bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2026–07–12
35 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Age-Dependent Spatiotemporal Remodeling of Brain Sphingolipids During LPS-Induced Neuroinflammation: MALDI-MSI Reveals Accelerated Sphingomyelin Depletion and Sulfatide Accumulation Linked to Mitochondrial Oxidative Stress.
  2. ZBTB7A-mediated regulation of astrocytic glycolysis in neurodegenerative diseases: insights from literature review and bioinformatics prediction.
  3. Lactylation in the ageing nervous system: Epi-metabolic regulation, disease mechanisms, and translational challenges.
  4. Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.
  5. Gangliosides in the 21st century: therapeutic prospects for the brain and spine.
  6. In vivo evidence for soluble Aβ oligomer-driven neuronal metabolic dysfunction in 5xFAD mice.
  7. Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.
  8. Zinc as a phase-specific therapeutic target in hypoglycemia-induced brain injury.
  9. Senescent cells accumulate lipid droplets.
  10. Interplay between Neuronal Metabolism and Signaling in Model Systems with Impaired α-Ketoglutarate Dehydrogenase Complex Activity.
  11. Altered hypothalamic metabolism in chronic cluster headache patients measured with 1H-MRS at ultra-high magnetic field.
  12. Notch Signaling Reprograms Glial Lipid Metabolism to Promote Hypoxia Resistance.
  13. Sex-Specific Relationships between Cerebral Cortex Metabolism, Behavior, and ECG Parameters in Rats under Physiological Conditions and after Pyruvate Dehydrogenase Inhibition.
  14. The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery.
  15. Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
  16. Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
  17. Fatty Acid Binding Protein 5 Mediates Astrocytic Pyroptosis and Neuroinflammation in Epilepsy via cGAS/STING Pathway.
  18. Mitochondrial regulation of brain development: evidence from zebrafish models.
  19. Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
  20. Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.
  21. High-resolution mri guided whole mouse brain neuronal cell type atlas using deep learning.
  22. N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
  23. Interaction of G2019S LRRK2 and metabolic syndrome in a two-hit mouse model of Parkinson's disease: LRRK2-driven systemic depletion of pyrimidine nucleosides.
  24. The role of mitochondrial Na⁺/Ca²⁺ exchanger in brain cell aging.
  25. B4GALT5 deficiency impairs glycosphingolipid biosynthesis: a new Congenital Disorder of Glycosylation?
  26. Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.
  27. State-Dependent Transcriptomic Collapse of the Brain's Lactate and Ketone Thermodynamic Sensors in Schizophrenia.
  28. Translational validity of rodent diet-induced obesity models for cognitive impairment in human metabolic disease.
  29. Brain aging in Type II GM1 gangliosidosis.
  30. Brain-muscle axis regulation of neuroinflammation and sarcopenia in Parkinson's disease: the bridging role of lactylation.
  31. Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery.
  32. Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
  33. Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
  34. Selective knockout of PKA regulatory subunits reveal opposite catalytic and metabolic consequences with implications for Alzheimer's disease.
  35. Brain health across the lifespan and the impact of nutrition, exercise, microbiota, and sleep.
  1. bioRxiv. 2026 Jul 01. pii: 2026.06.26.734865. [Epub ahead of print]
    Age-Dependent Spatiotemporal Remodeling of Brain Sphingolipids During LPS-Induced Neuroinflammation: MALDI-MSI Reveals Accelerated Sphingomyelin Depletion and Sulfatide Accumulation Linked to Mitochondrial Oxidative Stress.
    Kent Brown, Brayden Storey, Jacob Williams, Derrick Simet, Muhammad Bilal Umar, Emma Madsen, Zhiying Shan, Lanrong Bi.
      Aging is a major risk factor for exacerbated neuroinflammation and neurodegenerative diseases, yet the underlying lipid metabolic mechanisms remain incompletely understood. Here, we employed high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) combined with quantitative peak-area analysis and conceptual kinetic modeling to investigate age-dependent sphingolipid remodeling in the rat brain following intracerebro-ventricular (ICV) LPS challenge. In old rats, MALDI-MSI revealed pronounced and progressive sphingolipid dysregulation compared with young animals. Quantitative analysis showed a dramatic ∼10-fold reduction in SM(d36:1) and ∼4-fold reduction in SM(d42:2), accompanied by significant accumulation of long-chain sulfatides (2.12-fold increase in C24:1-sulfatide and 1.45-fold increase in C24(OH)-sulfatide) at both 24 h and 72 h post-LPS. Spatial imaging demonstrated that these changes were markedly amplified in white matter regions and became more widespread and intense at 72 h. A simplified Michaelis-Menten kinetic model successfully recapitulated the experimental data, identifying increased nSMase2 activity (higher Vmax) as the primary driver of accelerated sphingomyelin hydrolysis and subsequent ceramide rerouting into sulfatide synthesis. This metabolic shift generates excess ceramide that promotes Drp1-mediated mitochondrial fission, elevates mitochondrial ROS production, and disrupts bioenergetics, establishing a feed-forward loop linking sphingolipid remodeling to mitochondrial oxidative stress and white matter vulnerability in the aged brain. These findings provide the first spatially and temporally resolved demonstration of age-dependent sphingolipid metabolic reprogramming during neuroinflammation. By integrating multimodal MALDI-MSI, quantitative lipidomics, and kinetic modeling, this study reveals a previously underappreciated nSMase2-ceramide-mitochondrial axis in neuroinflammaging.
    Graphic Abstract:
    DOI:  https://doi.org/10.64898/2026.06.26.734865
  2. Front Aging Neurosci. 2026 ;18 1852019
    ZBTB7A-mediated regulation of astrocytic glycolysis in neurodegenerative diseases: insights from literature review and bioinformatics prediction.
    Ping Ye, Zhen Li, Xingang Cui, Hong Wu, Hong Jiang.
      The incidence of neurodegenerative diseases, including Alzheimer's disease (AD), continues to increase with the extension of human lifespan. However, their pathogenesis remains incompletely understood. Altered energy metabolism, particularly glucose metabolism involving glycolysis and oxidative phosphorylation, is widely recognized as an early pathological feature of neurodegenerative diseases. Astrocytes, the most numerous and widely distributed functional cells in the central nervous system (CNS), support neuronal energy demands through the astrocyte-neuronal lactate shuttle (ANLS). Glycolysis is a major pathway of astrocyte energy metabolism, and enhanced astrocytic glucose uptake and glycolytic flux may help attenuate the progression of neurodegenerative diseases such as AD. Zinc Finger and BTB Domain Containing 7A (ZBTB7A) is a POZ/BTB and Krüppel (POK) family transcription factor that has been implicated in the regulation of metabolic genes, including glycolysis-related genes, in several cellular contexts. However, its role in astrocyte glycolytic regulation under neurodegenerative conditions remains unclear. In this review, we summarize current knowledge of ZBTB7A biology, astrocyte glycolysis, and glial metabolic dysfunction in neurodegenerative diseases, and integrate published evidence with bioinformatics-based transcription factor binding prediction. Our analysis identified putative ZBTB7A-binding motifs in promoter regions of genes involved in glucose uptake, glycolytic flux, lactate production, and lactate transport. These findings suggest a potential association between ZBTB7A and the astrocytic glycolytic/lactate metabolic network. Therefore, this review provides a conceptual basis for future studies on ZBTB7A-associated transcriptional regulation in astrocyte metabolic remodeling and its potential relevance to neurodegenerative diseases.
    Keywords:  ZBTB7A; astrocyte-neuronal lactate shuttle; glycolysis; metabolic; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnagi.2026.1852019
  3. Ageing Res Rev. 2026 Jul 07. pii: S1568-1637(26)00236-9. [Epub ahead of print]121 103244
    Lactylation in the ageing nervous system: Epi-metabolic regulation, disease mechanisms, and translational challenges.
    Wenbo Li, Ying Chen, Zhanghan Liao, Lixing Yang, Junying Li.
      Lactate was long considered a waste metabolic byproduct. Currently, lactate functions as an energy substrate, signaling molecule, and epigenetic regulator in the central nervous system (CNS). Lysine lactylation (Kla), a novel lactate-dependent PTM, acts as a core epi-metabolic mediator by directly linking cellular metabolism to epigenetic remodeling. This review summarizes lactate production, shuttling, and the regulatory mechanism of lactylation (donors, writers, erasers, readers). We outline the multifaceted functions of lactylation in neurodevelopment, synaptic plasticity, and neural energy homeostasis, alongside its pathological dysregulation in major neurological disorders, with particular emphasis on ageing-related conditions. We further discuss the interplay between aberrant Kla and core ageing hallmarks, including mitochondrial dysfunction, impaired proteostasis, and inflammageing. Kla exerts site‑specific, cell‑type‑specific, and context‑dependent effects that are either protective or pathological. We also discuss therapeutic strategies targeting lactate metabolism and lactylation-modifying enzymes, analyzing the translational challenges involved. This review suggests Kla as an emerging epi-metabolic target that merits further investigation for therapeutic interventions in the ageing nervous system.
    Keywords:  Ageing; Central nervous system; Epi-metabolic mediator; Lysine lactylation; Neurological disorders; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.arr.2026.103244
  4. Transl Neurodegener. 2026 Jul 08. pii: 30. [Epub ahead of print]15(1):
    Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.
    Yun Teng, Chao Luo, Qingbo Xu, Jingyao Mu, Lucy Teng, Hongjia Qian, Yinan Huang, Minmin Liu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Jun Yan, Michael L Merchant, Huang-Ge Zhang.
       BACKGROUND: Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.
    METHODS: Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.
    RESULTS: Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.
    CONCLUSIONS: Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.
    Keywords:  Aging-related neurodegeneration; Cardiolipin; Cross-kingdom mitochondrial fusion; Microglia mitochondrial metabolism; Mitochondria transfer therapy; NADH dehydrogenase (Complex I); Plant mitochondrial microRNAs; Plant mitochondria; Reactive oxygen species (ROS); Reverse electron transport (RET)
    DOI:  https://doi.org/10.1186/s40035-026-00565-1
  5. Front Neurol. 2026 ;17 1795901
    Gangliosides in the 21st century: therapeutic prospects for the brain and spine.
    Pierre J Magistretti, Charles Finsterwald, Yutaka Itokazu, Simonetta Sipione, Fred H Geisler, Tarcisio Barros Filho.
      Gangliosides are sialylated glycosphingolipids highly enriched in the central nervous system, where they regulate membrane signaling, metabolism, neurogenesis, and immune responses. This Review integrates recent advances across distinct experimental and clinical domains. First, recent studies demonstrate that the monosialoganglioside GM1 enhances astrocyte-neuron metabolic coupling via the astrocyte-neuron lactate shuttle, thereby supporting neuronal bioenergetics and resilience. Complementary mechanistic work shows that specific gangliosides regulate adult neurogenesis through developmentally controlled epigenetic and transcriptional programs. In Huntington's disease models, preclinical evidence indicates that GM1 and related gangliosides attenuate microglia-mediated inflammatory responses and promote proteostasis through extracellular vesicle-dependent clearance of misfolded proteins. Finally, clinical evidence from acute spinal cord injury demonstrates that GM1 administration accelerates neurological recovery, underscoring its translational relevance. Together, these findings position gangliosides as multi-target modulators of neural repair and inflammation, and highlight their potential for therapeutic development.
    Keywords:  GM1; Huntington (disease); acute spinal cord injury (ASCI); astrocyte; extracellular vesicles; microglia; neurodegenenerative diseases
    DOI:  https://doi.org/10.3389/fneur.2026.1795901
  6. Alzheimers Res Ther. 2026 Jul 11.
    In vivo evidence for soluble Aβ oligomer-driven neuronal metabolic dysfunction in 5xFAD mice.
    Chaynita Dashora, Anant Bahadur Patel.
       BACKGROUND: Alzheimer's disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ). Brain glucose hypometabolism, an early feature of AD, reflects neuronal metabolic dysfunction before the onset of clinical symptoms. While Aβ plaques are central to AD pathogenesis, the mechanisms by which different Aβ species, such as plaques and soluble oligomers, drive cell-type-specific neurometabolic dysfunction during disease progression remain poorly understood. This study evaluated the roles of different Aβ species in the neurometabolic trajectory across the presymptomatic, symptomatic, and advanced stages of AD.
    METHODS: 5xFAD and wild-type (WT) mice were investigated for cognitive performance, quantitative Aβ levels, and glial activation markers at 3, 6, and 12 months of age. Neuronal and astroglial metabolic activities were evaluated ex vivo using state-of-the-art 1H-[13C]-NMR spectroscopy in conjunction with administration of [1,6-13C2]glucose and [2-13C]acetate, respectively.
    RESULTS: The 5xFAD mice exhibited cognitive decline from 6 months that further deteriorated by 12 months. There was a marked increase in Aβ-plaque burden and soluble oligomers from 3 to 12 months of age. These mice showed a significant reduction in hippocampal glutamatergic (0.145 ± 0.031 vs. 0.172 ± 0.016 µmol/g/min, p = 0.035) and GABAergic neuronal metabolic activity (0.027 ± 0.006 vs 0.033 ± 0.003 µmol/g/min, p = 0.028) as early as 3 months of age, with similar reductions observed in the cerebral cortex. The neurometabolic impairments further aggravated with age. Astrocytic metabolic activity was not significantly changed till 6 months but was increased at 12 months in 5xFAD mice in both the cerebral cortex (0.101 ± 0.014 vs. 0.084 ± 0.006 µmol/g/min, p = 0.011) and hippocampus (0.103 ± 0.006 vs. 0.089 ± 0.012 µmol/g/min, p = 0.011). The increase in astrocytic metabolic activity paralleled reactive gliosis, suggesting a shift from early neuronal metabolic impairment to heightened astroglial metabolic activity and inflammatory glial responses during the advanced AD stage. Notably, Aβ40 oligomers exhibited a greater sensitivity to impairment in neuronal glucose oxidation and cognitive function than Aβ42 oligomers or fibrillar plaques.
    CONCLUSIONS: These findings delineate a sequential neurometabolic cascade during AD progression, characterized by early neuronal glucose hypometabolism, subsequent cognitive decline linked to soluble Aβ40 oligomers, and late-stage astroglial metabolic activation. Collectively, these results suggest that soluble Aβ40 oligomers exhibit the greatest sensitivity to neurometabolic and cognitive impairment during AD.
    Keywords:   13C NMR spectroscopy; Alzheimer's disease; Amyloid-β oligomers; Astroglial metabolism; Gliosis; Neuronal metabolism
    DOI:  https://doi.org/10.1186/s13195-026-02130-4
  7. Brain. 2026 Jul 06. pii: awag234. [Epub ahead of print]
    Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.
    Te-Hsuan Tung, Sudhagar Babu, Xiangting Tang, Alec L Sciutto, Micah Romer, Prathima Racha, Rong Xu, Victoria Fiesler, Adrita Saha, Teresa Thai, Takashi Saito, Takaomi C Saido, Yongxin Zhao, Judith B Grinspan, Hansruedi Mathys, Takashi D Y Kozai, Franca Cambi.
      Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.
    Keywords:  lipid metabolism; microglia; mitochondria; neuroinflammation; neuroprotection; transcriptomics
    DOI:  https://doi.org/10.1093/brain/awag234
  8. Neurotherapeutics. 2026 Jul 09. pii: S1878-7479(26)00132-7. [Epub ahead of print]23(4): e00962
    Zinc as a phase-specific therapeutic target in hypoglycemia-induced brain injury.
    Dong Gyun Ko, Hyun Wook Yang, Hyun Ho Jeong, Min Kyu Park, Bo Young Choi, Seok Joon Won, Raymond A Swanson, Sang Won Suh.
      Hypoglycemia remains a major cause of neurological morbidity. However, effective targeted therapies for affected brain regions remain lacking. Although excitotoxicity and energy failure have long been implicated, emerging evidence has identified dysregulated zinc signaling as a central mediator of neuronal vulnerability and recovery. During acute glucose deprivation, synapse-released zinc accumulates intracellularly, impairing mitochondrial function, activating nicotinamide adenine dinucleotide phosphate oxidase, amplifying oxidative stress, and triggering poly (ADP-ribose) polymerase-dependent cell death pathways. Notably, neuronal injury is markedly exacerbated during glucose reperfusion, when zinc-reactive oxygen species coupling drives metabolic collapse. During the recovery phase, zinc contributes to neurogenesis, synaptic remodeling, and circuit repair, underscoring its phase-dependent duality. Here, we synthesize mechanistic and translational evidence supporting zinc as a dynamic regulator of neuronal fate in hypoglycemia-induced brain injury. We propose that zinc functions as a metabolic switch linking acute oxidative injury to subsequent regenerative processes. Importantly, this framework suggests a precision-timed therapeutic strategy involving acute zinc chelation or inhibition of zinc-coupled oxidative pathways during injury, followed by controlled restoration of zinc-dependent signaling during recovery. By redefining hypoglycemic brain injury through phase-specific zinc modulation, we identify new therapeutic opportunities relevant not only to hypoglycemia but also to broader metabolic and ischemic brain disorders.
    Keywords:  Excitotoxicity; Glucose deprivation and reperfusion; Hypoglycemia; Neuron death; Zinc
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00962
  9. Aging (Albany NY). 2026 Jul 01. 18(1): 768-786
    Senescent cells accumulate lipid droplets.
    Noa Rachmian-Cooper, Riva Shmulevich, Hagay Akiva, Sarka Pokorna, Bareket Dassa, Ulysse Cherqui, Sergey Malitsky, Maxim Itkin, Binyamin Amichai Kliger, Inna Goliand, Tomer Meir Salame, Valery Krizhanovsky.
      Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.
    Keywords:  Alzheimer’s disease; aging; lipid droplets; metabolism; senescence
    DOI:  https://doi.org/10.18632/aging.206390
  10. Biochemistry (Mosc). 2026 Jun;91(6): 893-909
    Interplay between Neuronal Metabolism and Signaling in Model Systems with Impaired α-Ketoglutarate Dehydrogenase Complex Activity.
    Márton Kokas, Attila Ambrus, László Tretter, Tímea Komlódi.
      The α-ketoglutarate dehydrogenase complex (KGDHC) serves as a master regulator of cell's molecular machinery. Beyond its classical role as a rate-limiting enzyme in the tricarboxylic acid (TCA) cycle, KGDHC has emerged as a critical redox sensor that can act as both a source and a target of reactive oxygen species (ROS), thereby regulating cellular redox homeostasis. This review summarizes evidence from genetically modified animal models and cell culture studies demonstrating that compromised KGDHC activity affects neuronal metabolism, redox homeostasis, and cellular signaling. KGDHC dysfunction causes mitochondrial failure, resulting in reduced ATP synthesis and activation of AMP-activated protein kinase (AMPK). Although inhibition of KGDHC reduces mitochondrial ROS formation, it also disrupts physiological ROS-dependent signaling mechanisms. In KGDHC-deficient mice, impaired ROS signaling and energy deficit decrease brain adaptability, increase susceptibility to neurotoxins, and disrupt crucial pathways by downregulating PGC-1α and Nrf2. These alterations result in suppression of antioxidant defences and lead to neuronal death in the hippocampus and memory impairment. Moreover, KGDHC dysfunction induces mitochondrial fragmentation and is strongly linked to excitotoxicity, further accelerating neuronal dysfunction. As observed in heterozygous models, even partial KGDHC deficiency can exacerbate persisting cellular and mitochondrial defects, leading to the development of more severe pathological conditions.
    Keywords:  cognitive decline; neuronal signaling; reactive oxygen species; succinylation; α-ketoglutarate dehydrogenase complex
    DOI:  https://doi.org/10.1134/S0006297926600663
  11. J Headache Pain. 2026 Jul 04. pii: 172. [Epub ahead of print]27(1):
    Altered hypothalamic metabolism in chronic cluster headache patients measured with 1H-MRS at ultra-high magnetic field.
    Avneesh Jain, Anna Xiu Rørnes, Anne Farestveit, Maria Tunset Grinde, Axel Karl Gottfrid Nyman, Beathe Sitter, Tore Wergeland, Erling Tronvik, Guglielmo Genovese.
       BACKGROUND: The hypothalamus is considered a central hub in the pathophysiology of cluster headache (CH), yet its neurochemical profile remains poorly understood. Proton magnetic resonance spectroscopy (1H-MRS) offers a non-invasive tool for in vivo assessment of brain metabolites related to neuronal integrity and energy metabolism, but previous studies in CH have been restricted to conventional magnetic field scanner (≤ 3 T), which has resulted in limited metabolic information. Ultra-high field (7 T) MR scanners enhance 1H-MRS with improved signal-to-noise ratio and separation of metabolite signals, providing more accurate and broader metabolic information, which may refine our understanding of hypothalamic dysfunction in chronic cluster headache (cCH). This study investigated whether patients with cCH exhibit altered hypothalamic metabolite concentrations compared with healthy volunteers (HVs).
    METHODS: 1H-MRS at 7 T was performed in 10 cCH patients and 11 HVs to measure the neurochemical profile of the hypothalamus. Spectra were quantified with LCModel, yielding ratios of 9 metabolites relative to total creatine (tCr). Welch's unpaired t-tests were performed as a first-level exploratory analysis to compare metabolites between the two groups. Then, group differences in metabolite ratios were examined using analysis of covariance, with age and sex included as covariates to control for potential demographic effects.
    RESULTS: Compared with HVs, cCH patients showed significantly reduced glutamate (Glu)/tCr (∼17%; p < 0.001) and N-acetyleaspartate (NAA)/tCr (∼10%; p = 0.048), with no other metabolite differences. After adjusting for covariates, a significant group effect was still observed for Glu/tCr (p = 0.0045), whereas no group difference was found for NAA/tCr (p = 0.079). Tissue composition within the voxel did not differ between groups, indicating that the observed metabolic differences were unlikely to be driven by partial-volume effects.
    CONCLUSIONS: This is the first study to characterize hypothalamic metabolism in cCH at 7 T. The observed reductions in Glu, together with a statistically less robust decrease in NAA, indicates hypothalamic neuronal involvement, possibly reflecting mitochondrial and energetic dysfunction. This ultrahigh-field finding extends previous results at conventional magnetic field intensities, offering more specific neurochemical evidence for hypothalamic involvement in cCH.
    Keywords:  7 T; Energy metabolism; Glutamate; Glutamatergic neurons; Mitochondria; N-acetyleaspartate; Neuronal metabolism
    DOI:  https://doi.org/10.1186/s10194-026-02446-4
  12. bioRxiv. 2026 Jun 29. pii: 2026.06.26.734874. [Epub ahead of print]
    Notch Signaling Reprograms Glial Lipid Metabolism to Promote Hypoxia Resistance.
    Yajuan Li, Qin Shuo, Anna Wang, Charlene Miciano, Allen Wang, Dan Zhou, Gabriel G Haddad, Lingyan Shi.
      Hypoxia poses a major threat to the developing nervous system, where high metabolic demand is required to support brain growth, glial and neuronal maturation, and function. Although glial cells are essential for maintaining neural homeostasis under stress, how specific glial subtypes remodel metabolism to promote hypoxia tolerance remains poorly understood. Here, we identify a Notch-dependent lipid metabolic program in excitatory amino acid transporter 1 (Eaat1)-positive glia that supports hypoxia adaptation in the developing Drosophila larval brain. Using stimulated Raman scattering (SRS) microscopy combined with deuterium-labeled metabolic probes, we visualized substrate-specific metabolic activity in vivo at subcellular resolution. In control, non-adapted flies, we found that acute hypoxia markedly increased de novo lipogenesis in Eaat1-positive glia. In flies adapted to chronic hypoxia, Eaat1-positive glia exhibited a pre-programmed metabolic shift, characterized by reduced glucose-derived lipogenesis and enhanced acetate-derived lipid synthesis. Constitutive activation of Notch signaling in Eaat1-positive glia was sufficient to phenocopy this acetate-favored lipogenic state, suggesting that Notch promotes metabolic plasticity under oxygen-limited conditions. To define the transcriptional programs associated with this response, we performed single-nucleus RNA sequencing (snRNA-seq) of the developing Drosophila central nervous system and mapped Eaat-1expressing cell populations across hypoxia and Notch activation. Notch activation reshaped hypoxia-associated transcriptional responses and counteracted metabolic suppression caused by low oxygen. Together, our findings identify Eaat1-positiveglia as a metabolically adaptive glial population and reveal a conserved Notch-regulated mechanism that rewires lipid metabolism to support hypoxia tolerance in the developing brain. These results provide insight into glial metabolic strategies that may be relevant to hypoxia-associated neurological conditions, including neonatal hypoxic-ischemic brain injury and ischemic stroke.
    DOI:  https://doi.org/10.64898/2026.06.26.734874
  13. Biochemistry (Mosc). 2026 Jun;91(6): 1006-1022
    Sex-Specific Relationships between Cerebral Cortex Metabolism, Behavior, and ECG Parameters in Rats under Physiological Conditions and after Pyruvate Dehydrogenase Inhibition.
    Anastasia V Graf, Alexey V Kazantsev, Victoria I Bunik.
      Sex-specific interactions between neurosignaling systems, which generate, propagate, and terminate signals in nervous tissue, and metabolic pathways that support these processes may underlie sex differences in adaptation and therapeutic efficacy. This study aimed to characterize these interactions as systemic indicators of sex-specific adaptive responses in a rat model of metabolic stress induced by the inhibition of pyruvate dehydrogenase complex (PDC), which catalyzes the key reaction linking anaerobic glycolysis to aerobic glucose oxidation. To inhibit brain PDC, we used a single intranasal administration of methyl acetylphosphinate (MeAcP), a phosphinate analog of pyruvate, or dimethyl acetylphosphonate (AcPMe2), a membrane-permeable precursor of phosphonate pyruvate analogs. Effects were assessed 24 h post-administration by measuring biochemical and physiological parameters in the cerebral cortex, including glutamate levels, glutamine synthetase (GS) activity, and activities of enzymes in the tricarboxylic acid (TCA) cycle and affiliated pathways. Neurosignaling was evaluated using surrogate indicators: ECG (electrocardiogram) parameters and spontaneous behavior in the open field test. Relationships between measured parameters were analyzed using Spearman's rank correlation coefficients, with the correlation strength classified according to the Chaddock's scale. In control animals, no sex differences were observed in the mean values of biochemical or ECG parameters. However, behavioral parameters (e.g., grooming and locomotion) and the overall structure of correlations between the studied parameters exhibited marked sex dependence. In control females, strong correlations were detected between ECG parameters and GS activity, whereas in males, ECG parameters were strongly associated with malic enzyme (ME) activity. Male controls also showed strong correlations between locomotor/exploratory behavior and activities of ME, PDC, and 2-oxoglutarate dehydrogenase complex (OGDC). Administration of PDC inhibitors induced a sex-specific reorganization of relationships between neurosignaling indicators and glutamate metabolism, which eliminated pronounced sex differences in locomotor activity observed in controls, while revealing new sex-related differences in glutamate levels, glutamate dehydrogenase (GDH) and ME activities, grooming bout duration, and freezing time. The reduction in glutamate levels observed in females following PDC inhibition was consistent with the established decrease in de novo glutamate synthesis from glucose under conditions of impaired substrate flux through the TCA cycle. Overall, these findings demonstrate that the relationships among metabolic, behavioral, and ECG parameters are inherently sex-specific. Moreover, the homeostatic response of the cerebral cortex to PDC inhibition reshapes these relationships, thereby modifying sex-dependent biochemical and behavioral characteristics observed under control conditions.
    Keywords:  2-oxoglutarate dehydrogenase complex; behavior; correlation analysis; dimethyl acetylphosphonate; glutamate; glutamate dehydrogenase; glutamine synthetase; heart rate variability; malic enzyme; methyl acetyl phosphinate; pyruvate dehydrogenase complex; pyruvate dehydrogenase inhibition; sex differences; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1134/S0006297926600444
  14. Eur J Neurosci. 2026 Jul;64(1): e70604
    The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery.
    Hannah van Susteren, Christine R Rose, Michel J A M van Putten, Hil G E Meijer.
      Cerebral ischemia impairs neuronal and glial function, ranging from transient synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model, including the first full implementation of the glutamate-glutamine cycle (GG-cycle), which is essential for proper functioning of glutamatergic synapses. We model a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium-potassium ATPase. To model synaptic transmission, we combine calcium-dependent glutamate release, its uptake by the sodium-dependent excitatory amino acid transporters (EAATs), and the GG-cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. This drives the neuron into depolarization block, with pathological ion concentrations and extracellular glutamate accumulation despite disrupted synaptic release. Synaptic transmission failure is not primarily caused by excessive glutamate release or by failure of glutamine synthetase, but mainly results from EAAT dysfunction, driven by the collapse of the sodium gradient. Restoring synaptic transmission is not possible by solely targeting glutamate dynamics but is possible by restoring ion gradients by inhibition of the voltage-gated Na+-channel. Our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in failure and recovery of synaptic function and the EAAT during metabolic stress.
    Keywords:  cerebral ischemia; computational model; glutamate; glutamine; neurotransmitter; synaptic transmission
    DOI:  https://doi.org/10.1111/ejn.70604
  15. Brain Behav. 2026 Jul;16(7): e71418
    Advances in the Core Role and Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease.
    Tianyi Gu, Hangyan Guo, Zixin Guo, Shengyu Hua.
       INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis involves multi-level pathological alterations. This review aims to systematically elucidate the central role and multifaceted molecular mechanisms of mitochondrial dysfunction in the progression of AD.
    METHODS: A comprehensive analysis of the existing literature was conducted, synthesizing findings from studies investigating mitochondrial involvement in AD pathology. The review focused on key mechanistic pathways, including energy metabolism deficits, oxidative stress, synaptic damage, mitochondrial dynamics, mitochondria-associated membranes (MAMs), mitophagy, and the gut-brain axis.
    RESULTS: The analysis revealed several critical mechanisms linking mitochondrial dysfunction to AD progression: (i) impaired mitochondrial energy metabolism, which establishes a causal relationship with oxidative stress and synaptic injury; (ii) dysregulation of mitochondrial fusion/fission dynamics, particularly the aberrant interactions of amyloid-beta (Aβ) and p-Tau with the fission protein Drp1 and the channel protein VDAC1; (iii) dysfunction of mitochondria-associated membranes (MAMs); (iv) defective mitophagy involving both the PINK1/Parkin pathway and receptor-mediated pathways; and (v) bidirectional crosstalk between mitochondria and the gut-brain axis. These interconnected pathways converge to amplify neuroinflammation and neuronal death.
    CONCLUSION: Accumulated evidence positions mitochondrial dysfunction as a critical hub that integrates Aβ/Tau pathology, neuroinflammation, and neuronal loss, thereby perpetuating a self-sustaining vicious cycle in AD. Targeting mitochondrial bioenergetics, dynamics, quality control, and the mitochondria-inflammation axis offers substantial therapeutic promise. Emerging small molecules such as SS31 and DDQ have demonstrated protective effects in preclinical models. Future investigations should prioritize mechanistic dissection and translational research to facilitate the clinical development of mitochondria-targeted therapies for AD.
    Keywords:  Alzheimer's disease; inflammation; mitochondrial dysfunction; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1002/brb3.71418
  16. J Neuroinflammation. 2026 Jul 07.
    Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
    Pilar González-García, Ignacio Serrano-Martínez, Eliana Barriocanal-Casado, Alejandro Cuenca-Martagón, Pablo Vargas-Rodríguez, Norma Adán, Irene Forte-Lago, Juan Carlos Morales, Patricia Gomez-Suaga, Júlia Bonet-Freixinet, Silvia Ginés, Luis C López, Elena González-Rey.
       BACKGROUND: Huntington's disease (HD) is an inherited, fatal neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene, leading to progressive motor, cognitive and psychiatric impairment. Despite its monogenic origin, HD pathogenesis is multifactorial, with convergent contributions from mitochondrial dysfunction, oxidative stress, synaptic failure, and chronic neuroinflammation, which drive neuronal vulnerability and degeneration, particularly within the striatum. Current clinical management remains exclusively symptomatic and fails to halt disease progression, highlighting a critical unmet need for strategies targeting fundamental pathogenic mechanisms. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory properties and has recently been implicated in the regulation of mitochondrial function. Notably, cortistatin deficiency is associated with exacerbated systemic and central inflammation, suggesting that impaired cortistatin signaling may contribute to neurodegeneration. However, its role in HD pathophysiology remains unexplored.
    METHODS: We performed a comprehensive reanalysis of publicly available transcriptomic datasets from HD patients to assess cortistatin expression, followed by validation in experimental HD models. Wild-type and cortistatin-deficient mice treated with 3-nitropropionic acid served as pharmacological HD models, enabling evaluation of cortistatin-dependent disease severity. Behavioral assessments, glial and oxidative markers, and immune factors were evaluated to determine neurological dysfunction and inflammatory responses. Complementary in vitro studies were conducted in striatal neurons expressing mutant huntingtin to examine mitochondrial integrity, inflammatory signaling, metabolic function, and mitochondria-endoplasmic reticulum interactions.
    RESULTS: Cortistatin expression was significantly reduced in postmortem HD human brains and across experimental HD models. Cortistatin deficiency exacerbated motor deficits, neuropathological alterations, inflammatory activation, and neuronal vulnerability in HD context. At the cellular level, reduced cortistatin expression was accompanied by amplified inflammatory signaling, disrupted mitochondrial integrity, impaired mitochondria-endoplasmic reticulum interactions, and increased oxidative stress. Conversely, exogenous cortistatin administration attenuated inflammatory mediator production, preserved mitochondrial structure, and improved redox balance in mutant huntingtin-expressing striatal neurons.
    CONCLUSIONS: Our findings identify cortistatin deficiency as a previously unrecognized contributor to HD pathogenesis and establish cortistatin as a key modulator of neuroinflammation and mitochondrial homeostasis. These results support cortistatin-based strategies as a promising disease-modifying therapeutic avenue for HD and related neurodegenerative disorders characterized by inflammatory activation and mitochondrial impairment.
    Keywords:  Cortistatin; Huntingtin; Huntington’s disease; Mitochondria; Neurodegenerative diseases.; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1186/s12974-026-03947-4
  17. Adv Sci (Weinh). 2026 Jul 06. e76377
    Fatty Acid Binding Protein 5 Mediates Astrocytic Pyroptosis and Neuroinflammation in Epilepsy via cGAS/STING Pathway.
    Chen Chen, Yao Zhao, Yangye Lian, Yifei Hou, Lifen Gong, Tingting Wu, Yulin Yang, Jiaqi Zhu, Xin Wang, Kaihua Zhang, Jing Ding.
      Pyroptosis is an inflammatory type of programmed cell death that may contribute to epilepsy initiation and progression through neuroinflammation. Fatty acid binding protein 5 (FABP5), a lipid chaperone, has been implicated in chronic inflammation. However, whether FABP5 regulates pyroptosis and its pathological role in epilepsy remains uncharacterized. Here, FABP5 was upregulated in astrocytes from temporal lobe epilepsy (TLE) patients, epileptic mice, and primary cells. Deletion of astrocytic Fabp5 significantly attenuated pyroptosis, neuronal loss, and seizure activity in epilepsy. Furthermore, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway was identified as the downstream signaling of FABP5 by RNA sequencing analysis. Mechanistically, Fabp5 knockdown reduced lipid overload, alleviated mitochondrial dysfunction, and suppressed cGAS-STING activation. Pharmacological inhibition of mitochondrial fatty acid import recapitulated these protective effects. In contrast, Sting overexpression abolished the reduced pyroptosis level by Fabp5 knockdown, whereas STING inhibition using C-176 attenuated pyroptosis and seizure activity. Collectively, these findings revealed the regulatory role of FABP5-cGAS-STING-pyroptosis axis in the progression of epilepsy and highlighted the promising potential of astrocytic FABP5 as a therapeutic target for epilepsy.
    Keywords:  astrocytes; cGAS‐STING pathway; epilepsy; fatty acid binding protein 5; pyroptosis
    DOI:  https://doi.org/10.1002/advs.76377
  18. Fish Physiol Biochem. 2026 Jul 06. pii: 114. [Epub ahead of print]52(4):
    Mitochondrial regulation of brain development: evidence from zebrafish models.
    Ahmet Topal.
      Mitochondria play a vital role in maintaining cellular energy balance, regulating apoptosis and controlling redox signaling during neurodevelopment. Disruption of these biological processes has emerged as a key mechanism underlying neurodevelopmental disorders and developmental neurotoxicity. Mitochondria influence neurodevelopmental phases, including neuronal proliferation and differentiation. The zebrafish serves as an exemplary model for examining the impact of mitochondria and energy metabolism on neurodevelopment, owing to its optical transparency, rapid embryonic development, and suitability for genetic manipulation. In this review, we summarize current knowledge on how mitochondrial processes direct brain development in zebrafish, providing a comprehensive overview of findings related to energy metabolism, calcium signaling, oxidative stress, and apoptosis. The findings show that mitochondrial health is a decisive factor for neurodevelopment and suggest that zebrafish-based models may play a critical role in developing new treatment strategies for neurodevelopmental disorders in the future.
    Keywords:  Brain; Energy metabolism; Mitochondria; Zebrafish
    DOI:  https://doi.org/10.1007/s10695-026-01739-4
  19. Sci Adv. 2026 Jul 10. 12(28): eaed6477
    Optical photothermal infrared imaging of fatty acid esterification in the ER of living cells.
    Hannah B Castillo, Caitlin M Davis.
      Lipotoxicity is an accumulation of lipids that leads to cell death and metabolic disease. Saturated fatty acids are more likely to cause lipotoxicity; however, the mechanism remains unclear due to challenges visualizing reactions in live cells. Here, we use optical photothermal infrared microspectroscopy to investigate palmitic acid (PA) metabolism in hepatocytes with submicron spatial resolution. Upon PA feeding, we found a time-dependent ester carbonyl stretch localized to the endoplasmic reticulum (ER) near lipid droplets with abnormal morphology. This stretch is assigned to diacylglycerol intermediates in the glycerol-3-phosphate pathway. C─D stretches of deuterated PA provide complementary molecular details, supporting a model whereby PA acyl chain packing in the ER reduces enzyme diffusion slowing PA metabolism. Our results provide a deeper understanding of how phase changes induced by high melting temperature fatty acids and their metabolites change ER chemistry as well as provide a tool for detecting chemical and environmental changes associated with lipotoxicity in live cells.
    DOI:  https://doi.org/10.1126/sciadv.aed6477
  20. ASN Neuro. 2026 ;18(1): 2696821
    Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.
    Salaheldeen Elsaid, Muhammad Asad Usmani, Xiangdong Wu, Junkai Hu, Nigus Ambaye, Sui Seng Tee.
      Excess fructose consumption has been implicated in metabolic disease, yet its impact on brain physiology and cellular metabolism remains poorly understood. The hippocampus expresses fructose transporters and fructolytic enzymes, suggesting potential vulnerability to fructose-induced metabolic stress. Here, we investigated fructose uptake mechanisms and downstream functional responses in BV2 microglia and HT22 hippocampal neurons using sodium manipulation, pharmacological inhibition, transporter expression profiling, and live-cell fluorescent sugar uptake assays. Hippocampal neurons exhibited strong sodium-sensitive, phlorizin-responsive fructose uptake, accompanied by reduced expression of facilitated hexose transporters and selective induction of Sglt1. In contrast, microglia demonstrated both sodium-sensitive and sodium-independent components of fructose uptake, associated with coordinated remodeling of GLUT and SGLT family members. Functionally, fructose exposure was associated with membrane hyperpolarization and reduced extracellular vesicle (EV) release in neurons, whereas microglia displayed membrane depolarization, enhanced EV secretion, and induction of pro-inflammatory genes. Knockdown of ketohexokinase (KHK) attenuated inflammatory gene expression and EV release in microglia, while pharmacological inhibition of sodium-dependent transport selectively reduced EV secretion. Complementary secondary analysis of hippocampal RNA-seq data from mice exposed to high-fat/high-fructose feeding revealed coordinated regulation of sodium-coupled transporters, ion channels, and synaptic gene programs, with partial normalization following SGLT inhibition. Together, these findings identify cell-type-specific fructose handling strategies in hippocampal neurons and microglia and suggest that sodium-dependent transport and fructolytic metabolism differentially influence membrane polarization, vesicle signaling, and inflammatory activation under metabolic stress.
    Keywords:  Fructose uptake; SGLTs; hippocampal neurons; microglia; neuroinflammation
    DOI:  https://doi.org/10.1080/17590914.2026.2696821
  21. Commun Biol. 2026 Jul 07.
    High-resolution mri guided whole mouse brain neuronal cell type atlas using deep learning.
    Xinyue Han, Rui Hu, Zhuoheng Liu, Jie Chen, Mubashir Jafry, Haoyu Song, Yi Zhao, Mingquan Lin, Leonard E White, G Allan Johnson, Nian Wang.
      Cell types represent groups of cells with shared anatomical and functional properties. Traditional brain cell type atlases rely on single-cell sequencing, which provides molecular detail but lacks whole-brain, isotropic resolution. Diffusion magnetic resonance imaging (dMRI) offers a complementary approach for probing cytoarchitecture and myeloarchitecture, with quantitative metrics increasingly used as biomarkers of brain development and neurodegenerative disorders. However, the capacity of dMRI to predict cell types remains unclear. Here, we develop a multimodal framework by integrating high-resolution dMRI and three-dimensional light-sheet microscopy of adult mouse brains through registration to the Allen Mouse Brain Common Coordinate Framework. We investigate correlations between dMRI and spatial transcriptomics-derived cell types and generate a whole-brain neuronal cell type atlas at 10 µm isotropic resolution using deep learning. Together, these results establish an efficient, high-resolution strategy for brain neuron atlas generation and underscore the potential of advanced imaging techniques to illuminate cellular mechanisms of the brain.
    DOI:  https://doi.org/10.1038/s42003-026-10608-y
  22. bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]
    N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
    Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.
      N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.
    DOI:  https://doi.org/10.64898/2026.06.29.735215
  23. NPJ Parkinsons Dis. 2026 Jul 08.
    Interaction of G2019S LRRK2 and metabolic syndrome in a two-hit mouse model of Parkinson's disease: LRRK2-driven systemic depletion of pyrimidine nucleosides.
    Yue Ma, Madalynn L Erb, Kayla A Sipple, Alina V Offerman, Junwei Niu, Zachary B Madaj, Zhen Fu, Kin H Lau, Darren J Moore.
      G2019S LRRK2 is the most common cause of familial Parkinson's disease (PD) and is associated with sporadic PD, arising from the interplay of genetic predisposition, environmental exposure and aging. Metabolic syndrome is implicated as a risk factor for PD, but the interaction between G2019S LRRK2 and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant LRRK2 mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in G2019S LRRK2 knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of G2019S LRRK2 knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in G2019S LRRK2 knockin mice. This conditional "two-hit" phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.
    DOI:  https://doi.org/10.1038/s41531-026-01465-x
  24. J Bioenerg Biomembr. 2026 Jul 09. pii: 37. [Epub ahead of print]58(1):
    The role of mitochondrial Na⁺/Ca²⁺ exchanger in brain cell aging.
    Andrey M Khaitin, Alina A Lebedeva, Anastasia E Kunitsyna, Svetlana V Demyanenko.
      Considering the world's population aging and the importance of mitochondrial calcium regulation for all brain pathologies, researchers cannot neglect the role of mitochondrial sodium/calcium exchanger (NCLX) not only in pathologies like Alzheimer's and Parkinson's diseases, but in physiological "healthy" aging as well. Despite its critical role in mitochondrial metabolism upon neurodegeneration, the role of NCLX in physiological aging of CNS is almost unknown. NCLX interacts with regulatory partners like TMEM65 and signal pathways of PKA and HIF, connecting to broader metabolic networks of hypoxia, inflammation, oxidative stress, and autophagy. Understanding precise mechanisms of NCLX regulation and its cell-specific roles remains critical for developing targeted interventions to preserve brain function in aging. NCLX is functioning differently in neurons and glial cells, which should be investigated further and considered when studying brain aging. In this review we aim to encompass the current state and connections of this understudied topic and discuss the future prospects and implications.
    Keywords:  Brain aging; Mitochondrial calcium; NCLX; Neurodegeneration
    DOI:  https://doi.org/10.1007/s10863-026-10118-w
  25. J Lipid Res. 2026 Jul 09. pii: S0022-2275(26)00132-X. [Epub ahead of print] 101102
    B4GALT5 deficiency impairs glycosphingolipid biosynthesis: a new Congenital Disorder of Glycosylation?
    Linda Montavoci, Michele Dei Cas, Anna Caretti, Omar Ben Mariem, Ivano Eberini, Laura Giaquinto, Alessandro De Falco, Maria Antonietta de Matteis, Nicola Brunetti-Pierri, Marco Trinchera.
      Lactosylceramide is a glycosphingolipid precursor synthesized by two dedicated galactosyltransferases, B4GALT5 and B4GALT6. The specific roles of B4GALT5 and B4GALT6 in humans have not yet been clearly defined. Here, we report the first human case with bi-allelic loss-of-function variants in B4GALT5, suggesting that intact B4GALT5 activity is indispensable for normal glycosphingolipid biosynthesis and human development. We identified bi-allelic variants in the B4GALT5 gene in a child presenting with microcephaly, mild cognitive impairment, and bilateral cataracts. B4GALT5/6 double KO cells transfected with B4GALT5 carrying either of the variants identified in the patient lacked lactosylceramide synthase activity and failed to produce glycosphingolipids. In-silico analyses predicted decreased protein stability and impaired UDP-Gal binding for both B4GALT5 variants. Together, these findings indicate that both variants result in deficient B4GALT5 activity, leaving B4GALT6 as the sole source of lactosylceramide synthase activity. Consistent with this, patient plasma and fibroblasts exhibited an approximately 80% reduction in glycosphingolipid levels compared with healthy controls. Unexpectedly, when expressed in model cells human B4GALT6 displayed lower expression and lower catalytic activity, than human B4GALT5, raising questions about its capacity to compensate for B4GALT5 deficiency. In conclusion, we identified a potential new congenital disorder of glycosylation caused by deficient lactosylceramide synthase activity that may be insufficient to support glycosphingolipids synthesis at levels required for normal brain function.
    Keywords:  CRISPR-Cas9 genome editing; brain lipids; fluorescence microscopy; galactosyltransferase; glycolipids; homology modeling; intellectual disability; lactosylceramide synthase; lipidomics; sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2026.101102
  26. bioRxiv. 2026 Jun 29. pii: 2026.06.25.734633. [Epub ahead of print]
    Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.
    Eleni Katafygiotou, Ada Squires, Anne Liang, Holden Hadfield, João A Paulo, Walid Idi, Steven P Gygi, Joongkyu Park, Jeeyun Chung.
      Lipid droplets (LDs) are conserved organelles that buffer lipid storage and stress, yet their dynamics and functions in neurons remain largely unknown. Here, we report activity-dependent dynamics of neuronal LDs, visualized by a novel, genetically encoded LD reporter (termed LipiDew), in both cultured neurons and mouse motor cortex. Using LipiDew, we found that various paradigms of neuronal activation induced predominant and transient formation of LDs in neurites. Disruption of autophagic LD degradation (lipophagy) resulted in abnormal lipid accumulation in dendritic spines and shafts, promoted recruitment of synaptic scaffolding proteins to LDs, and altered intracellular calcium kinetics in neurons. In addition, mice with neuron-specific genetic impairment of lipophagy showed motor function defects. Together, these findings identify activity-dependent LD formation and lipophagic clearance in neuronal compartments as a crucial regulatory mechanism of synaptic integrity and neuronal function.
    DOI:  https://doi.org/10.64898/2026.06.25.734633
  27. bioRxiv. 2026 Jul 01. pii: 2026.06.26.734782. [Epub ahead of print]
    State-Dependent Transcriptomic Collapse of the Brain's Lactate and Ketone Thermodynamic Sensors in Schizophrenia.
    Bryan A Krantz.
      Metabolic psychiatry has recently achieved unprecedented clinical rescue in treatment-resistant Schizophrenia (SCZ) utilizing targeted ketogenic interventions. However, the field has operated without a defined genomic anchor, leaving the biophysical mechanism of these therapies largely unexplained. Here, we report the discovery of the definitive metabolic sensor array driving this pathology. By integrating high-resolution topological mapping of SCZ GWAS summary statistics, 3D chromatin conformation (Hi-C), and multi-tissue transcriptomics, we identify massive, non-coding structural variances flanking the HCAR2/HCAR1 tandem locus-the brain's master thermodynamic governor. We demonstrate that while the protein-coding hardware of these receptors remains intact, their shared 3D Topologically Associating Domain (TAD) is fundamentally fractured. This structural collapse drives a perfect transcriptomic double dissociation in the human cortex: the 3' mutational "skyscraper" severely downregulates the HCAR1 lactate emergency brake, while the 5' mutational cluster selectively paralyzes the HCAR2 β-hydroxybutyrate (BHB) and niacin cooling switch. This dual-flank enhancer failure elegantly provides a definitive genomic etiology for historical SCZ biomarkers, physically explaining both chronic cerebrospinal fluid lactate pooling and the infamous "absent niacin flush." Furthermore, peripheral eQTL mapping reveals profound antagonistic pleiotropy, characterized by a hyper-activation of the HCAR1 lactate shuttle in the testis, explaining the evolutionary conservation of this metabolically catastrophic architecture. Ultimately, we reframe Schizophrenia not as an intrinsic neurological defect, but as an evolutionary "fuel mismatch." The high-performance cognitive architecture of the hominid brain, evolved for ancestral ketogenic environments, experiences a catastrophic thermodynamic crash when deprived of its requisite BHB coolant by modern, high-glycemic diets.
    DOI:  https://doi.org/10.64898/2026.06.26.734782
  28. An Acad Bras Cienc. 2026 ;pii: S0001-37652026000202602. [Epub ahead of print]98(2): e20251174
    Translational validity of rodent diet-induced obesity models for cognitive impairment in human metabolic disease.
    João M N Duarte.
      Type 2 diabetes and obesity, often modelled in rodents through high-fat diet interventions, are associated with altered brain energy metabolism and cognitive impairments. However, discrepancies between rodent high-fat diet models and human metabolic diseases challenge the translation of findings. This review provides a view on clinical and preclinical studies examining the effects of high-fat diet-induced metabolic dysfunction on brain function, focusing on the limitations of current rodent models, including diet composition, duration, and control diets. It is discussed how these factors influence brain metabolism and cognition, and highlight the need for standardized, longitudinal, and sex-inclusive studies. The present analysis underscores that while studies using high-fat diet-fed rodents provide valuable mechanistic insights, their metabolic profiles do not fully replicate human obesity and type 2 diabetes. These findings emphasize the importance of refining experimental models to better understand diet-induced brain dysfunction and to develop effective interventions.
    DOI:  https://doi.org/10.1590/0001-3765202620251174
  29. Commun Med (Lond). 2026 Jul 06.
    Brain aging in Type II GM1 gangliosidosis.
    Connor J Lewis, Selby I Chipman, Precilla D'Souza, Jean M Johnston, Muhammad H Yousef, William A Gahl, Cynthia J Tifft, Maria T Acosta.
       BACKGROUND: GM1 gangliosidosis is an inherited, progressive, and fatal neurodegenerative lysosomal storage disorder with no approved treatment. In this study, we present the first use of MRI-based predicted brain age in GM1 gangliosidosis aimed at assessing the neuronal degeneration in this cohort.
    METHODS: We calculated a predicted brain age and Brain Structures Age Gap Estimation (BSAGE) for 81 MRI scans from 41 Type II (26 juvenile and 15 late-infantile) GM1 gangliosidosis patients and 897 MRI scans from 556 neurotypical controls (NC) utilizing BrainStructuresAges, a machine learning MRI analysis pipeline.
    RESULTS: NC shows whole-brain aging at a rate of 0.83 per chronological year compared with 1.57 in juvenile GM1 patients and 12.25 in late-infantile GM1 patients. Accelerated and distinct brain aging is observed throughout midbrain structures, including the thalamus and caudate nucleus, hindbrain structures, including the cerebellum and brainstem, and the ventricles in juvenile and late-infantile GM1 patients compared to NC, reflecting neurodegeneration from disease progression. Cross-sectional evaluations of BSAGE for the whole brain show an average BSAGE = 35.50 years in the late-infantile cohort, 21.19 years in the juvenile cohort, and 0.03 years in NC. Predicted brain age and BSAGE both correlate with cross-sectional and longitudinal clinical outcome assessments.
    CONCLUSIONS: Predicted brain age accurately reflects the neurodegenerative clinical trajectories of the Type II GM1 disease subtypes. Correlations with clinical outcome assessments indicate evaluations of predicted brain aging may be an important candidate neuroimaging outcome measure for clinical trials in GM1 gangliosidosis.
    DOI:  https://doi.org/10.1038/s43856-026-01745-w
  30. Neurol Sci. 2026 Jul 04. pii: 612. [Epub ahead of print]47(8):
    Brain-muscle axis regulation of neuroinflammation and sarcopenia in Parkinson's disease: the bridging role of lactylation.
    WenXia Sun, Huiwen Huang, Xiyan Lan, An Yin, Qiong Deng, Yanbiao Zhong, MaoYuan Wang.
       BACKGROUND: Sarcopenia is a common and often overlooked nonmotor symptom of Parkinson's disease (PD), significantly increasing the risk of falls and exacerbating the disease burden. Increasing evidence suggests that PD is not merely a neurodegenerative disease confined to the central nervous system (CNS) but also involves significant systemic metabolic disturbances and peripheral tissue dysfunction, indicating a systemic pathological character. In recent years, epigenetic modifications have gradually become an important perspective for understanding the inflammatory progression of PD. Lactate is no longer simply considered the end product of glycolysis, but can regulate gene transcription and protein function through protein lactylation.
    OBJECTIVE: This paper systematically proposes that lactylation is a key molecular bridge between neuroinflammation and sarcopenia in PD.
    METHODS: We searched literature from the PubMed database from 2010 to 2026, screened qualified English articles, and integrated the latest research advances in neuroimmunology, skeletal muscle biology, and metabolic epigenetics.
    RESULTS: In PD, microglia epigenetic modifications and metabolic reprogramming lead to lactate accumulation, which may drive a persistent neuroinflammatory response through lactate modification. Simultaneously, chronic inflammation and metabolic abnormalities can propagate along the brain-muscle axis, promoting skeletal muscle protein metabolic imbalance and accelerating the development of sarcopenia. Based on this, this paper systematically proposes that lactylation is a key molecular bridge between neuroinflammation and sarcopenia in PD. Combining the latest research advances in neuroimmunology, skeletal muscle biology, and metabolic epigenetics, this paper elucidates the potential mechanisms by which abnormal lactate metabolism and lactylation play a role in altered glial cell inflammatory phenotypes and skeletal muscle homeostasis imbalances. Furthermore, in conjunction with exercise intervention studies, this paper explores how lactylation, as a key regulatory molecule, can achieve bidirectional improvement in CNS inflammation and peripheral muscle function, providing a new theoretical basis for systemic intervention strategies for PD.
    Keywords:  Lactate; Lactylation; Neuroinflammation; Parkinson’s disease; Sarcopenia
    DOI:  https://doi.org/10.1007/s10072-026-09199-7
  31. Alzheimers Dement. 2026 Jul;22(7): e71666
    Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery.
    Yuto Hasegawa, Hiroki Kawai, Robyn Wiseman, Gianluca Ursini, Hannah Alton, Feiyi Xiong, Sohan Gummadi, Naomi Mao, Kyle Mailhot, Yannan Li, Xiaolei Zhu, Tomoyo Sawada, Barbara Slusher, Atsushi Kamiya.
       INTRODUCTION: Perioperative neurocognitive disorder is a common and debilitating complication in the elderly, yet its cellular and molecular mechanisms in the aging brain remain poorly understood.
    METHODS: Using aged mice, we examined the impact of abdominal surgery on cognition, glymphatic activity, and astrocyte function. Sex-dependent mechanisms were investigated by integrating single-cell RNA sequencing with astrocyte-specific genetic and pharmacological manipulation.
    RESULTS: Abdominal surgery induced male-specific deficits in recognition and spatial memory, reduced hippocampal glymphatic influx, and glutamate accumulation in aged mice. These changes were associated with male-specific upregulation of glutamate signaling in a distinct astrocyte subpopulation, enhanced astrocytic glutamate carboxypeptidase II (GCPII) activity, and loss of aquaporin-4 (AQP4) polarization. Astrocyte-specific GCPII knockdown rescued cognitive deficits and hippocampal glymphatic influx, consistent with pharmacological GCPII inhibition ameliorating glutamate levels, AQP4 polarization, and cognitive performance.
    DISCUSSION: These findings identify astrocytic GCPII-mediated glutamate dysregulation as a mechanism contributing to sex-specific postoperative cognitive vulnerability in aging.
    Keywords:  aging; astrocytes; glutamate carboxypeptidase II; glymphatic system; perioperative neurocognitive disorder; sex differences
    DOI:  https://doi.org/10.1002/alz.71666
  32. Front Immunol. 2026 ;17 1837643
    Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.
    Hui Guo, Ziyu Yang, Long Cheng.
      Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.
    Keywords:  cholinergic signaling; immunometabolism; microglia; neuroinflammation; vagus nerve stimulation
    DOI:  https://doi.org/10.3389/fimmu.2026.1837643
  33. Free Radic Biol Med. 2026 Jul 07. pii: S0891-5849(26)00931-7. [Epub ahead of print]
    Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
    Xiangna Guo, Huiyi Jiang, Yitian Lu, Yixin Lin, Junwei Liu, Zaisheng Qin, Tao Tao.
      Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondria damage in neurons subjected to oxygen-glucose deprivation /reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.
    Keywords:  Cerebral ishemia-reperfusion injury; FUNDC1; LONP1; VDAC1; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.010
  34. bioRxiv. 2026 Jun 29. pii: 2026.06.26.734839. [Epub ahead of print]
    Selective knockout of PKA regulatory subunits reveal opposite catalytic and metabolic consequences with implications for Alzheimer's disease.
    Leigh-Ana M Rossitto, Tsanwen Lu, Yuliang Ma, Pallavi Kaila Sharma, Valeria Burghi, Carlos C Gonzalez, Jessica Bruystens, Svetlana Maurya, Jian Wu, Alexis Lona, Irina Kufareva, J Silvio Gutkind, David J Gonzalez, Xu Chen, Susan S Taylor.
      cAMP-dependent Protein Kinase A (PKA) is a master regulator of cell signaling involved in energy metabolism, synaptic plasticity, and stress response. Dysregulated PKA signaling is implicated in diseases including neurodegeneration and cancer. PKA catalytic activity is regulated by two nonredundant regulatory subunits, Type I (RIα/RIβ) and Type II (RIIα/RIIβ), whose divergent functions are not fully understood. We generated double-knockout (KO) cell lines of RIα/RIβ and RIIα/RIIβ subunits and performed multiplexed MS-based proteomic and phosphoproteomic profiling under basal and glucose-perturbed conditions. We found that RI and RII loss drives distinct, and often opposite, remodeling of the cellular proteome and phosphoproteome. While both mutants blunted metabolic flexibility to glycolytic stressors and stimuli, RI and RII KO cells exhibited elevated and depressed glycolytic signaling, respectively. Interestingly, RI KO increased the abundance and kinase activity of the PKA catalytic subunit Cα isoform, leading to an increase in PKA substrate phosphorylation, whereas RII KO decreased the abundance, kinase activity, and substrate phosphorylation by the catalytic subunit Cβ isoform. Notably, one of the most differentially affected PKA sites between RI and RII KOs maps to Tau, whose hyperphosphorylation is a hallmark of Alzheimer's disease. Loss of RI increased Tau phosphorylation, which was not only caused by increased PKA catalytic activity, but also a higher binding affinity of Tau to RII subunits on the negatively-charged flexible linker region. Overall, the present study demonstrates that PKA RI and RII subunits play nonredundant roles in modulating PKA activity, metabolic flexibility, and phospho-regulation of key disease-associated substrates such as Tau.
    DOI:  https://doi.org/10.64898/2026.06.26.734839
  35. Ageing Res Rev. 2026 Jul 07. pii: S1568-1637(26)00237-0. [Epub ahead of print]121 103245
    Brain health across the lifespan and the impact of nutrition, exercise, microbiota, and sleep.
    Andrew C Shin, Zobayda F Haque, Shannon Galyean, Marleigh Hefner, Mina Esmaeili, J Josh Lawrence, Bruce A Watkins.
      Dietary strategies that support long-term cognitive health and resilience against neurodegenerative diseases are important with aging and senescence. Brain aging is a consequence of intricate biological changes that occur over the lifespan. The process of aging involves the decline in metabolic and physiologic functions, and changes in anatomical structure. However, our lifestyle practices, including diets and nutrient intakes, physical exercise, sleep quality, and cognitive activity can help to minimize the aging effects on the brain. Furthermore, neurodegenerative diseases often have detrimental effects on brain neurons, that show gradual damage leading to compromised cognitive function and impaired body movement. Our review describes the biochemical and physiological changes in brain with advancing age. We introduce several aspects of nutrients (lipids, glucose, vitamins, and protein), dietary factors (flavonoids), and diet practices that afford benefits to reduce the effects of aging on the brain. In addition, many aspects of metabolic dysregulation of macronutrients are described in brain aging. Vital to the lifestyle factors that improve brain health and reduce or delay the negative effects on brain aging are physical exercise and sleep. The importance of brain-derived neurotrophic factors, exerkines, and endocannabinoids are described. Herein is a concise overview of the aging brain, role of nutrition in brain health, importance of nutrition in aging and senescence of the brain, and the systemic actions of physical exercise on brain plasticity and health. Original research with models, clinical studies, and landmark reviews on the topic are cited in our novel and comprehensive approach to nutrition the aging brain.
    Keywords:  Aging; Brain; Diet; Health; Neurodegenerative disease; Physical exercise; Plasticity
    DOI:  https://doi.org/10.1016/j.arr.2026.103245
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