individuals. MR-predicted mitochondrial density and tissue respiratory capacity declined with age, whereas intrinsic mitochondrial respiratory capacity was relatively preserved. Correlations among predicted features matched known mitochondrial biology, supporting preliminary construct validity. In patients with genetically confirmed mitochondrial diseases, predicted maps revealed region-specific alterations, notably the expected compensatory upregulation of nuclear- encoded complex II. Predicted features were further associated with the energetic stress marker GDF15 and with cognitive performance, linking brain mitochondrial estimates to systemic physiology and behavior. These findings introduce a first-generation, label-free neuroimaging-based mitochondrial mapping as a non-invasive window into living human brain mitochondria.

DOI: https://doi.org/10.21203/rs.3.rs-10117408/v1
Commun Biol. 2026 Jul 27. pii: 979. [Epub ahead of print]9(1):

Energy paradox in REM sleep: balancing supply and consumption in brain metabolism.

Yusuke Takahashi, Yoko Ikoma, Ko Matsui.

The brain's capacity for information processing depends on precisely regulated energy dynamics. Yet how metabolic supply adapts to shifting computational demands across brain states remains unclear. Using wide-field fluorescence imaging through the intact skull of live mice, we simultaneously monitored brain blood volume (BBV), astrocytic pyruvate, and neuronal ATP levels during natural sleep. We found that large-scale metabolic dynamics are coupled to neuronal activity but reorganize in a state-dependent manner. During non-rapid eye movement (NREM) sleep, theta-band electrocorticogram (ECoG) activity predicted subsequent blood volume changes, accompanied by rapid anterior-to-posterior vascular waves. In contrast, REM sleep was marked by a pronounced increase in BBV, originating in the posterior cortex and slowly propagating across the brain. This was accompanied by elevated astrocytic pyruvate; paradoxically, however, neuronal ATP levels declined sharply. These findings reveal a dynamic interplay among neurons, astrocytes, and the vasculature, suggesting that distinct energy-allocation strategies underlie the brain's computational flexibility.

DOI: https://doi.org/10.1038/s42003-026-10646-6
Molecules. 2026 Jul 09. pii: 2418. [Epub ahead of print]31(14):

Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.

Bao Ting Zhu.

  It is hypothesized that in most cases of sporadic late-onset Alzheimer's disease (LOAD), the abnormally elevated cholesterol level in brain neurons represents a critical causative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and deposition of amyloid β (Aβ) plaques. It is speculated that Aβ accumulation and plaque formation in most LOAD cases only represent characteristic secondary pathological changes and are usually not the main force driving the pathogenesis of LOAD. As discussed in detail in this paper, abnormally elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also induce tauopathy and reduce the formation of cholinergic vesicles. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in hippocampus and posterior parietal cortex, which are then followed by neurodegenerative and atrophic changes in other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because it has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly offers strong support for the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD. Considerable efforts are made to apply the proposed hypothesis to offer a better mechanistic explanation for many of the poorly understood experimental and/or clinical observations related to AD (mostly LOAD).

Keywords:  Alzheimer’s disease; amyloid β; apolipoprotein E; cholesterol; neuronal cholesterol dysregulation; pathogenic mechanism; tauopathy

DOI:  https://doi.org/10.3390/molecules31142418
Neurochem Res. 2026 Jul 25. pii: 223. [Epub ahead of print]51(4):

ApoTransferrin Induces Accumulation of Lipid Droplets in Oligodendroglial Cell.

Estefanía Chamorro-Aguirre, Nicolás O Favale, Lucila G Pescio, María Julia Pérez, Jorge Correale, Juana Pasquini.

  Transferrin is the principal iron-carrier protein and is primarily synthesized in the liver, oligodendrocytes (OLG), and choroid plexus. We previously demonstrated that apotransferrin (aTf) treatment induces OLG maturation in vitro and in vivo. Given that approximately 80% of myelin consists of lipids, predominantly cholesterol, tight regulation of lipid metabolism is essential during myelin formation. Lipid droplets (LDs) are dynamic intracellular organelles that store fatty acids as neutral lipids, including triglycerides and cholesterol esters. Recent studies have demonstrated the presence and regulated turnover of LDs in glial cells, suggesting roles in both physiological and pathological processes. During OLG maturation, the demand for lipid synthesis increases markedly to sustain membrane expansion and myelin production. Because this high lipid demand, we hypothesized that aTf-induced OLG maturation is associated with metabolic reprogramming involving lipid droplet dynamics, which may serve as a source of fatty acids for membrane biogenesis and energy production. In this context, LDs may represent a critical metabolic hub through which OLGs regulate lipid homeostasis and adapt to increased bioenergetic demands. However, the mechanisms governing LD biogenesis and turnover in oligodendroglial cells during development and under different metabolic conditions remain poorly understood. Importantly, LDs are now recognized as active participants in cellular metabolism, stress responses, and membrane biogenesis rather than passive lipid storage compartments. The aim of this study is to characterize LD dynamics, as well as specific lipid and protein profiles, in the Oli-Neu cell line and in oligodendroglial cells during the maturation process in the presence of aTf. We specifically investigate whether the aTf-induced increase in LD abundance reflects enhanced membrane biosynthetic requirements, with augmented energy production supported by β-oxidation of fatty acids released from triglycerides stored within LDs.

Keywords:  Differentiation; Lipid droplets; Low glucose; Oligodendrocytes; Transferrin

DOI:  https://doi.org/10.1007/s11064-026-04825-4
bioRxiv. 2026 Jul 14. pii: 2026.07.13.738356. [Epub ahead of print]

PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.

Eduardo Gutierrez-Kuri, Juliet Lynn Marie Garcia-Rogers, Jaid Perez, Sabrina Smith, Matthew R Kenwood, Kahealani S Archuleta, Yangming Xiao, Gabriela Campos, Savannah Barannikov, Hu Wang, Sammy Pardo, Trevor B Romsdahl, Henry Miller, Ann M Stowe, Russell William, Mark Goldberg, Xianlin Han, Kevin F Bieniek, Susan T Weintraub, Ann V Griffith, Sarah C Hopp, Juan Pablo Palavicini.

   Background: Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimer's disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLCγ2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined.
Methods: We analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments.
Results: Plcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP2, despite very low bulk PLCγ2 protein abundance relative to other PLC family members. PLCγ2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains.
Conclusions: Loss of PLCγ2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk.
Limitations: Because constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.

Keywords:  Alzheimer’s disease; PLCG2; RNA profiling; lipidomics; microglia; oligodendrocytes; proteomics

DOI:  https://doi.org/10.64898/2026.07.13.738356
Curr Issues Mol Biol. 2026 Jul 05. pii: 691. [Epub ahead of print]48(7):

Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.

Patricia Fernanda Schuck, Gustavo da Costa Ferreira, Hércules Rezende Freitas.

  The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT's role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer's disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = -0.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: -0.307 to -0.349, FDR < 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation.

Keywords:  APOE4; Alzheimer’s disease; NaCT; SEA-AD; SLC13A5; astrocyte subtypes; astrocytes; citrate metabolism; pseudoprogression; single-nucleus RNA-seq

DOI:  https://doi.org/10.3390/cimb48070691
Transl Neurodegener. 2026 Jul 29. pii: 35. [Epub ahead of print]15(1):

Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease.

Xiaoyu Hu, Ying Yu, Haorui Luo, Jiabing Li, Xiaofei Zhang, Gang Wang, Jianping Li, Juan Li, Hongzhuan Chen, Yu Qiu.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.
METHODS: Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.
RESULTS: Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.
CONCLUSION: These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.

Keywords:  Alzheimer’s disease; Cognition; Glucose metabolism; Metabolic homeostasis; Neuron; Pentose phosphate pathway; Transaldolase 1

DOI:  https://doi.org/10.1186/s40035-026-00567-z
bioRxiv. 2026 Jul 20. pii: 2026.07.14.738110. [Epub ahead of print]

Spatial MALDI-MSI Reveals a Coordinated Vicious Cycle of Oxidative Membrane Damage and Ceramide-Driven Sphingolipid Dysregulation in the Chronically Neuroinflamed Brain.

Kent Brown, Brayden Storey, Jacob Williams, Derrick Simet, Muhammad Bilal Umar, Emma Madsen, Zhiyang Shan, Lanrong Bi.

Background: Chronic neuroinflammation is a major driver of cognitive decline, vascular cognitive impairment, and Alzheimer's disease. However, the spatial lipidomic alterations underlying neuroinflammatory brain injury remain poorly defined. Oxidative stress and sphingolipid dysregulation have been implicated, but their regional distribution and interplay in the brain are not well characterized.
Methods: We performed positive-ion mode matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on coronal brain sections from middle-aged spontaneously hypertensive rats (SHR), a model of chronic neuroinflammation, and normotensive Wistar-Kyoto (WKY) controls. Spatial distributions and relative abundances of multiple lipid classes, including phosphatidylcholines (PCs), sphingomyelins (SMs), hexosylceramides (HexCers), ceramides, phosphatidylserines (PSs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), phosphatidic acids (PAs), and sulfatides, were mapped and compared between genotypes. Region-of-interest analysis was used to quantify changes across cortex, hippocampus, and white-matter tracts.
Results: SHR brains exhibited a coordinated lipidomic signature characterized by pronounced oxidative stress and membrane remodeling. Oxidized and short-chain PCs were markedly upregulated (up to 11.6-fold), while major structural diacyl PCs were broadly downregulated. Concurrently, sphingolipids were significantly altered, with robust upregulation of SM(d36:1) (7.5-fold) and multiple HexCer species (1.5-1.9-fold), accompanied by accumulation of ceramides. These changes were accompanied by heterogeneous redistribution of PS, PI, and PE species, particularly within the hippocampus. Sulfatide patterns in white-matter tracts were also altered, suggesting myelin remodeling. Region-of-interest analysis confirmed that the most pronounced lipid alterations were concentrated in the hippocampus and white-matter regions.
Conclusions: Chronic neuroinflammation induces a spatially organized, multi-class lipid remodeling response in the brain, driven by advanced oxidative membrane damage and a shift toward a pro-apoptotic sphingolipid profile. The convergence of these pathways creates a vicious cycle of membrane injury, mitochondrial dysfunction, and sustained neuroinflammation that is especially prominent in the hippocampus and white matter. These spatially resolved findings provide direct evidence that oxidative stress and sphingolipid dysregulation are central, interrelated mechanisms contributing to neurovascular injury and increased risk of cognitive impairment. The study highlights the power of MALDI-MSI to uncover region-specific lipid pathology and identifies potential lipid-based targets for therapeutic intervention in neuroinflammatory brain disease.

DOI: https://doi.org/10.64898/2026.07.14.738110
Biomedicines. 2026 Jul 03. pii: 1506. [Epub ahead of print]14(7):

Congenital Disorders of Glycosphingolipid Biosynthesis: Ultrarare Severe Syndromes or Relatively Frequent Mild Neurocognitive Illnesses?

Linda Montavoci, Michele Dei Cas, Sara Penati, Marco Trinchera.

  Glycosphingolipids (GSLs) are glycoconjugates in which a short and heterogeneous saccharide chain is attached to a lipid moiety called ceramide. Based on their sugar backbone, mammalian GSLs are primarily grouped into the ganglio-, lacto-/neolacto-, and globo-series. Sialic acid-containing GSLs are known as gangliosides. Complex ganglio-series gangliosides are particularly abundant in the brain, whereas simple ganglio-series gangliosides, as well as those belonging to other series or neutral GSLs, are less abundant and typical of non-neural tissues. Congenital disorders in the biosynthesis of the lipid moiety of sphingolipids (SLs) result from defects in enzymes and proteins involved in ceramide biosynthesis and transport. Congenital disorders in the biosynthesis of the sugar chain of GSLs specifically affect ganglio-series ganglioside biosynthesis and are caused by pathogenic variants in GM3 synthase (ST3GAL5) or GM2/GD2/asialo-GM2 synthase (B4GALNT1). Defective variants of the sialyltransferase ST3GAL3 and the galactosyltransferase B4GALT5 have been reported and proposed to impair GSL biosynthesis. The occurrence of these syndromes has provided new insights into the physiological and pathological roles of GSLs. Most of these disorders are associated with completely inactive enzyme variants, leading to severe neurological syndromes. Only a few cases highlighted variants that retained partial activity, resulting in milder phenotypes, which included non-syndromic intellectual disability. It is therefore conceivable that many undiagnosed patients, with mild neurological symptoms, may carry variants retaining residual enzyme activity, insufficient to ensure normal levels of brain GSLs. The purpose of this article is to encourage clinicians to look for additional GLS hereditary disorders associated with a milder phenotype. We also hope to boost future investigations by highlighting the most critical issues emerging from recent literature on SL and GSL biosynthesis and their related defects.

Keywords:  ceramides; congenital disorders of glycosylation; epilepsy; gangliosides; intellectual disability

DOI:  https://doi.org/10.3390/biomedicines14071506
JACS Au. 2026 Jul 27. 6(7): 4153-4165

Spatially Resolved Free Fatty Acid Profiling Reveals Region- and Age-Dependent Remodeling of Alzheimer's Disease Plaques.

Sona Hakhverdyan, Sofie Hansson, Pascal Kadej, Sophia B Orlovsky, Siarhei Hladkou, Birger Viirman, Anna Nilsson, Martin Lord, Stephanie M Cologna, Justin T Mohr, Stina Syvänen, Per E Andrén, Wojciech Michno.

  Free fatty acids (FFAs) are bioactive mediators of inflammation, energy metabolism, and membrane remodeling, yet their spatial organization within the Alzheimer's disease (AD) brain and at individual amyloid-β (Aβ) plaques has remained inaccessible. We developed a novel, chemically tailored MALDI workflow that enables simultaneous, spatially resolved detection of nearly 30 FFAs alongside over 100 complex lipid species within the same tissue section. Applying this approach to a transgenic AD mouse model across brain regions and disease stages, and combining it with single-plaque microenvironment analysis (SPMA) that treats each plaque as an individual analytical object, we uncover two previously inaccessible dimensions of plaque-associated lipid biology. FFA distributions form highly structured spatial compartments reflecting regional cytoarchitecture, with distinct enrichment of saturated, monounsaturated, and polyunsaturated species across cortical layers. Within Aβ plaques, nearly 75% of detected FFAs are significantly remodeled, with reciprocal enrichment of short saturated and highly unsaturated species alongside depletion of long-chain monounsaturated FFAs. This pattern is consistent with concurrent disruption of ELOVL-mediated elongation and FADS-mediated desaturation, including opposing enrichment of pro-inflammatory arachidonic acid and pro-resolving docosahexaenoic acid. Machine learning of single-plaque profiles reveals that FFA composition alone classifies plaque age with high accuracy, demonstrating that lipid remodeling continues after Aβ peptide composition has stabilized. Together, these findings establish spatial FFA profiling as a new analytical dimension in neurodegeneration research, revealing that Aβ plaques are dynamic lipid-metabolic microenvironments that continue to remodel long after Aβ deposition has stabilized.

Keywords:  Alzheimer’s disease (AD); amyloid-β (Aβ) pathology; free fatty acids (FFA); lipid metabolism; mass spectrometry imaging (MSI); matrix-assisted laser desorption/ionization (MALDI); spatial lipidomics

DOI:  https://doi.org/10.1021/jacsau.6c00649
Neurocrit Care. 2026 Jul 28.

Effects of Hypertonic Lactate Solutions on Intracranial Dynamics, Cerebral Oxygenation, and Metabolism in Patients with Acute Brain Injury: A Scoping Review.

Sebastián Vásquez-García, Karol Martínez-Palacios, Andrés M Rubiano, Daniel Agustín Godoy.

  Hyperosmolar therapies remain a cornerstone in the management of intracranial hypertension in patients with acute brain injury (ABI). Beyond their osmotic properties, hypertonic lactate solutions have recently gained interest as a potential therapeutic strategy capable of influencing not only intracranial dynamics but also cerebral metabolism and systemic physiology. However, the extent and consistency of these physiological effects in human studies remain incompletely characterized. To map and synthesize the available clinical evidence evaluating the effects of hypertonic lactate solutions on intracranial dynamics, cerebral oxygenation, cerebral metabolism, and systemic physiology in adult patients with ABI. A scoping review was conducted following Joanna Briggs Institute methodological guidance and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension. Systematic searches were performed in PubMed, Embase, Scopus, and Web of Science. Two reviewers independently screened studies and extracted data using a standardized charting form. Twelve studies published between 2009 and 2025 were included. Across studies, hypertonic lactate administration was consistently associated with reductions in intracranial pressure (ICP) while preserving cerebral perfusion pressure. Several investigations also reported physiological signals suggesting modulation of cerebral metabolism, including increases in cerebral microdialysis lactate and glucose concentrations and potential improvements in markers of oxidative metabolism. Systemic effects were generally predictable and well tolerated, including moderate increases in arterial lactate, sodium, and alkalinizing metabolic shifts within clinically acceptable ranges. Hypertonic lactate appears to act as a physiologically integrated therapy combining osmotic control of ICP with potential metabolic and systemic effects. Although current human evidence suggests promising physiological benefits, what is ultimately required is a large-scale, adequately powered clinical trial incorporating clinically relevant outcome biomarkers, including functional neurological recovery, quality of life measures, and validated biomarkers of neuronal injury to determine whether these physiological benefits translate into meaningful patient benefit.

Keywords:  Acute brain injury; Cerebral metabolism; Hypertonic lactate; Intracranial pressure; Neurocritical care; Osmotherapy

DOI:  https://doi.org/10.1007/s12028-026-02566-4
FASEB J. 2026 Aug 15. 40(15): e72155

Oligodendroglial TANGO2 Regulates Lipid Metabolism to Control Motor Coordination.

Jiewen Chen, Zhili Liu, Fengling Chen, Yongfei Cui, Liming Qin, Mengdi Wang, Xiangbin Zhu, Na Li, Can Huang, Bo Zhang, Kunfu Ouyang.

  TANGO2 deficiency disorder (TDD) is a rare genetic disease caused by mutations in the TANGO2 gene, characterized by prominent neurological symptoms. However, the pathological mechanisms underlying TANGO2 loss-of-function in neurologic symptoms remain unknown. Here, we generated constitutive and cell-type-specific Tango2 knockout mouse models to examine TANGO2's role in the central nervous system (CNS). Behavioral analyses revealed that both constitutive and oligodendrocyte-specific deletion of Tango2 recapitulate the motor deficits associated with individuals with TDD. Morphological quantifications further showed that Tango2 deletion led to robust cerebellar myelin loss and an increase in synapse number in the cerebellar cortex. In addition, transcriptional analysis and lipidomic profiling demonstrated that Tango2 deletion downregulated key processes involved in phospholipid metabolism. Significantly, vitamin B5 supplementation alleviated motor deficits and cerebellar myelin defects in Tango2 knockout mice. Overall, our findings establish that TANGO2 is essential for maintaining normal motor behaviors by regulating lipid metabolism in oligodendroglia.

Keywords:  TANGO2 deficiency disorder; lipid metabolism; motor deficits; myelin; oligodendrocyte

DOI:  https://doi.org/10.1096/fj.202601407RR
bioRxiv. 2026 Jul 21. pii: 2026.07.16.738974. [Epub ahead of print]

Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury.

Thomas Delgado, Tanzil M Arefin, Ian Pagan, Benjamin H Weekley, Joel Rodwell-Bullock, Mohammad R Chowdhury, Anthony B Crum, Ian Maze, Paul S Brookes, Julian P Meeks, Gail V W Johnson.

Mild traumatic brain injury (mTBI) is the most common form of central nervous system (CNS) injury and is often characterized by persistent neuroinflammation, metabolic dysregulation, and oxidative stress. Repetitive injuries compound these pathologies and lead to multifocal axonal injuries and long-term functional deficits. Despite the prevalence of mTBIs, the cellular mechanisms that facilitate or prevent recovery following injury remain poorly defined. Here, we extend our previous work on the role of the protein transglutaminase 2 (TG2) in CNS injury and we hypothesize that transcriptional regulation by TG2 restricts metabolic versatility in astrocytes following TBI, thereby impairing neuronal energetic support and worsening pathological outcomes. We utilized an established weight-drop model of repetitive mTBI followed by multi-parametric analysis of TBI pathology in complete TG2 knockout (TG2-/-) and wild type mice. At 28 days post-injury, TG2-/- mice showed marked attenuation of TBI pathology, compared to wild type mice, in vulnerable white matter and default mode network (DMN) regions, as assessed by diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and immunohistochemistry. Integrated epigenomic, proteomic, and metabolomic profiling of cortical astrocytes isolated 28 days after injury revealed a pronounced metabolic restriction in wild type astrocytes which was remarkably attenuated in the TG2-/- mice. This rescue was associated with a de-repression of gene networks involved in glutamate recycling, lipid metabolism, and metabolic homeostasis. Together, these studies provide novel mechanistic insights into the metabolic dysregulation that characterizes persistent TBI pathology, and establish a foundation for evaluating TG2 as a therapeutic target for TBI.

DOI: https://doi.org/10.64898/2026.07.16.738974
Int J Mol Sci. 2026 Jul 09. pii: 6144. [Epub ahead of print]27(14):

Exploring the Metabolic Impact of Traumatic Brain Injury in CCI Mouse Models: A Focus on Early and Prolonged Injury Responses.

CTRC (Canadian TBI Research Consortium) and the CCCTBG (Canadian Critical Care Translational Biology Group)

  Traumatic brain injury (TBI) disrupts brain metabolism, which evolves over time and varies with the severity of the injury. Monitoring these metabolomic changes may reveal biomarkers indicating early damage, mechanisms of injury, and potentially help predict outcomes. This study used untargeted plasma metabolomics to investigate systemic time-dependent metabolic changes in mice exposed to controlled cortical impact (CCI) with or without replacement of a modified skull cap designed to reduce compensatory space for cerebral edema modelling a severe closed skull TBI, compared to sham controls. Male mice were subjected to CCI, CCI + CAP, or sham procedures comprised a scalp incision or a craniotomy. Plasma samples were collected at 4, 8, and 16 h, and 3 and 7 days after injury. Hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) was used to profile metabolites in all groups and time points, while ion-pair liquid chromatography-mass spectrometry (RPIPLC-MS) was used in CCI and sham mice at the early time points. The largest metabolic changes occurred at 8 h post-injury, distinguishing mice with CCI from sham controls. The early changes concerned metabolism of amino acids, energy, and nucleotide pathways, with metabolites such as succinate, phenylalanine, and cytidine showing significant changes. By 7 days, the metabolic patterns of the injured mice, especially CCI mice, had partially converged toward the sham state, although oxidative and mitochondrial disturbances persisted. The CCI + CAP mice had more pronounced and persistent metabolic disturbances compared to the CCI mice, which may reflect the effect of increased intracranial pressure post-injury. Plasma metabolomics can efficiently capture the evolving biochemical effects of TBI. The findings identified circulating metabolites that were associated with progression and severity of brain injury and provide a basis for future translational studies in human TBI.

Keywords:  HILIC–MS; biomarker discovery; controlled cortical impact (CCI) mouse model; metabolic profiling; plasma metabolomics; traumatic brain injury (TBI)

DOI:  https://doi.org/10.3390/ijms27146144
Res Sq. 2026 Jul 23. pii: rs.3.rs-10305293. [Epub ahead of print]

Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer's disease.

Yohannes Ambaw, Alissa Nana, Zhuoning Li, Shubham Singh, Mara Monetti, Bruce Miller, Salvatore Spina, Lea Grinberg, William Seeley, Tobias Walther, Robert Farese.

Frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick's disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes, GRN associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except C9orf72 associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.

DOI: https://doi.org/10.21203/rs.3.rs-10305293/v1
Sci Adv. 2026 Jul 31. 12(31): eaeh9771

Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.

Xiaoai Zhao, Ryan M Feitzinger, Jeeyoon Na, Xin Yan, Andrew Erickson, Kévin Contrepois, Olivia Y Zhou, Francesco Vallania, Mathew Ellenberger, Chloe M Kashiwagi, Stephanie D Gagnon, Cynthia J Siebrand, Matias Cabruja, Gavin M Traber, Andrew McKay, Daniel Hornburg, Purvesh Khatri, Michael P Snyder, Richard N Zare, Anne Brunet.

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs). While mechanisms that restore old NSC function have started to be identified, the role of lipids-especially complex lipids-in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related changes in complex lipids in quiescent NSCs in vitro and in vivo. Moreover, several polyunsaturated fatty acids increase across lipid classes in quiescent NSCs during aging. Using spatial lipidomics, we find that some of the changes in complex lipids are also observed in situ. Several age-related changes in complex lipids and side chain composition are occurring at the plasma membrane, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we show that aging is accompanied by a decrease in plasma membrane order, a key membrane biophysical property, in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knocking out the phospholipid acyltransferase MBOAT2 exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. Mboat2 overexpression reverses age-related lipidomic changes in old quiescent NSCs and boosts their ability to activate in vitro and in vivo. Moreover, supplementation of plasma membrane lipids from young NSCs improves the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs, which has important implications for countering brain decline during aging.

DOI: https://doi.org/10.1126/sciadv.aeh9771
Mar Drugs. 2026 Jun 25. pii: 224. [Epub ahead of print]24(7):

Omega-3 Fatty Acids and Alzheimer's Disease: Toward a New Understanding of Neuroprotective Mechanisms and Intervention Strategies.

Giacoma Galizzi.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Despite recent advances, current therapies offer little benefit, and AD remains a significant challenge. Polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have attracted attention for their neuroprotective effects primarily through anti-inflammatory and antioxidant properties, but also for their ability to influence membrane fluidity and neuronal function. DHA is the predominant omega-3 PUFA in nerve cell membranes and is critical for synaptic plasticity and cognitive function. Some evidence has demonstrated that marine omega-3 supplementation reduces Aβ deposition, modulates microglial activation, and prevents cognitive decline in animal models. Even with heterogeneous results, preclinical and clinical studies suggest that long-term DHA/EPA supplementation can improve cognitive function in subjects with mild cognitive impairment (MCI) and reduce neuroinflammation markers. However, individual variability and brain bioavailability pose significant challenges. This review summarizes and discusses the current knowledge on the importance of PUFAs for human health, exploring novel mechanistic hypotheses, such as the effect of omega-3 fatty acids on brain iron homeostasis, the microbiota-gut-brain axis, the glymphatic system, and miRNAs. Furthermore, it focuses on the therapeutic potential of PUFAs in the treatment of AD and proposes future directions for translational research.

Keywords:  Alzheimer’s disease; DHA; EPA; PUFA; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3390/md24070224
CNS Neurosci Ther. 2026 Jul;32(7): e71060

Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.

Ruchong Fan, Chuan Wang, Zi Lin, Shiling Chen, Chao Pan, Hao Nie, Chuan Qin, Xuan Wu, Zhouping Tang.

   BACKGROUND: Stroke remains a major global cause of death and disability, with many patients either missing the therapeutic window or responding poorly to current first-line treatments. Consequently, secondary neurological injury, driven predominantly by neuroinflammation, has emerged as a critical therapeutic target. Microglia rapidly sense post-stroke microenvironmental changes and adopt distinct inflammatory phenotypes that shape pathophysiological outcomes.
RESULTS: Accumulating evidence, including high-resolution spatial profiling and single-cell omics, positions mitochondrial dysfunction at the core of these responses. This review synthesizes recent findings on microglial mitochondrial dysfunction in stroke, introducing the concept of a microglial mitochondrial "storm center". In this model, reactive oxygen species (ROS) trigger an inflammatory cascade, while impairments in mitochondrial quality control (MQC) exacerbate pathogenic signaling. Metabolic reprogramming further sustains inflammatory polarization, influencing interactions with neurons, astrocytes, and endothelial cells.
CONCLUSIONS: This "storm center" provides a conceptual framework for developing strategies to mitigate secondary brain injury. Finally, this review highlights key molecular mechanisms, potential therapeutic targets, and translational opportunities, providing a stronger foundation for future stroke research and therapeutic innovation.

Keywords:  fusion/fission dynamics; metabolic reprogramming; microglia; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; neuroinflammation; stroke

DOI:  https://doi.org/10.1002/cns.71060
Eur J Nucl Med Mol Imaging. 2026 Aug 01.

Regional brain metabolism and metabolic connectivity alterations in corticobasal syndrome assessed with [18F]FDG-PET.

Matilde Nerattini, Andrea Leo, Valentina Bessi, Anna De Rosa, Giovanna De Michele, Valeria Gaudieri, Giulia Giacomucci, Alberto Cuocolo, Giuseppe De Michele, Valentina Berti, Sabina Pappatà.

   PURPOSE: Corticobasal syndrome (CBS) is a clinically defined phenotype with different underlying neuropathological substrates most commonly the 4-repeat tauopathy corticobasal degeneration (CBD). 2-[18F] fluoro-2-deoxy-D-glucose Positron Emission Tomography ([18F]FDG-PET) studies have described regional metabolic abnormalities but detailed subcortical and cerebellar structures involvement is less known and metabolic connectivity remains unexplored. This study combined voxel-based, region-of-interest (ROI) analyses and connectivity approaches to further characterize metabolic alterations and to provide a network-level framework in CBS.
METHODS: Thirty-nine CBS patients underwent [18F]FDG-PET at two sites, with images flipped to align the most affected hemisphere; 99 controls were drawn from a national normative database. Voxel-based SPM method and ROIs analysis were performed. Thirty-six bilateral cortical and subcortical regions of interest were processed to perform interregional correlation and network-based analyses within five functional networks. Pairwise Spearman correlations were computed from normalized regional signals. Group differences were assessed at regional and network levels using Fisher-transformed correlations, Cohen's q, permutation testing (10,000 iterations), and graph-theoretical metrics (node strength, clustering coefficient; threshold ρ > 0.25).
RESULTS: CBS patients showed asymmetric hypometabolism predominantly in frontal, parietal, and temporal cortices, caudate and thalamus of the predominantly affected hemisphere, with additional contralateral involvement, notably in the cerebellum and caudate. Metabolic connectivity analyses revealed widespread intra- and inter-network disconnection, particularly involving frontal, parietal, and sensorimotor cortices, and thalamo-cortical pathways, with significant lateralization toward the affected hemisphere. Graph analysis showed decreased cortical node strength with relative increases in subcortical hubs and mixed changes in clustering coefficients, suggesting network reorganization.
CONCLUSION: This first [18F]FDG-PET metabolic connectivity study in CBS demonstrates asymmetric and bilateral regional hypometabolism, widespread and lateralized network disconnection, and subcortical reorganization. These findings reflect both degenerative, functional and compensatory mechanisms and highlight metabolic connectivity as a sensitive marker of network-level alterations in neurodegenerative disease.

Keywords:  Brain networks; Corticobasal syndrome; FDG-PET; Metabolic connectivity; Neurodegeneration

DOI:  https://doi.org/10.1007/s00259-026-08108-6
Toxicol Sci. 2026 Jul 29. pii: kfag093. [Epub ahead of print]

Mitochondrial Dysfunction, Cerebral Metabolic Crisis, and Exploratory Bioenergetic Biomarkers in a Translational Swine Model of Acute Carbon Monoxide Poisoning.

Abigail Insana, Alistair Lewis, John C Greenwood, Matthew Kelly, Frances S Shofer, Shih-Han Kao, McKenna Mason, Stephen Baak, Jonathan Starr, Jarelis Cabrera, Johannes K Ehinger, Todd J Kilbaugh, Tiffany Ko, Angela N Viaene, Wesley B Baker, David H Jang.

  Carbon monoxide (CO) poisoning remains a major cause of toxicologic morbidity and mortality and is a leading cause of acute neurologic injury among poisoned patients, yet the mechanisms underlying cerebral bioenergetic dysfunction remain incompletely understood. In addition to impaired oxygen delivery through carboxyhemoglobin (COHb) formation, CO poisoning is associated with mitochondrial respiratory dysfunction and cerebral metabolic injury. We characterized systemic physiology, cerebral metabolism, mitochondrial bioenergetics, and exploratory translational biomarkers in a swine model of acute CO poisoning. Yorkshire swine underwent sham exposure or inhalational CO exposure at 1000 or 2000 ppm with serial physiologic monitoring, arterial blood gas analysis, cerebral microdialysis, high-resolution mitochondrial respirometry, ATP quantification, western blotting, and histologic/immunohistochemical analyses. Peripheral blood mononuclear cell (PBMC) mitochondrial respiration was explored as a systemic correlate of cerebral mitochondrial function. CO exposure produced dose-dependent elevations in COHb and lactate with associated metabolic acidosis and hemodynamic impairment. Cerebral microdialysis demonstrated variable lactate-to-pyruvate ratios, while extracellular glycerol was significantly increased following severe CO exposure, consistent with membrane injury and metabolic dysfunction. Mitochondrial respiration was impaired in both cortical and hippocampal tissue, with Complex IV-linked respiration among the most consistently affected respiratory states. Cortical ATP content was significantly reduced in severely exposed animals, supporting cerebral bioenergetic failure. Western blot analysis demonstrated increased HO-1 expression without significant reductions in citrate synthase or Complex IV protein abundance, suggesting functional respiratory inhibition rather than loss of mitochondrial content. Collectively, these findings demonstrate that acute CO poisoning produces early cerebral bioenergetic dysfunction characterized by impaired mitochondrial respiration, ATP depletion, and metabolic alterations, while supporting the exploratory potential of PBMC mitochondrial respiration as a translational biomarker of cerebral mitochondrial dysfunction.

Keywords:  bioenergetic biomarkers; carbon monoxide poisoning; cerebral metabolism; cerebral microdialysis; mitochondrial dysfunction; swine model

DOI:  https://doi.org/10.1093/toxsci/kfag093
Nat Neurosci. 2026 Jul 29.

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.

Xiuli Dan, Deborah L Croteau, Wenlong Liu, Xixia Chu, Ross A McDevitt, Paul D Robbins, Vilhelm A Bohr.

Dysfunctional mitophagy is proposed as a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights are still lacking. Here we show that AD model mice expressing a mitophagy reporter (APP/PSEN1/mt-Keima) develop large accumulation of acidic and neutral mitochondria within neuronal processes that form a previously unrecognized pathological structure termed mitochondrial plaques (MPs). The development of MPs is driven by abnormal mitochondrial buildup and lysosomal recruitment occurs as a delayed response to promote mitochondrial degradation. However, degradation through mitophagy is incomplete due to impaired lysosomal functions, resulting in accumulation of both neutral and acidic mitochondria. MPs frequently codevelop with amyloid to form mixed plaques but can also emerge independently at early stages of disease. Notably, MPs were also identified in the 5xFAD AD mouse model and postmortem human AD brains. These findings establish MPs as a new pathological entity in AD.

DOI: https://doi.org/10.1038/s41593-026-02390-1
Front Immunol. 2026 ;17 1864729

The brain's sweet spot: why microglia can run on fructose metabolism.

Yasmina Eshac, Julieanne Cabang, Jason Miska.

  Microglia are the resident myeloid cells of the central nervous system (CNS), and their identity and function are shaped by developmental origin, local signaling, and metabolic specialization. The fructose transporter GLUT5 (SLC2A5) stands out as a selective and conserved microglial marker that remains strongly associated with resident microglia across homeostatic and disrupted CNS states. In the CNS, fructose appears to be regulated locally rather than reflecting circulating levels, raising the possibility that fructose metabolism serves a unique functional role in microglia. Recent studies suggest that this pathway has a meaningful functional role. Fructose availability in the CNS can directly reshape microglial behavior by altering phagocytosis, redox balance, metabolic state, and downstream immune signaling in contexts ranging from neurodevelopment to glioblastoma. Our recent study showed that microglia fructose metabolism in glioblastoma drives an immunosuppressive state, limiting antigen presentation and downstream anti-tumor immunity. In this review, we examine microglial identity and metabolism in the context of GLUT5 and fructose uptake, summarize evidence that fructose acts as a context-dependent regulator of microglial function, and discuss how this may reflect broader metabolic strategies used by resident cells in distinct fluid and tissue barriers. We propose that microglial fructose metabolism is not simply an incidental feature of these cells, but a biologically meaningful feature of CNS physiology with important implications for development, injury, and disease, though the mechanistic basis of this relationship remains an active area of investigation.

Keywords:  brain tumors; fructose; microglia; neurodevelopment; traumatic brain injury

DOI:  https://doi.org/10.3389/fimmu.2026.1864729
Aging Dis. 2026 Jul 22.

Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.

Vijay Kumar, Sinae Jang, Yebeen Choi, Sujin Kim, Yunkwon Nam, MyeongHeon You, Minho Moon.

Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.

DOI: https://doi.org/10.14336/AD.2026.0606
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602775123

Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.

Wasi Iqbal, Ben Zucker, Xiaoying Liu, Ruiru Wang, Hongfei Zhu, Sijie Chen, Renjie Zhou, Xingguo Liu, Michael M Kozlov, Liting Duan.

  Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.

Keywords:  membrane elasticity; membrane pearling; membrane tension; mitochondria; mitochondrial fission

DOI:  https://doi.org/10.1073/pnas.2602775123
Metab Brain Dis. 2026 Jul 31. pii: 179. [Epub ahead of print]41(1):

Polysaccharide-driven gut microbial metabolism in neurodegenerative brain diseases: from SCFAs and tryptophan catabolites to neuroinflammatory regulation.

Chengqi Peng, Lingxiao Chen, Zongyao Wu, Cizhen Danzeng, Xiaorui Cheng.

  The gastrointestinal tract constitutes the principal anatomical interface of the microbiota-gut-brain axis (MGBA), orchestrating neuroimmune and metabolic crosstalk. Dysregulation within this network drives neurodegenerative pathogenesis through altered microbial metabolism, peripheral immune activation, and subsequent aggregation of pathological proteins in the central nervous system (CNS). Natural bioactive polysaccharides modulate this axis primarily via indirect, microbiota-dependent mechanisms-acting as fermentable prebiotics that reshape gut ecology and metabolite profiles-rather than through direct CNS penetration of intact macromolecules. These macromolecules promote neuroprotective short-chain fatty acids (SCFAs) that reinforce mucosal and blood-brain barrier (BBB) integrity. At the molecular level, polysaccharide interventions attenuate the TLR4/NF-κB/NLRP3 inflammatory cascade and upregulate Nrf2/BDNF neurotrophic signaling, effects predominantly mediated by microbiota-derived metabolites and peripheral-to-central signaling, with limited evidence for direct CNS entry of low-molecular-weight fractions. This review evaluates the pharmacological mechanisms of natural polysaccharides in neurodegenerative disorders, focusing on microbe-derived metabolic regulation, immune homeostasis, and clearance of neuropathological aggregates. While preclinical efficacy is promising, clinical translation demands rigorous structure-activity relationship mapping and specialized targeted delivery platforms.

Keywords:  MGBA; Mechanism; Natural bioactive polysaccharides; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s11011-026-01946-1
Cell Rep. 2026 Jul 29. pii: S2211-1247(26)00827-2. [Epub ahead of print]45(8): 117749

CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.

Ying-Ying Jiao, Zhu Zhu, Rui-An Wang, Ben-Yu He, Hang Yao, Zhi-Yong Zhou, Yun-Fan Shi, Cong Wang, Lei Cao, Yang Liu, Gang Hu, Ren-Hong Du, Ming Lu.

  Depression is linked to microglial activation, but the precise triggers and downstream pathways remain elusive. Through single-cell RNA sequencing of human blood samples, we find upregulation of the CCL5-CCR5 axis in patients with major depressive disorder. Using a chronic social defeat stress mouse model, we show that CCR5 is specifically elevated in activated hippocampal microglia. Microglia-specific deletion of CCR5 alleviates depressive-like behaviors and prevents microglial activation. Mechanistically, CCR5 binding to VHL stabilizes HIF-1α, redirecting microglial metabolism toward aerobic glycolysis. This metabolic shift results in lactate accumulation, which drives histone H4 lysine 12 lactylation (H4K12la). Genome-wide profiling reveals that H4K12la enrichment at complement gene promoters facilitates their transcription, ultimately leading to excessive microglial engulfment of neuronal spines and synaptic loss. Importantly, either inhibiting glycolysis or exogenous lactate supplementation can respectively rescue or mimic the pathological synaptic pruning and depressive-like behaviors. Our findings indicate a CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors, offering potential targets for therapeutic intervention.

Keywords:  CCR5; CP: neuroscience; depression; histone lactylation; metabolic reprogramming; metabolism; microglia; synaptic pruning

DOI:  https://doi.org/10.1016/j.celrep.2026.117749
Neuroscience. 2026 Jul 25. pii: S0306-4522(26)00498-7. [Epub ahead of print]

Adolescent drinking causes a loss of aspartoacylase-expressing oligodendrocytes and hypomyelination of anterior cingulate and corpus callosum axons in male mice, but not females.

Said Akli, Annabelle Flores-Bonilla, Sirisha Nouduri, Samuel Scott, Heather N Richardson.

  Adolescent binge drinking is a strong predictor of alcohol use disorder and related mental health outcomes in adulthood, which may be due to disruptions in myelination during this dynamic period of brain development. White matter expansion in frontal regions during adolescence is essential for mature decision-making and stress regulation, yet the cellular mechanisms by which alcohol impairs myelination remain poorly understood. Multi-label immunofluorescence and confocal microscopy were used to visualize proteins in oligodendrocyte lineage cells and myelin ensheathment of axons in the anterior cingulate cortex (Cg1) and corpus callosum (CC) of male and female C57BL/6NJ mice following four weeks of episodic voluntary binge drinking during adolescent development using the Drinking-in-the-Dark model. Contrary to our hypothesis, alcohol targeted mature oligodendrocytes rather than early-stage oligodendrocyte precursor cells (OPCs). Binge drinking reduced oligodendrocytes expressing aspartoacylase (ASPA) in the Cg1 and CC. This enzyme is essential for lipid biosynthesis and myelin production, and cellular loss was accompanied by hypomyelination of axons. Notably, males appear especially sensitive to adolescent alcohol, as ASPA+ oligodendrocytes and myelin were not reduced in binge-drinking females. Differential vulnerability could carry important implications for adult neurodevelopmental outcomes. Altogether the findings advance our mechanistic understanding of myelin deficits after alcohol, identifying late-stage oligodendroglial development and ASPA as possible targets for therapeutic intervention in the treatment of alcohol use disorder and demyelinating diseases.

Keywords:  Adolescence; Alcohol; Aspartoacylase; Oligodendrocyte; Sex difference

DOI:  https://doi.org/10.1016/j.neuroscience.2026.07.054
Am Heart J Plus. 2026 Sep;69 100826

Cholesterol crystal formation and embolism in the central nervous system and their potential role in Alzheimer's disease.

Ali Houmani, F N U Parul, Moiz Saeed, Ryan Skowronek, Venkat Katkoori, Irina A Pikuleva, Maria B Grant, Julia V Busik, Majid Yavari, George S Abela.

  The brain and nervous tissues are very rich in cholesterol with local sterol biosynthesis being the primary source. The production of cholesterol in the brain may also lead to cholesterol crystal formation that in turn can cause inflammation which potentially can contribute to Alzheimer's disease. In this review we provide examples of cholesterol crystals (CCs) in human brains of Alzheimer patients. Moreover, cholesterol in the arterial circulation is also a major contributor to brain pathology. Specifically, CCs embolization released during plaque rupture may lead to reduced cognitive function, transient ischemic attacks, and ischemic strokes. Ischemic strokes can be caused by either thrombotic emboli from atrial fibrillation or CC emboli and platelets from ruptured plaques in the carotid arteries and aortic arch. CC emboli can cause blood flow obstruction, localized inflammation, and vasospasm of the local arterial vasculature, all contributing to ischemia and brain injury. Prevention and treatment of CC emboli with statins and aspirin has been found to be effective. Moreover, previous studies have demonstrated that both statins and aspirin can dissolve CCs. Thus, preventing formation and/or dissolving CCs could potentially be effective in reducing end organ injury induced by both CCs formation and emboli. Although further investigation with human studies remain lacking, recent studies have demonstrated prevention of thrombus formation induced by CCs may also provide another approach to inhibiting end-organ ischemic injury.

Keywords:  Alzheimer's Disease; Cholesterol crystal emboli; Cognitive dysfunction

DOI:  https://doi.org/10.1016/j.ahjo.2026.100826
Cell Rep Methods. 2026 Jul 30. pii: S2667-2375(26)00238-9. [Epub ahead of print] 101537

ATP-Red enables single-cell bioenergetic phenotyping by flow cytometry.

Jose Marin, Bharati Singh, Amanda Fuchs, Tatiana Tarasenko, Emily Warren, Martha Kirby, Stacie Anderson, Stephen M Wincovitch, Eliza M Gordon-Lipkin, Shannon Kruk, A Phillip West, Peter J McGuire.

  Most established bioenergetic assays lack single-cell resolution and may mask metabolic heterogeneity. The main flow-cytometry-based approach for bioenergetic analysis infers energetic state from protein synthesis, although translation can become uncoupled from ATP availability under physiologic and pathologic conditions. Here, we evaluated ATP-Red as a flow-cytometry-compatible readout of energetic state at single-cell resolution. We benchmarked ATP-Red against orthogonal approaches, including colorimetric ATP quantification, the ATP/ADP biosensor PercevalHR, and extracellular flux analysis, across ATPase inhibition, glycolytic and oxidative blockade, mitochondrial dysfunction, and immune activation. Across these settings, ATP-Red tracked biologically meaningful energetic changes as a relative ATP-linked fluorescence readout. When combined with immunophenotyping, ATP-Red also captured bioenergetic heterogeneity and pathway use in T cells following activation and during influenza virus infection. These findings support ATP-Red as a practical and scalable approach for single-cell bioenergetic phenotyping.

Keywords:  ATP-Red; CP: metabolism; flow cytometry; glycolysis; immunometabolism; metabolic phenotyping; mitochondrial dysfunction; oxidative phosphorylation; single-cell bioenergetics

DOI:  https://doi.org/10.1016/j.crmeth.2026.101537
bioRxiv. 2026 Jul 17. pii: 2026.07.16.738975. [Epub ahead of print]

The Disease Gene THAP12 is a Transcriptional Regulator of Mitochondrial ETC Complex I.

Brandon R Desousa, Yohei Abe, Martin Kampmann, Isha H Jain.

Complex I (CI) is the largest and most disease-associated component of the mitochondrial electron transport chain. While many diseases are linked to defects in specific CI subunits, the extent to which non-mitochondrial proteins contribute to CI function or disease is less clear. Here, we perform genome-wide CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively. These screens identify THAP12 as a previously unrecognized transcriptional regulator of CI biogenesis. THAP12 loss selectively destabilizes CI and impairs oxidative ATP production. Mechanistically, THAP12 functions in the nucleus as a DNA-binding factor that directly activates genes required for CI assembly and iron-sulfur cluster maintenance, including NDUFAF3, NDUFAF4 and BOLA3. Patient-derived fibroblasts carrying THAP12 mutations exhibit conserved transcriptional defects and profound CI deficiency, establishing THAP12-associated neurodevelopmental disorder as a secondary mitochondrial CI disease. Finally, hypoxia rescues growth defects in THAP12-deficient cells, nominating low-oxygen therapy as a potential treatment strategy. Together, these findings identify THAP12 as a dedicated regulator of CI assembly and expand the genetic landscape of CI disease.

DOI: https://doi.org/10.64898/2026.07.16.738975
Neurotherapeutics. 2026 Jul 29. pii: S1878-7479(26)00147-9. [Epub ahead of print]23(5): e00977

Exosome-mediated delivery of 3-n-butylphthalide rescues microglial energy crisis and ameliorates neuroinflammation in ischemic stroke.

Bangyue Wang, Muchen Xi, Keyi Lin, Qinglong Guo, Yuyang Wang.

  Stroke remains the second leading cause of death and the primary cause of long-term disability worldwide, with ischemic stroke accounting for the majority of cases. Ischemia triggers robust microglial activation, yet the precise regulatory mechanisms underlying microglial functional reprogramming remain incompletely understood. Here, we demonstrate that excessive mitophagy drives metabolic energy failure in microglia following cerebral ischemia, resulting in impaired phagocytosis and exacerbated neuroinflammation. Analysis of single-cell RNA-sequencing data from mouse brains in the sham, transient middle cerebral artery occlusion (tMCAO, mMCAO), and permanent middle cerebral artery occlusion (pMCAO, sMCAO) groups revealed that mitophagy was markedly activated in microglia under sustained ischemia and was associated with impaired phagocytic and cytoskeletal pathways. In vitro oxygen-glucose deprivation (OGD) assays showed that phagocytosis of apoptotic neurons by microglia induced upregulation of Drp1, triggering excessive mitochondrial fission and mitophagy, which caused ATP depletion and reduced clearance capacity. The mitophagy inhibitor 3-methyladenine alleviated inflammatory responses but failed to restore mitochondrial quality. In contrast, 3-n-butylphthalide (NBP) stabilized mitochondrial membrane potential, restored ATP production, and improved microglial phagocytic defects and inflammation. To achieve targeted delivery, we constructed BV2 microglia-derived exosomes encapsulating NBP (BV2exo@ NBP), which efficiently enhanced drug accumulation in ischemic lesions and significantly improved neurological outcomes in stroked mice. These results identify excessive mitophagy as a core mechanism underlying microglial energy crisis after cerebral ischemia and provide a mitochondria-targeted therapeutic strategy for ischemic stroke. Importantly, the neuroprotective efficacy, mitochondrial restoration, and anti-inflammatory effects of BM@NEB were fully recapitulated in 18-month-old aged mice, a clinically relevant model that more closely reflects the stroke patient population, supporting the translational potential of this exosome-based therapeutic strategy.

Keywords:  3-n-butylphthalide; Cerebral ischemia; Energy metabolism; Microglia; Mitophagy

DOI:  https://doi.org/10.1016/j.neurot.2026.e00977
Res Sq. 2026 Jul 15. pii: rs.3.rs-10057949. [Epub ahead of print]

Astrocytic lactate shuttle disruption and the energy-starved lysosome in Alzheimer's disease.

YoungOuk Kim, WooMyung Heo, Se Jin Park, YoungChul Kim, Ye Eun Cho.

  Lysosomal dysfunction is central to Alzheimer's disease (AD), yet why structurally intact vacuolar H+-ATPase (V-ATPase) proton pumps fail to maintain lysosomal pH remains unresolved. Because V-ATPase activity depends on continuous ATP supply, we hypothesized that disruption of the astrocyte-neuron lactate shuttle imposes a cross-cellular energy deficit-an "energy-starved lysosome" (ESL) state. Integrating single-nucleus transcriptomics (SEA-AD; 1.3 million nuclei, 84 donors) with cerebrospinal fluid proteomics (ADNI Emory; n = 1,105), we found that astrocytic lactate-export genes, led by MCT4 (- 43%), declined far faster than V-ATPase, and that astrocytic MCT4 was coupled to neuronal V-ATPase independently of disease stage (donor-level partial r = + 0.466). At the protein level, V-ATPase V1A abundance was preserved across diagnostic groups-consistent with structural pump integrity-while, at the individual level, glycolytic capacity (hexokinase-1, HK1) tracked Tau pathology; this glycolysis-Tau coupling reproduced on an independent proteomic platform and against immunoassay Tau, whereas an apparent CSF V1A-Tau correlation did not survive distribution-robust analysis or validation against immunoassay Tau and is not interpreted as an individual-level marker. These findings position cross-cellular metabolic decoupling, rather than structural pump loss, as a candidate upstream constraint on lysosomal acidification, defining a candidate intervention window.

Keywords:  ADNI; Alzheimer’s disease; Astrocyte-neuron lactate shuttle (ANLS); Cerebrospinal fluid biomarkers; Lysosomal acidification; MCT4; Multi-omics; SEA-AD; V-ATPase

DOI:  https://doi.org/10.21203/rs.3.rs-10057949/v1
Int J Mol Sci. 2026 Jul 16. pii: 6334. [Epub ahead of print]27(14):

Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury Through ROS-Dependent Remodeling of Microglial Mitochondrial Dynamics.

Haotian Wei, Xingyue Du, Shushu Xu, Qiuli Bo, Yanan Guo, Lihua Xu, Zhenglin Jiang, Xia Li, Yuan Yuan.

  Hyperbaric oxygen (HBO) shows neuroprotective potential in cerebral ischemia-reperfusion (CIR) injury, but its variable efficacy suggests that the underlying cellular mechanisms remain incompletely defined. We previously showed that HBO suppresses microglial NLRP3 inflammasome activation after CIR injury in a reactive oxygen species (ROS)-dependent manner; yet, how ROS couples to this effect remains unclear. Since mitochondria regulate ROS and inflammasome signaling, we investigated whether HBO modulates microglial mitochondrial dynamics in CIR injury. In adult male ICR mice (n = 71, 8-12 weeks) subjected to 60 min middle cerebral artery occlusion followed by 24 h reperfusion, HBO improved neurological function, reduced infarct area, and decreased ASC-positive microglia/macrophages. In lipopolysaccharide/nigericin-stimulated primary microglia, HBO suppressed IL-1β release, reduced mitochondrial fragmentation, preserved mitochondrial membrane potential, maintained mitofusin 2 (MFN2) protein level, and reduced DRP1 Ser616 phosphorylation without altering total DRP1 or FIS1 expression. MitoTEMPOL abolished HBO-mediated protection against mitochondrial fragmentation, MFN2 reduction, and DRP1 Ser616 phosphorylation in vitro. Edaravone, when combined with HBO, attenuated HBO-mediated neuroprotection and counteracted HBO-induced regulation of MFN2 and DRP1 Ser616 phosphorylation in vivo. These findings support ROS-dependent remodeling of microglial mitochondrial dynamics as a mechanism contributing to HBO-mediated suppression of inflammasome-associated inflammation after CIR injury.

Keywords:  cerebral ischemia–reperfusion injury; hyperbaric oxygen; microglia; mitochondrial dynamics; neuroinflammation; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms27146334
Trends Cell Biol. 2026 Jul 31. pii: S0962-8924(26)00135-2. [Epub ahead of print]

Cellular lipid imaging at the ultrastructural level.

Fikadu G Tafesse, Carsten Schultz.

Lipids are fundamental organizers of biological membranes, yet visualizing lipid species within subcellular organelles has remained beyond experimental reach. Lennartz et al. introduce Lipid-correlative light and electron microscopy (CLEM), a CLEM workflow that maps lipid species onto membrane ultrastructure with nanoscale precision, uncovering active sphingomyelin sorting within the early endosome.

DOI: https://doi.org/10.1016/j.tcb.2026.07.002