bims-medebr 2026-04-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–04–26
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

A Flawed Conjecture Keeps Haunting Brain Energy Metabolism Research.
Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.
Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.
Repeatability of Metabolic Imaging With Hyperpolarized Pyruvate: Back-to-Back Neuroimaging and Blood Analysis.
Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.
A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations.
Comparative analysis of milk and brain fatty acids reveals human-specific signatures in brain development.
Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.
From metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.
Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.
Lactylation at the crossroads of metabolism and epigenetics in neuroinflammation.
Lipidomics Reveals Circulating Lipid Biomarkers for Retinopathy of Prematurity in Preterm Infants.
A multi-tiered workflow for examining organic acid profiles delineates tissue-specific changes in fatty acyl partitioning during aging.
Microglial cholesterol reprogramming drives cognitive impairment under hypobaric hypoxia.
Spectrolipidomics of glial cell lines: A deuterated probe for semiquantitative monitoring of cannabidiol-induced cholesterol modulation.
mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.
Lactate and lactylation in neuropsychiatric disorders: a comprehensive review.
Region-specific proteomic profiling of brain interstitial fluid via a micro-invasive sampling platform.
Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.
Prebiotics/synbiotics as natural alternatives for brain development and aging - focus on nutrigenomic and direct effects: a systematic review.

NeuroSci. 2026 Apr 22. pii: 49. [Epub ahead of print]7(3):

A Flawed Conjecture Keeps Haunting Brain Energy Metabolism Research.

Avital Schurr.

  In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as "aerobic glycolysis". Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, "The Astrocyte Neuron Lactate Shuttle Hypothesis" and "The Efficiency Tradeoff Hypothesis," respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate.

Keywords:  TCA cycle; active brain; energy metabolism; glucose; glycolysis; lactate; oxidative phosphorylation; pyruvate

DOI:  https://doi.org/10.3390/neurosci7030049
Adv Clin Exp Med. 2026 Apr 21.

Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.

Dorota Wesół-Kucharska, Magdalena Alicja Kaczor, Ewa Ehmke Vel Emczyńska-Seliga.

   BACKGROUND: The ketogenic diet (KD) is an established therapeutic option for epilepsy and selected inborn errors of metabolism (IEMs), particularly glucose transporter type 1 deficiency (GLUT1D) and pyruvate dehydrogenase complex deficiency (PDCD). Increasing evidence suggests broader applications of KD in pediatric metabolic disorders; however, data on its safety and efficacy in heterogeneous IEM populations remain limited.
OBJECTIVES: To evaluate the efficacy, clinical benefits, and adverse effects (AEs) of KD in pediatric patients with various IEMs.
MATERIAL AND METHODS: A retrospective analysis was conducted in pediatric patients with IEMs receiving KD treatment. Patients were categorized into 3 groups: 1) other IEMs (n = 7), 2) mitochondrial diseases (MD) (n = 17), and 3) GLUT1D and PDCD (n = 20). The median age at initiation of KD was 37, 53, and 53 months, respectively, and the median duration of KD treatment was 5, 11, and 55 months in groups 1, 2, and 3.
RESULTS: The KD was associated with clinical benefits in 84% of patients. Among children with epilepsy (n = 23), a seizure reduction of >50% was observed in 73.9% of patients, including complete seizure freedom in 4 individuals. Improvements were also noted in muscle tone (27.6%), exercise tolerance (51.2%), ataxia (83.3%), and involuntary movements (60%). Lactate levels decreased in 84.6% of patients with mitochondrial disease and in all patients with PDCD. The KD was discontinued in 12 patients due to insufficient efficacy (n = 5) or AEs (AEs; n = 7). The most common AEs included gastrointestinal (GI) symptoms, dyslipidemia, hyperuricemia, metabolic acidosis, and decreased free carnitine; most were transient. No significant association was found between median β-hydroxybutyrate (BHB) levels and clinical outcomes.
CONCLUSIONS: The KD is an effective and generally well-tolerated therapeutic option in pediatric IEMs, with benefits extending beyond seizure control. Adverse effects are typically manageable, although GI intolerance may limit long-term use. Ketogenic diet should be considered not only for refractory epilepsy but also for selected metabolic indications.

Keywords:  epilepsy; inborn errors of metabolism; ketogenic diet; mitochondrial diseases; pediatric metabolic disorders

DOI:  https://doi.org/10.17219/acem/219994
Eur J Histochem. 2026 Apr 20. 70(2):

Ketogenic diet regulates Uch-L1(C) to improve cerebral energy metabolism and cognitive function in Alzheimer's disease mice.

Nana Bao, Min Zhang, Ming Tang, Ziyi Shen, Shenglin Wang, Guohui Jiang.

  The ketogenic diet (KD), a high-fat, low-carbohydrate diet, can effectively regulate energy metabolism in the brain. The regulation of cerebral energy metabolism in patients with Alzheimer's disease (AD) has attracted the attention of researchers. Recent studies have shown that ubiquitin carboxyl terminal hydrolase L1 (Uch-L1) deficiency leads to neurodegeneration by increasing energy demand and endoplasmic reticulum stress. However, the effect of Uch-L1 on AD remains to be explored. This study first combined Uch-L1 with cerebral energy metabolism to explore its role in long-term KD in AD. We found that AD mice with long-term KD showed better spatial recognition and working memory. KD promoted Uch-L1(C) and Mfn2 expression by inhibiting oxidative stress in the hippocampus of mice, improved mitochondrial function, increased ATP content, and significantly reduced neuronal apoptosis. In conclusion, KD can increase Uch-L1(C) and Mfn2 expression in the brain, and improve cerebral energy metabolism and cognitive function in AD mice.

Keywords:  Alzheimer's disease; Ketogenic diet; Uch-L1; cognition; energy metabolism; oxidative stress

DOI:  https://doi.org/10.4081/ejh.2026.4548
Magn Reson Med. 2026 Apr 23.

Repeatability of Metabolic Imaging With Hyperpolarized Pyruvate: Back-to-Back Neuroimaging and Blood Analysis.

Jun Chen, Sung-Han Lin, Jessica Sudderth, Kelley A Derner, Crystal E Harrison, Maheen Zaidi, Jeannie D Baxter, Jeff Liticker, Zohreh Erfani, Craig R Malloy, Marco C Pinho, Ralph J DeBerardinis, Jae Mo Park.

   PURPOSE: 13C MRI with hyperpolarized [1-13C]pyruvate enables noninvasive imaging of metabolic pathways. Considering the high dose of pyruvate used in hyperpolarized 13C-pyruvate studies, circulating 13C-pyruvate and the resulting 13C-lactate in plasma may influence subsequent pyruvate metabolism, yet the guidance on consecutive injections does not exist. This study is to characterize blood pyruvate and lactate dynamics following [1-13C]pyruvate injection and to evaluate the repeatability of 13C neuroimaging with consecutive pyruvate injections.
METHODS: Sixteen healthy adults (mean age, 39.0 ± 15.9 years; 8 men) underwent blood sampling or MRI. Eight participants received bolus injections of non-hyperpolarized [1-13C]pyruvate following both overnight fasting and postprandial states. Blood samples were collected at baseline and up to 60 min post-injection to quantify pyruvate and lactate concentrations and 13C fractional enrichments using mass spectrometry. In parallel, eight participants underwent 13C/1H MRI that included two injections of hyperpolarized [1-13C]pyruvate with intervals of 6-55 min for time-resolved measurement of 13C-pyruvate and 13C-lactate in the brain.
RESULTS: Plasma 13C-pyruvate peaked within 30 s and returned to baseline within 5-10 min, while 13C-lactate peaked at 2-3 min. Lactate 13C enrichment was higher in fasting versus fed states, and total lactate concentration in blood was unchanged by pyruvate injection. Brain 13C-lactate/pyruvate showed excellent repeatability (ICC = 0.9842), with all points within the 95% Bland-Altman limits. Voxel-wise Pearson's correlation between injections was 0.72 ± 0.22 and within-subject coefficient of variation was 17.6% ± 4.6%.
CONCLUSION: Consecutive injections of hyperpolarized [1-13C]pyruvate yield repeatable blood and brain metabolic measurements in humans, supporting multi-injection protocols in 13C MRI studies.

Keywords:  hyperpolarized pyruvate; lactate clearance; neuroimaging; repeatability

DOI:  https://doi.org/10.1002/mrm.70402
medRxiv. 2026 Apr 08. pii: 2026.04.07.26350339. [Epub ahead of print]

Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.

Adam C Raikes, Melissa Garza, Angela N Murrell, Roberta Diaz Brinton.

Importance: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A 2 ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A 2 ND glucose dysregulation spatial signature remains undescribed.
Objective: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A 2 ND.
Data Sources: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).
Study Selection: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.
Data Extraction and Synthesis: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.
Main Outcomes and Measures: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.
Results: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A 2 ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A 2 ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A 2 ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.
Conclusions and Relevance: These data demonstrate dysregulated glucose metabolism as a common A 2 ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A 2 ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.

DOI: https://doi.org/10.64898/2026.04.07.26350339
J Neurochem. 2026 Apr;170(4): e70428

A Comprehensive Characterization of the Phospholipid and Cholesterol Composition of the Uncinate Fasciculus in the Human Brain: Evidence of Age-Related Alterations.

Kelly Perlman, Chuck T Chen, Mackenzie E Smith, John Kim, Gustavo Turecki, Richard P Bazinet, Naguib Mechawar.

  The uncinate fasciculus (UF) is a long-range association fiber tract connecting the anterior temporal lobe with the orbitofrontal cortex and has been linked to a multitude of physiological and pathophysiological conditions such as aging, epilepsy, and the vulnerability to psychopathology posed by a history of childhood abuse (CA). Since the myelin sheath is highly enriched in lipids, changes in white matter (WM) microstructure observed via neuroimaging may reflect alterations in the myelin lipid profile. Given that the UF does not exist in rodents, its molecular properties are highly understudied. Therefore, we sought to quantify the phospholipid FA and cholesterol quantities of the human postmortem UF and evaluate any lipid-related or myelin-constituent gene/protein changes associated with age and history of CA. UF samples were analyzed from individuals with depression who died by suicide with (DS-CA) or without (DS) severe CA, and control individuals (CTRL), with an age span of 15 to 85 years. Phospholipids were separated by thin-layer chromatography; FAs and nonderivatized cholesterol were quantified by gas chromatography-flame ionization detection. The relative expression of myelin-constituent genes and proteins was measured by RT-qPCR and immunoblotting, respectively. We found no robust relationships between CA or depression and lipid measures or myelin-constituent gene/protein levels. In contrast, phospholipids showed pronounced age effects that differed by fraction, with an overall trend of monounsaturated FAs increasing and long-chain omega-6 polyunsaturated FAs decreasing with age. The expression of most myelin-constituent genes and proteins declined with age; PLP1 and MAG showed significant decreases. Therefore, changes in lipid composition and lipid-protein interactions likely contribute to age-related myelin deficits and may in part underlie age-associated cognitive decline.

Keywords:  aging; brain; childhood maltreatment; cholesterol; depression; fatty acid; phospholipid; postmortem; uncinate fasciculus; white matter

DOI:  https://doi.org/10.1111/jnc.70428
Commun Biol. 2026 Apr 22.

Comparative analysis of milk and brain fatty acids reveals human-specific signatures in brain development.

Aleksandra Mitina, Yunmei Wang, Waltraud Mair, Anna Vanyushkina, Nickolay Anikanov, Olga Efimova, Song Guo, Pavel Mazin, Philipp Khaitovich.

Lipids constitute the majority of brain dry weight and play essential structural and signaling roles. During early life, their supply depends largely on breast milk, yet how milk composition aligns with brain fatty acids (FA) across species has not been systematically explored. We analyzed 837 milk samples from seven mammalian species and 194 brain samples from five species using LC-MS. We identified 81 FA in milk and 33 in brain, with 31 shared across both tissues. FA composition in milk and brain was strongly correlated, particularly in humans and macaques, with the strongest associations observed in the prefrontal cortex and during the first four weeks postpartum. Humans were uniquely enriched in very- and ultra-long-chain unsaturated FAs (≥24 carbons) in both milk and brain, suggesting a role in species-specific neurodevelopment. Infant formula clustered closer to bovids than to human milk, underscoring compositional differences of potential nutritional relevance. These findings reveal conserved and human-specific features of milk and brain FAs, highlight the importance of early milk supply for neurodevelopment, and provide evolutionary and translational insights into infant nutrition.

DOI: https://doi.org/10.1038/s42003-025-09401-0
Neuroprotection. 2026 Mar;4(1): 30-47

Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.

Jun Han Kuan, Roshan S Raghavan, Dawn Li Wei Koh, Wing Yeng Tan, Igor Iezhitsa, Renu Agarwal.

  Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.

Keywords:  Alzheimer's disease; Huntington's disease; Parkinson's disease; cholesterol/metabolism; hydroxymethylglutaryl‐CoA reductase inhibitors; multiple sclerosis; neurodegenerative diseases; neuroinflammation; neuroprotection; oxidative stress

DOI:  https://doi.org/10.1002/nep3.70026
Front Mol Neurosci. 2026 ;19 1779468

From metabolic substrate to epigenetic regulation: roles and mechanisms of lactylation in brain health and disease.

Wei Chen, Ruobing Li, Jinlong Zhang, Jun Lei, Xicheng Jiang, Xiaowei Sun.

  Lactate, traditionally regarded as a metabolic byproduct of glycolysis, is now recognized as a critical signaling molecule in the central nervous system. Emerging evidence indicates that lactate participates in a dynamic metabolic-epigenetic regulatory network through protein lactylation, a post-translational modification capable of modulating chromatin structure and gene transcription. We summarize the physiological roles of lactate in neuronal-glial metabolic coupling and highlight cell-type-specific functions of the lactate-lactylation axis under both normal and pathological conditions. Particular emphasis is placed on its involvement in ischemic stroke, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Available findings indicate that this axis is integral to synaptic plasticity, neuroinflammatory balance, and metabolic homeostasis. Under pathological conditions, excessive lactate accumulation promotes aberrant lactylation patterns that may drive persistent inflammation, metabolic reprogramming, and neuronal dysfunction by reshaping chromatin accessibility and transcriptional landscapes. Collectively, the lactate-lactylation axis represents a unifying mechanistic framework linking metabolic flux to epigenetic regulation in neurological disorders and may serve as a promising source of diagnostic biomarkers and precision therapeutic targets.

Keywords:  epigenetic regulation; lactate; lactate metabolism; neurological disorders; protein lactylation

DOI:  https://doi.org/10.3389/fnmol.2026.1779468
Front Nutr. 2026 ;13 1748196

Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.

Katharina Fleig, Leoni Haslinger, Christine Dawczynski, Iris-Tatjana Kolassa.

  Nutritional psychiatry is an emerging field. Micro- and macro-nutrients play a role in energy metabolism and the regulation of inflammation; particularly, an insufficient dietary intake of omega-3 fatty acids and an imbalanced intake of omega-6/omega-3 fatty acids, with a shift toward increased inflammation, are of relevance for the pathophysiology of mental disorders. This review summarizes evidence on the role of omega-3 fatty acids in the pathophysiology of mental disorders (schizophrenia, affective and anxiety disorders, post-traumatic stress disorder, and eating disorders), neurodevelopmental disorders (attention-deficit/hyperactivity disorder and autism spectrum disorder) and neurodegenerative disorders (Alzheimer's disease) and explores potential treatment implications. In addition, the underlying neurobiological mechanisms through which omega-3 fatty acids might exert a protective effect are also discussed. Despite methodological variability and heterogeneous results, an increasing body of evidence suggests that omega-3 deficiency and altered fatty acid profiles are modifiable risk factors and potential biomarkers for mental disorders. The integration of omega-3 supplementation as an adjuvant to state-of-the-art therapy offers the potential for a low-risk intervention with meaningful clinical outcomes. However, clinical monitoring is recommended to avoid adverse effects and to adjust the dosage according to individual and disease-specific factors.

Keywords:  docosahexaenoic acid; eicosapentaenoic acid; fatty acid profile; mental disorders; nutritional psychiatry; omega-3 fatty acids; omega-6/omega-3 ratio

DOI:  https://doi.org/10.3389/fnut.2026.1748196
Front Immunol. 2026 ;17 1784112

Lactylation at the crossroads of metabolism and epigenetics in neuroinflammation.

Haoyue Wang, Kangmei Shao, Ran Zhou, Jiajia Xi, Wenjing Zhang, Yazhen Hao, Jingjing Song, Zhaoming Ge.

  Lactate has moved from being viewed as an inert glycolytic end-product to a pleiotropic metabolite that shapes cellular signaling and gene regulation. A major inflection point is the identification of lysine lactylation (Kla), a post-translational modification that can couple glycolytic state to chromatin remodeling and protein function. In the central nervous system, lactate production, compartmentalization, and transport-coordinated by cell-type-specific expression of lactate dehydrogenases and monocarboxylate transporters within the neurovascular unit-create dynamic microenvironments that are increasingly recognized as determinants of neuroinflammatory tone. Emerging evidence indicates that Kla occurs on both histone and non-histone substrates and can reprogram inflammatory and stress-response networks in microglia, astrocytes, endothelial cells, and neurons, intersecting with canonical pathways such as NF-κB, inflammasome signaling, and cytokine-driven transcriptional programs. However, the field faces key mechanistic and translational gaps, including incomplete definition of Kla "writers/erasers/readers," uncertainty about the quantitative relationship between lactate flux and site-specific lactylation, and marked context dependence across disease stage, cell state, and brain region. This review integrates current understanding of CNS lactate metabolism and trafficking with the expanding landscape of Kla biology, synthesizes cell- and disease-specific evidence across acute injury and neurodegeneration, and outlines priorities for causal mapping, biomarker development, and time-windowed, cell-targeted therapeutic strategies that attenuate maladaptive inflammation without compromising repair.

Keywords:  epigenetic regulation; ischemic stroke; lactylation; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1784112
Ophthalmol Sci. 2026 May;6(5): 101125

Lipidomics Reveals Circulating Lipid Biomarkers for Retinopathy of Prematurity in Preterm Infants.

Kajetan Trošt, Qian Gao, Jasmin Pernille Hjerresen, Porntiva Poorisrisak, Mia Ortved Bjerager, Anna Carolina Hvelplund, Brian Rafn Hjelvang, Kristian Vestergaard Jensen, Ivan Brandslund, Gorm Greisen, Thomas Moritz, Carina Slidsborg.

   Objective: Retinopathy of prematurity (ROP) is a multifactorial eye disease affecting children born premature and is a leading cause of blindness in preterm infants worldwide. Although it has primarily been associated with high oxygen supplementation from respiratory support, there are indications that additional metabolic factors, like circulating lipids, may play a role in the disease's pathophysiology.
Design: An exploratory study on the development of ROP in preterm infants was conducted in Denmark during 2018 and 2019. Infants who developed a maximum of stage 1 ROP were classified as having mild retinopathy, whereas those who developed stage 2 or 3 were classified as having severe retinopathy.
Participants: The study involved 110 preterm infants born before 32 weeks of gestational age.
Methods: During hospitalization in the neonatal wards, the infants were screened for ROP, and blood samples were collected every 2 weeks. A total of 485 lipid species were analyzed using lipidomics methodology, and mixed linear models were applied.
Main Outcome Measures: The association of lipids in early life (postnatal weeks 3-4) and their change throughout the study period was investigated.
Results: All lipid classes, involving 310 lipid species, changed significantly during the neonatal period. In early postnatal life, the lipid profiles of some classes (especially phosphatidylcholines and ether-linked phosphatidylcholines) were associated with the severity of ROP. In infants with stage 2 or 3 ROP, glycerophospholipids and sphingolipids changed more slowly compared with infants with no ROP. Similarly, glycerophospholipid pathways were enriched in infants with ROP.
Conclusions: The lipidomic plasma profile in preterm infants shows significant change across the neonatal period, involving all lipid classes. The association with ROP suggests that lipid metabolism may also play a role in ROP pathogenesis. Dyslipidemia associated with ROP should be addressed in further studies.
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Keywords:  Blood biomarkers; Lipidomics; Metabolism; Preterm; ROP

DOI:  https://doi.org/10.1016/j.xops.2026.101125
Cell Rep Methods. 2026 Apr 21. pii: S2667-2375(26)00113-X. [Epub ahead of print] 101413

A multi-tiered workflow for examining organic acid profiles delineates tissue-specific changes in fatty acyl partitioning during aging.

Zhiyang Zhou, Chenyin Cao, Taochao Lu, Yuyuan Ruan, Bowen Li, Mingjun Cao, Luyue Mo, Guanghou Shui, Sin Man Lam.

  Fatty acids (FAs), as the predominant organic acids, form a major component of the metabolome. We present a multi-tiered method that comprehensively captures FA diversity-including chain lengths (C2-C34), unsaturation, isomers, and endogenous forms-within a single biological specimen. This workflow quantifies the broadest range of free FAs reported to date. Integrated with two complementary tiers profiling the total FA pool from alkaline hydrolysis and esterified acyl compositions across lipid classes, our multi-tiered workflow enables the investigation of differential fatty acyl partitioning. Applying this platform to quantify >540 unique lipids (free and esterified forms) and polar carboxylic acids, we investigated FA remodeling in the brain, retina (eyeball), and skeletal muscles of young and aged mice. We found that aged glycolytic tissues preferentially partition odd-chain and diunsaturated FAs (with lower β-oxidizability) into triacylglycerols. Additionally, aging shifts the FA18:1 partitioning into diacylglycerols over anionic phospholipids, which may mitigate pro-aging lipid signatures in the skeletal muscle.

Keywords:  CP: metabolism; LCFA; SCFA; VLCFA; aging; brain aging; fatty acids; lipidomics; organic acids; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.crmeth.2026.101413
J Neuroinflammation. 2026 Apr 23.

Microglial cholesterol reprogramming drives cognitive impairment under hypobaric hypoxia.

Sitong Cao, Wenyu Ni, Yujie Fang, Qianqian Luo, Li Zhu, Zhangji Dong, Xueting Wang.



Keywords:  Cholesterol reprogramming; HSP90; High-altitude cognitive impairment; Lipid droplets; Microglia; NRF1; Neuroinflammation; SREBP2; Synaptic pruning

DOI:  https://doi.org/10.1186/s12974-026-03830-2
Spectrochim Acta A Mol Biomol Spectrosc. 2026 Apr 19. pii: S1386-1425(26)00518-4. [Epub ahead of print]359 127947

Spectrolipidomics of glial cell lines: A deuterated probe for semiquantitative monitoring of cannabidiol-induced cholesterol modulation.

Karolina Chrabąszcz, Tycjan Kossowski-Kołodziej, Agnieszka Panek, Katarzyna Pogoda.

  Understanding lipid metabolism in peripheral glial cells is crucial for elucidating the molecular mechanisms underlying neurodegeneration, cancerogenesis and therapy resistance. Here, we introduce a spectrolipidomic sensing approach that integrates Raman, FT-IR, and AFM-IR spectroscopy to monitor nanoscale cholesterol remodeling in glial cells exposed to cannabidiol (CBD). Deuterated cholesterol (dChol) was employed as an intrinsic, spectroscopically active molecular probe, enabling selective tracking of cholesterol transformations through characteristic CD vibrational signatures within the 2300-2000 cm-1 silent spectral region. Multimodal vibrational spectroscopy provided label-free, spatially resolved insight into lipid organization, redistribution, and metabolic reprogramming across micro- and nanoscales. The dChol probe enabled semiquantitative evaluation of cholesterol uptake, esterification, and membrane integration, revealing that the sequence of CBD exposure, before or after probe addition, triggers distinct lipid metabolic pathways. Raman spectroscopy demonstrated superior sensitivity, with reliable detection of intracellular dChol at concentrations as low as 10 μM, outperforming FT-IR imaging and confirming its suitability for cell lipid sensing. This analytical platform establishes deuterium-labeled lipids as powerful vibrational sensors for probing lipid metabolism and CBD-induced remodeling in situ. The presented spectrolipidomic framework paves the way for next-generation, spectroscopy-based biosensing systems capable of visualizing lipid dynamics, membrane restructuring, and drug-lipid interactions under pharmacological or environmental stress conditions.

Keywords:  Biosensing; Cannabidiol; Cholesterol metabolism; Nanospectroscopy; Raman imaging; Spectrolipidomics

DOI:  https://doi.org/10.1016/j.saa.2026.127947
Exp Neurol. 2026 Apr 16. pii: S0014-4886(26)00151-2. [Epub ahead of print]402 115787

mtHsp70 overexpression enhances neuroprotection through ATF5-dependent UPRmt signaling after traumatic brain injury.

Yuanqing Zhang, Yi Jin, Runze Han, Yucheng Shen, Zongqi Wang, Xiaoou Sun, Jiangang Liu.

  Traumatic brain injury (TBI) induces secondary neuronal damage, in which mitochondrial dysfunction plays a central role. Mitochondrial heat shock protein 70 (mtHsp70) is a key mitochondrial chaperone involved in protein folding and proteostasis, yet its role in TBI pathology remains unclear. In the present study, we investigated the neuroprotective function of mtHsp70 and its underlying mechanisms using a controlled cortical impact (CCI) mouse model. We found that CCI selectively reduced mtHsp70 levels within mitochondria, accompanied by its cytoplasmic accumulation, while total cellular mtHsp70 expression remained unchanged. Stereotactic AAV-mediated overexpression of mtHsp70 in the cortex significantly reduced neuronal apoptosis, improved motor and cognitive behavioral outcomes, and increased neuronal survival following CCI. In vitro, mtHsp70 overexpression in HT22 cells attenuated H₂O₂-induced neuronal injury, improved mitochondrial respiration (OCR), and reduced mitochondrial protein aggregation. Mechanistically, mtHsp70 overexpression increased the expression of mitochondrial unfolded protein response (UPRmt)-related proteins, including HSP60 and Lonp1, and restored mitochondrial membrane potential. Importantly, ATF5 knockdown attenuated mtHsp70-induced upregulation of UPRmt-associated proteins and diminished mitochondrial respiratory improvement, suggesting that mtHsp70-mediated protection is dependent on ATF5-associated UPRmt signaling. Together, these findings indicate that mitochondrial mtHsp70 deficiency contributes to neuronal injury after CCI, whereas restoration of mtHsp70 improves mitochondrial proteostasis and neuronal survival. Targeting the mtHsp70-UPRmt pathway may represent a potential therapeutic strategy for TBI.

Keywords:  DNAJA3; Mitochondrial proteostasis; Mitochondrial unfolded protein response; Neuroprotection; Traumatic brain injury; mtHsp70

DOI:  https://doi.org/10.1016/j.expneurol.2026.115787
Mol Biol Rep. 2026 Apr 21. pii: 639. [Epub ahead of print]53(1):

Lactate and lactylation in neuropsychiatric disorders: a comprehensive review.

Zhenzhen Wu, Yongjun Chen, Yucen Xia.



Keywords:  Energy metabolism; Lactate; Lactylation; Neuropsychiatric disorders

DOI:  https://doi.org/10.1007/s11033-026-11814-x
Lab Chip. 2026 Apr 21.

Region-specific proteomic profiling of brain interstitial fluid via a micro-invasive sampling platform.

Qun Cao, Hannah D Jackson, Aidan J Duncan, Yufei Cui, Haley O Higginbotham, Stella Lesnik, Yunseo Jo, Jiaquan Yu, Forest M White, Michael J Cima.

Interstitial fluid (ISF) within the brain parenchyma contains secreted factors related to brain function, metabolism, and neurodegenerative disorders. Cerebrospinal fluid (CSF) is commonly sampled due to its accessibility in well-defined spaces, but it does not fully capture the diversity of the brain secreted proteome. The brain is remarkably heterogeneous on a millimeter scale or smaller, and the secreted proteome likely reflects that heterogeneity. Traditional methods like cerebral microdialysis suffer from recovery loss and tissue damage due to semipermeable membranes and large probe sizes. This study develops a micro-invasive, membrane-free platform for ISF sampling, enabling mass spectrometry analysis of small sample volumes with high spatial resolution and minimal tissue damage. Also, this platform collects samples within approximately 15 minutes, representing a major reduction in sampling time compared to microdialysis. We analyzed proteomic profiles of ISF from the nucleus accumbens and substantia nigra, revealing significant differences in protein abundance and composition indicative of their biological functions. We also compared ISF with CSF and found significantly more proteins associated with brain-specific functions, such as synaptic transmission and vesicle-mediated transport. This novel ISF sampling method can enhance clinical liquid biopsy techniques for brain diseases and provides insights into distinct molecular profiles of different brain regions.

DOI: https://doi.org/10.1039/d6lc00038j
Nat Commun. 2026 Apr 18. pii: 3589. [Epub ahead of print]17(1):

Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.

Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari, Ulas Isildak, Pol Alonso-Pernas, Isabela Santos Valentim, Fengting Su, Lilia Espada, Melike Bayar, Li Fu, Andreas Koeberle, Handan Melike Dönertaş, Maria A Ermolaeva.

Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.

DOI: https://doi.org/10.1038/s41467-026-71508-7
Nat Commun. 2026 Apr 21.

GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.

Jigyasha Timsina, Chenyang Jiang, Daniel L McCartney, Feifei Tao, Maria Carolina Dalmasso, Jenna Najar, Federica Anastasi, Olena Ohlei, Raquel Puerta Fuentes, Chenyu Yang, Joseph Bradley, Daniel Western, Muhammad Ali, Ciyang Wang, Chengran Yang, Ying Wu, Menghan Liu, John Budde, Julie Williams, Rebecca Mahoney, Atahualpa Castillo Morales, Timothy J Hohman, Logan Dumitrescu, Ting-Chen Wang, Niccolo' Tesi, Silke Kern, Margda Waern, Ingmar Skoog, Argonde van Harten, Yolande A L Pijnenburg, Wiesje M van der Flier, Pascual Sánchez-Juan, Eloy Rodriguez-Rodriguez, Luca Kleineidam, Oliver Peters, Anja Schneider, Fahri Küçükali, Céline Bellenguez, Benjamin Grenier-Boley, Sami Heikkinen, Itziar de Rojas, Dan Rujescu, Norbert Scherbaum, Lucrezia Hausner, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Rik Vandenberghe, Sebastiaan Engelborghs, Stefanie Heilmann-Heimbach, Matthias Schmid, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Raquel Sánchez-Valle, Victoria Álvarez, Pablo García-González, Pablo Mir, Luis M Real, Gerard Piñol-Ripoll, Jose María García-Alberca, Harro Seelaar, Inez Ramakers, Janne Papma, Marc Hulsman, Christoph Laske, Stefan Teipel, Josef Priller, Robert Perneczky, Katharina Buerger, Markus M Nöthen, Piotr Lewczuk, Johannes Kornhuber, Harald Hampel, Ina Giegling, Oliver Goldhardt, Janine Diehl-Schmid, Victor Andrade, Michael Mt Heneka, Lutz Frölich, Jonathan Vogelgsang, Caroline Graff, Hakan Thonberg, Abbe Ullgren, Goran Papenberg, Jean-François Deleuze, Carole Dufouil, Michael Wagner, Frank Jessen, Henne Holstege, Cornelia van Duijn, Thibaud Lebouvier, Olivier Hannon, Ville Leinonen, Hilkka Soininen, Sanna-Kaisa Herukka, Vilmantas Giedraitis, Malin Löwenmark, Lena Kilander, Patricia Genius, Blanca Rodríguez, Emma S Luckett, Arcadi Navarro, Amanda Cano, Marta Marquié, Kaj Blennow, Henrik Zetterberg, Alberto Lleo, Mercè Boada, Agustin Ruiz, Virginia Man-Yee Lee, Vivianna M Van Deerlin, Yuetiva Deming, Sterling C Johnson, Corinne D Engelman, Pau Pastor, Ignacio Alvarez, Elaine R Peskind, Amanda J Heslegrave, Andrew J Saykin, Kwangsik Nho, Suzanne E Schindler, John C Morris, David M Holtzman, Eric McDade, Alan E Renton, Alison Goate, Laura Ibanez, Matthias Riemenschneider, Marilyn S Albert, Simon M Laws, Tenielle Porter, Eleanor K O'Brien, Leslie M Shaw, Betty M Tijms, Martin Ingelsson, Pieter Jelle Visser, Mikko Hiltunen, Kristel Sleegers, Craig W Ritchie, Rebecca Sims, Michael Belloy, Jean-Charles Lambert, Natalia Vilor-Tejedor, Maria Victoria Fernández, Qingqin S Li, Michael W Nagle, Riccardo E Marioni, Alfredo Ramirez, Lars Bertram, Sven J van der Lee, Carlos Cruchaga.

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

DOI: https://doi.org/10.1038/s41467-026-71682-8
Nutr Neurosci. 2026 Apr 24. 1-17

Prebiotics/synbiotics as natural alternatives for brain development and aging - focus on nutrigenomic and direct effects: a systematic review.

Lilian Vanessa Penha Gonçalves, Pedro Fernandes Gusmão de Holanda, Arthur Vinicius da Silva Cabral, Ricardo Gomes Dos Santos Nunes, Yanka Vitória de Santana Lira, Moara Rodrigues Costa, Ingrid Prata Mendonça, Aline Ananias de Lima, Êndel Alves Gomes de Oliveira, Christina Alves Peixoto, Filipe Silveira Duarte, Belmira Lara da Silveira Andrade-da-Costa.

   OBJECTIVES: This review highlights the importance of prebiotics and their combination with probiotics as essential nutrients for brain development and as potential therapeutic alternatives for neurodegenerative diseases. It further highlights the nutrigenomic action of prebiotics or synbiotics.
METHODS: A literature search of PubMed, Scopus, and Web of Science was conducted for studies published from 2010 to 2025. Key search terms included ('prebiotics' OR 'synbiotics)' AND ('brain development' OR 'neurodevelopment' OR 'cognition' OR 'neuroplasticity' OR 'brain aging)' AND ('epigenetics' OR 'nutrigenomics' OR 'gene expression' OR 'DNA methylation' OR 'histone modification' OR 'microRNA)'.
RESULTS: A literature search on the selected databases has identified 503 potentially relevant articles to this topic. After analysis of inclusion and exclusion criteria and duplicated studies, 79 articles (a total of 47 animal in vivo studies, 18 in vitro studies and 13 human studies) have been selected to be reviewed. Despite the importance of prebiotics or synbiotics as a prime source of energy, their diverse direct or indirect mechanisms of action have only recently been described, especially those involving these nutraceuticals as substrates for epigenetic effects.
DISCUSSION: The literature shows that further studies are necessary to elucidate mechanisms and strategies for prebiotic intervention in the brain epigenome during brain development, adulthood and aging. Notwithstanding, the current data can help to initiate novel health approaches for treating brain disorders. The development of targeted therapy, using prebiotics or synbiotics as nutrigenomic substrates, seems to restore normal interaction between systemic diseases and brain function.

Keywords:  Dysbiosis; brain development; epigenetics; neurodegenerative diseases; prebiotic; synbiotic

DOI:  https://doi.org/10.1080/1028415X.2026.2649604