bims-medebr 2026-06-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–06–21
thirty papers selected by
Regina F. Fernández, Johns Hopkins University

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.
APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.
Direct quantification of the metabolic heat output of individual Drosophila brains.
Ketone metabolism at the interface of atherosclerosis and brain dysfunction.
NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition.
The riddle of sphingolipid structure-function relationship in the nervous system.
A pharmacodynamic study of rapid lactate metabolic modulation by intravenous L-arginine in brain metastases.
C26:0-lysophosphatidylcholine in X-linked adrenoleukodystrophy.
Monocarboxylate transporter 2 regulates maintenance of myelin and axonal integrity by oligodendrocytes.
Role of Cholesterol Metabolism in the Link Between Diabetes and Alzheimer's Disease.
Bioenergetic dysregulation in the basal ganglia and cerebellum of patients with premanifest and manifest Huntington's disease.
Disruption of dopamine transmission by cholesterol depletion is associated with alterations in protein lipid raft partitioning and actin dynamics.
Stage- and Region-Dependent Proteomic Alterations in a Mouse Model of Creatine Transporter Deficiency.
CYP46A1-Targeted Treatment Alleviates Long-Term White Matter Injury Following Traumatic Brain Injury by Promoting Cholesterol Metabolic Clearance and Remyelination.
Sex-dependent neurobiological and metabolic dysfunction in an aged rat model of post-traumatic stress disorder.
Glucose metabolism echoes long-range temporal correlations in the human brain.
Proteomics reveal PTEN as a critical mediator of sustained mitochondrial dysfunction during chronic spinal cord injury.
Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.
PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.
Focused Ultrasound Modulation of PGC-1α Pathways in Neurological Disease: Mechanistic Rationale and Translational Opportunities.
Detection of elevated levels of taurine and creatine in the brain of hypoxic-ischemic newborn rat using a magnetic resonance spin echo full intensity acquired localization sequence.
Genetic dissection of the role of Piga and Pgap2 in the embryonic mouse brain.
Unraveling Aberrant Metabolic Patterns in Alzheimer's Disease Subtypes: From Perturbed Metabolic Pathways to Candidate Drug Targets.
Glycogen Synthase Kinase-3β Inhibition Ameliorates Synaptic and Mitochondrial Dysfunction in a Sporadic Alzheimer's Disease-Like Model.
Dysregulation of a novel autophagosome-mitochondria contact contributes to tauopathy-related neurodegeneration by disrupting autophagy.
Posttranscriptional Regulation of Metabolism in Glioblastoma: A Multipathway Review.
Insight into the metabolism of gliomas by MRI and MRS.
Characterization of blood-brain barrier L-arginine uptake using in situ brain perfusions in a female mouse model.
In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant.

Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]

Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.

Amandine Grimm, Undine Lang, Anne Eckert.

  Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.

Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes

DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
Alzheimers Dement. 2026 Jun;22(6): e71594

Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.

Evelyn Pardo, Taylor Kim, Horst Wallrabe, Kristine E Zengeler, Vijay Kumar Sagar, Garnett Mingledorff, Xuehan Sun, Ammasi Periasamy, John R Lukens, George S Bloom, Andrés Norambuena.

   INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.
METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.
RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.
DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.

Keywords:  Alzheimer's disease; NADPH; PS19; brain metabolism; endocytosis; mitochondria; tau spreading

DOI:  https://doi.org/10.1002/alz.71594
Front Aging Neurosci. 2026 ;18 1796680

APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation.

Tian Wang, Yuan Shang, John W McLean, Fei Yin, Roberta Diaz Brinton.

   Introduction: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at increased AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further exacerbated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.
Methods: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages from pre- to postmenopause.
Results: APOE3/3 mice exhibited dynamic regulation of metabolic systems that supported postmenopausal brain bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice exhibited accelerated and compromised metabolic adaptation, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and compromised brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.
Discussion: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.

Keywords:  APOE4; Alzheimer’s; brain; menopause; metabolism; women’s health

DOI:  https://doi.org/10.3389/fnagi.2026.1796680
Cell Rep Methods. 2026 Jun 15. pii: S2667-2375(26)00202-X. [Epub ahead of print] 101501

Direct quantification of the metabolic heat output of individual Drosophila brains.

Kanishka Panda, Rohith Mittapally, Qianqian Chen, Akshay Manoj Bhaskaran, Pramod Reddy, Edgar Meyhofer, Swathi Yadlapalli.

  Quantitative insights into brain metabolism are essential for advancing our understanding of the energy dynamics in the brain. Here, we present a nanowatt-resolution biocalorimeter capable of real-time metabolic heat output measurements of individual, live Drosophila melanogaster brains. Using this platform, we show that female brains, across multiple genotypes, exhibit a significantly higher metabolic rate (∼10%-15%) than male brains at a young age (<10 days old) and follow distinct metabolic trajectories across the lifespan. We also find that parkin mutants, a genetic model for Parkinson's disease, exhibit a ∼15% reduction in brain metabolic output relative to controls, revealing that defective mitophagy due to parkin deficiency affects brain metabolism. Further, we demonstrate that the metabolic output of a Drosophila brain is ∼2.5-fold higher than reproductive tissues like ovary and testis. Together, these advances open new avenues for investigating the impact of aging, neurodegeneration, and disease states on brain metabolism.

Keywords:  CP: metabolism; Drosophila; aging; biocalorimetry; brain; metabolism; neurodegeneration

DOI:  https://doi.org/10.1016/j.crmeth.2026.101501
Pharmacol Res. 2026 Jun 15. pii: S1043-6618(26)00216-1. [Epub ahead of print]230 108301

Ketone metabolism at the interface of atherosclerosis and brain dysfunction.

Young-Kook Kim, Juhyun Song.

  Atherosclerosis and brain dysfunction converge through vascular inflammation, endothelial injury, and regional bioenergetic failure of the neurovascular unit. Ketone bodies, including acetoacetate and D-β-hydroxybutyrate, perform critical roles in metabolic signaling by serving as alternative oxidative substrates for ATP production and bioactive signaling molecules that modulate cellular pathways. In the arterial wall, ketones improve endothelial function, reduce inflammation, and shift macrophages away from proinflammatory states, as well as induce changes that are predicted to limit lesion growth and enhance plaque stability. In the brain, ketone bodies serve as alternative energy substrates under conditions of hypoperfusion or impaired glucose metabolism, while also improving synaptic resilience through mitochondrial and epigenetic mechanisms. By coupling vascular inflammation with cerebral energetics via convergent immunometabolism pathways, ketone metabolism has emerged as a versatile therapeutic target. Nonetheless, effective clinical translation will require individualized strategies that account for metabolic and genetic variability, thereby positioning personalized ketone-based interventions as a promising avenue at the critical intersection of cardiovascular disease and neurodegeneration. Thus, this review aims to summarize the evidence on metabolic alterations spanning hepatic ketogenesis to cellular utilization, highlighting the implications of these alterations for vascular function and brain function.

Keywords:  Acetoacetate; Atherosclerosis; Brain dysfunction; Ketogenic diet; Ketone body; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.phrs.2026.108301
Sci Adv. 2026 Jun 19. 12(25): eadt2527

NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition.

Kateryna Murlanova, Ksenia Novototskaya-Vlasova, Shovgi Huseynov, Olga Pletnikova, Rebecca D Howell, Yan Jouroukhin, Dong Won Kim, Adrian Eddy-Sulaiman Jenson, Juhyun Lee, Cheng Qin, Stephen R Thompson, Vikyath Saraf, Michael J Morales, Eduardo Cortes Gomez, Russell L Margolis, Frederick C Nucifora, Spencer R Rosario, Andrew A Pieper, Henry G Withers, Samir Haj-Dahmane, Juhyun Kim, Mikhail V Pletnikov.

The basic helix-loop-helix transcription factor neuronal PAS (Per, Arnt, Sim) domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways and is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction under several neuropsychiatric conditions, but the underlying brain cell type-specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondrial bioenergetics in astrocytes in the mouse brain. Selective deletion of Npas3 in mature astrocytes decreases expression of mitochondrial glutamate carrier 2 involved in glutamate oxidation, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit reduces intrinsic excitability, dendritic spine density, and excitatory synaptic transmission of medial prefrontal cortex (mPFC) pyramidal neurons. Mice with Npas3-deficient mPFC astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondrial bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.

DOI: https://doi.org/10.1126/sciadv.adt2527
J Biol Chem. 2026 Jun 16. pii: S0021-9258(26)02130-7. [Epub ahead of print] 113258

The riddle of sphingolipid structure-function relationship in the nervous system.

Susana Muñoz-Gil, Stefka D Spassieva.

  Sphingolipids are ubiquitous in the membranes of nervous system cells. They constitute about 20% of brain lipids. Perturbations of their metabolism result in dysregulation of nervous system homeostasis leading to pathologies. The structural characteristics of sphingolipid precursors, the long-chain bases and ceramides, determine their and complex sphingolipids biophysical properties and function. In the current review, we are focusing on the role of chain length, saturation, and hydroxylation of sphingolipid precursors in nervous system physiology and pathology. We discuss the enzymes from the sphingolipid metabolic pathway catalyzing the reactions introducing the structural changes in the long chain bases and ceramides. We also focus on a recently discovered class of atypical neurotoxic sphingolipids as intermediates in peripheral neuropathies.

Keywords:  ceramide; ceramide synthase; long-chain base; nervous system; serine palmitoyltransferase; sphingolipid

DOI:  https://doi.org/10.1016/j.jbc.2026.113258
Front Oncol. 2026 ;16 1845249

A pharmacodynamic study of rapid lactate metabolic modulation by intravenous L-arginine in brain metastases.

Xueping Liu, Guobo Du, Nai Mu, Lang He.

   Objective: L-arginine may enhance radiotherapy efficacy through nitric oxide (NO)-mediated glycolysis inhibition; however, its real-time metabolic effects in brain metastases remain undefined. This proof-of-concept study aimed to characterize, for the first time in vivo, the rapid pharmacodynamic profile of intravenous L-arginine on lactate metabolism in brain metastases and generate hypotheses for future trials.
Methods: Twenty patients with solid tumor brain metastases were randomized 1:1:1:1 to receive normal saline or 10 g, 20 g, or 30 g intravenous L-arginine. Serial magnetic resonance spectroscopy (MRS) was performed at baseline and multiple post-infusion timepoints (approximately 19-36 minutes) to quantify lactate dynamics. The primary endpoint was lactate reduction at T3 (approximately 30 minutes).
Results: All patients completed the study. The pooled L-arginine group showed significantly greater lactate reduction at T3 compared with controls (median ΔLac_T3: -1.09 vs. 0.00, p = 0.0012). Lactate reduction was most prominent and consistent in the 30 g group, with a peak reduction of 63.5% at 30 minutes (ρ = -0.753, p < 0.001). No treatment-related adverse events were observed up to 24 hours post-infusion.
Conclusion: This proof-of-concept study demonstrates that intravenous L-arginine rapidly and safely suppresses lactate metabolism in brain metastases, with a peak effect at approximately 30 minutes. The 30 g dose yielded the most robust metabolic suppression within the 10-30 g range. The "30 g L-arginine followed by radiotherapy within 30 minutes" regimen is proposed as a priority candidate for validation in future phase II trials. Clinical benefits require further confirmation in larger randomized controlled trials.
Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2400080841.

Keywords:  L-arginine; brain metastases; lactate; magnetic resonance spectroscopy; radiosensitization; radiotherapy; therapeutic window

DOI:  https://doi.org/10.3389/fonc.2026.1845249
Pharmacol Ther. 2026 Jun 19. pii: S0163-7258(26)00097-5. [Epub ahead of print] 109070

C26:0-lysophosphatidylcholine in X-linked adrenoleukodystrophy.

Yorrick R J Jaspers, Inge M E Dijkstra, Marc Engelen, Stephan Kemp.

  X-linked adrenoleukodystrophy (ALD) is a progressive neurometabolic disorder caused by pathogenic variants in the ABCD1 gene, resulting in the systemic accumulation of very-long-chain fatty acids (VLCFAs). C26:0-lysophosphatidylcholine (LPC(26:0)) is the primary biochemical marker of ALD and the basis for newborn screening programs worldwide. LPC(26:0) arises from the accumulation of VLCFA-CoA species that are incorporated into phosphatidylcholine via the lysophospholipid acyltransferase LPLAT10, followed by phospholipase A2-mediated hydrolysis. Compared to conventional plasma VLCFA analysis, measurement of LPC(26:0) by liquid chromatography or flow injection tandem mass spectrometry in plasma or dried blood spots offers superior sensitivity and specificity, even in female patients, for whom VLCFA analysis yields false-negative results in 15-20% of cases. Beyond diagnosis, accumulating evidence indicates that LPC(26:0) and the broader landscape of VLCFA-containing lipids correlate with disease severity. Higher levels are associated with cerebral ALD, adrenal insufficiency, and severe spinal cord disease, and data from newborn screening cohorts suggest that neonatal LPC(26:0) levels may also stratify risk for early-onset disease manifestations. LPC(26:0) accumulates in CNS lipoproteins and exhibits direct neurotoxic and proinflammatory properties in experimental models. This implicates LPC(26:0) not only as a biomarker, but also as a potential mediator of ALD pathology. Furthermore, LPC(26:0) shows promise as a pharmacodynamic biomarker of biochemical correction across therapeutic strategies, from hematopoietic stem cell transplantation to emerging approaches including ELOVL1 inhibition. However, key questions remain regarding the cell type and tissue origin of circulating LPC(26:0), its precise contribution to neuroinflammation, and the threshold levels that reliably predict clinical outcomes in individual patients.

Keywords:  Biomarker; Disease severity; Lipidomics; Lysophosphatidylcholine; Newborn screening; Prognosis; Therapeutics

DOI:  https://doi.org/10.1016/j.pharmthera.2026.109070
Nat Commun. 2026 Jun 18.

Monocarboxylate transporter 2 regulates maintenance of myelin and axonal integrity by oligodendrocytes.

Leire Izagirre-Urizar, Luna Mora-Huerta, Irene Soler-Saez, Raquel Morales-Gallel, Mary-Amélie Masson, Maria-Jose Ulloa-Navas, Juan-Carlos Chara, Stefano Calovi, Cyrille Deboux, Laura Merino-Cacho, Maria Andrés-Bilbao, Alejandro Carretero-Guillén, Citlalli Netzahualcoyotzi, Maria Domercq, José L Zugaza, Luc Pellerin, Francisco Garcia-Garcia, Jose-Manuel Garcia-Verdugo, Carlos Matute, Brahim Nait-Oumesmar, Vanja Tepavčević.

Myelin alterations, tightly linked to axonal degeneration, are common in neurodegenerative diseases, including multiple sclerosis (MS). However, the metabolic mechanisms that sustain white matter integrity remain elusive. Monocarboxylates are important energy fuels, but their role in myelinating oligodendrocyte function remains unclear. Here, we show that myelinating oligodendrocytes express high affinity monocarboxylate transporter 2 (MCT2), which is downregulated in progressive MS. While deletion of MCT2 in the mouse spinal white matter using oligodendrotropic AAV injection does not affect oligodendrocyte survival, it downregulates lipid synthesis-associated enzymes and increases inflammation, leading to a failure of myelin maintenance. These changes, not evidenced in AAV-control mice that only show mild inflammation, are accompanied by axonal upregulation of lactate dehydrogenase A and injury, effects alleviated by ketogenic diet. Therefore, our findings show that oligodendroglial MCT2 regulates myelin maintenance and axonal support under mild inflammation. This appears disrupted in progressive MS but might be compensated for by specific metabolic therapies to preserve white matter integrity.

DOI: https://doi.org/10.1038/s41467-026-74488-w
CNS Neurol Disord Drug Targets. 2026 Jun 18.

Role of Cholesterol Metabolism in the Link Between Diabetes and Alzheimer's Disease.

Pratishtha Sharma, Rohinee Dodiya, Dipa K Israni, Devesh U Kapoor.

   INTRODUCTION: Type 2 Diabetes Mellitus (T2DM) and Alzheimer's Disease (AD) share complex metabolic disturbances, with cholesterol dysregulation emerging as a central mechanistic link. Although brain cholesterol metabolism operates largely independently of peripheral lipid pools, it is highly susceptible to disruption, particularly in the insulin-resistant ApoE4 genotype.
METHODS: This review follows a structured literature approach using PubMed, Scopus, and Web of Science (2000-2025) to critically evaluate mechanistic and translational evidence on cholesterol- T2DM-AD interplay. It critically evaluates current evidence on cholesterol production, transport, and elimination in the Central Nervous System (CNS), focusing on the roles of astrocytes, neurons, and transporters such as ATP-binding cassette transporter A1 (ABCA1). It also explores how peripheral metabolic stress in T2DM affects central cholesterol homeostasis and contributes to amyloid- beta (Aβ) accumulation and neurodegeneration. Pharmacological approaches targeting cholesterol regulation, including statins, liver X receptor (LXR) modulators, and glucagon-like peptide-1 (GLP-1) receptor agonists, are discussed.
RESULTS: Findings indicate that impaired cholesterol regulation disrupts neuron-astrocyte interactions, enhances Aβ deposition, and accelerates neurodegeneration. Controversies remain regarding the relative impact of peripheral vs. central cholesterol imbalance and Blood-Brain Barrier (BBB) permeability in therapy. In T2DM, peripheral insulin resistance and hypercholesterolemia exacerbate central cholesterol imbalance, thereby intensifying AD pathology. Emerging therapeutic studies suggest that modulation of cholesterol pathways may reduce neuroinflammation, promote Aβ clearance, and slow cognitive decline.
DISCUSSION: The overlap between T2DM and AD highlights cholesterol metabolism as a pivotal pathogenic axis. While peripheral factors worsen central dysregulation, CNS-specific disturbances independently drive disease progression. Targeted modulation of cholesterol pathways, through statins, LXR modulators, and GLP-1 agonists, shows promise but demands precision approaches tailored to genotype and BBB permeability.
CONCLUSION: The cholesterol-AD-T2DM axis represents a promising therapeutic target. Addressing cholesterol dysregulation could enable novel, personalized strategies to mitigate neurodegeneration and cognitive decline.

Keywords:  Alzheimer’s disease; ApoE4; GLP-1 receptor agonists.; LXR modulators; amyloid-beta (Aβ); blood-brain barrier; type 2 diabetes mellitus

DOI:  https://doi.org/10.2174/0118715273444881260119053309
Neurobiol Dis. 2026 Jun 13. pii: S0969-9961(26)00225-1. [Epub ahead of print]227 107480

Bioenergetic dysregulation in the basal ganglia and cerebellum of patients with premanifest and manifest Huntington's disease.

Jannik Prasuhn, Maximilian G Ködderitzsch Mertins, Marta M Pokotylo, Joke-Lina Aßmann, Leon van Well, Julia Henkel, Jan Uter, Sebastian Loens, Alexander Münchau, Norbert Brüggemann.

   BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. While early striatal degeneration is a well-established hallmark, emerging evidence points to broader network-level dysfunction involving the cerebellum and profound alterations in mitochondrial energy metabolism. However, in vivo studies systematically examining region-specific bioenergetic changes across disease stages are scarce.
METHODS: Using 31Phosphorus magnetic resonance spectroscopic imaging (31P-MRSI), we quantified metabolite ratios and absolute concentrations of alpha adenosine triphosphate (ATP-α), phosphocreatine (PCr), and inorganic phosphate (Pi) in the anterior basal ganglia and cerebellum of 31 patients with HD (15 manifest, 16 premanifest) and 19 healthy controls without pathogenic HTT expansion (HC).
RESULTS: Basal ganglia (ATP-α + PCr)/Pi and ATP-α/Pi were significantly elevated in premanifest (+10.0% and + 13.9%) and manifest patients (+16.4% and + 19.2%) compared to HC. High-energy phosphate (HEP) levels showed a stage-dependent pattern, with ATP-α PCr and ATP-α elevated in premanifest patients (+7.7% and + 3.9%) and reduced in manifest patients (-7.6% and -12.8%). All metabolite ratios showed no correlation with clinical scores but were inversely associated with subcortical atrophy, particularly in the caudate (rho = -0.327, p = 0.022), putamen (r = -0.372, p = 0.008), and globus pallidus (r = -0.327, p = 0.022).
CONCLUSIONS: These findings reveal stage-dependent, region-specific alterations in HEP metabolism in patients with HD. The observed changes in the brain energy metabolism precede motor symptoms and are linked to structural atrophy rather than symptomatic burden, supporting the potential of 31P-MRSI as a sensitive in vivo biomarker of bioenergetic dysfunction in HD.

Keywords:  (31)phosphorus magnetic resonance spectroscopy imaging ((31)P-MRSI); Huntington's disease (HD); Metabolism; Mitochondrial dysfunction; Neuroimaging

DOI:  https://doi.org/10.1016/j.nbd.2026.107480
Neuropharmacology. 2026 Jun 13. pii: S0028-3908(26)00252-2. [Epub ahead of print]298 111078

Disruption of dopamine transmission by cholesterol depletion is associated with alterations in protein lipid raft partitioning and actin dynamics.

Anna I Neel, Evelyn T Lee, Alyssa M West, Monica H Dawes, Rebekah D Schlitzer, Reid A Suddaby, Glen S Marrs, Sara R Jones, Rong Chen.

  Disrupted brain cholesterol homeostasis is implicated in neurological disorders involving aberrant dopamine (DA) signaling; however, the direct effects of cholesterol on DA transmission in native tissue have not yet been demonstrated. Using ex vivo fast-scan cyclic voltammetry in nucleus accumbens slices from male rats, we found that membrane cholesterol depletion with methyl-β-cyclodextrin (MβCD, 3-10 mM) significantly reduced evoked DA release and decreased the apparent maximal rate of DA reuptake via the dopamine transporter (DAT). Because cholesterol is critical for the formation of lipid raft microdomains, cholesterol depletion could disrupt DA transmission by altering the membrane localization of proteins involved in neurotransmitter release. Using sucrose density gradient fractionation, we found that MβCD decreased the raft association of vesicle-associated membrane protein 2 (VAMP2) without altering the localization of syntaxin-1A, synaptosomal-associated protein 25, synaptotagmin-1, and N-type voltage-gated calcium channels. Therefore, MβCD may reduce DA release by disrupting localization of VAMP2, a core component of the vesicle fusion machinery. We also examined actin polymerization, a key regulator of vesicle docking and fusion, and found that MβCD treatment decreased actin polymerization, as evidenced by an increased globular-to-filamentous actin ratio and reduced phalloidin labeling of filamentous actin in striatal slices. Finally, although DAT lipid raft localization was unchanged, MβCD attenuated cocaine's ability to inhibit DAT reuptake function, suggesting that cholesterol depletion disrupts the outward-facing conformation of DAT required for high-affinity ligand binding. Overall, these findings provide new mechanistic insights into how cholesterol depletion may contribute to dysregulated DA signaling in diseases involving altered brain cholesterol metabolism.

Keywords:  Actin polymerization; Cholesterol; Dopamine release; Dopamine reuptake; Dopamine transporter; Lipid rafts

DOI:  https://doi.org/10.1016/j.neuropharm.2026.111078
J Neurosci. 2026 Jun 17. pii: e2010252026. [Epub ahead of print]

Stage- and Region-Dependent Proteomic Alterations in a Mouse Model of Creatine Transporter Deficiency.

Shingo Ito, Yumi Iwata, Tatsuki Uemura, Michihiko Sugimoto, Haruka Kumabe, Ayaka Miyano, Teruya Nakamura, Naoto Tashiro, Megumu Ieiri, Moeka Umezaki, Shoma Chikamatsu, Takeshi Masuda, Satohiro Nakao, Naomi Nakagata, Toru Takeo, Kimi Araki, Sumio Ohtsuki.

SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the blood-brain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G>C (G561R) variant of Slc6a8, which corresponds to a variant identified in SLC6A8 in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G>C point mutation into the mouse Slc6a8 gene using the CRISPR/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.Significance Statement Creatine transporter deficiency (CTD) causes cerebral creatine depletion and intellectual disability; however, the developmental mechanisms linking creatine loss to brain dysfunction remain unclear. We performed developmental proteomic profiling of the hippocampus and cerebral cortex using a mouse model carrying a pathogenic Slc6a8 variant identified in patients with CTD. Creatine transporter dysfunction induces distinct region- and stage-dependent molecular responses during postnatal brain maturation. The hippocampus shows early alterations in cytoskeleton-dependent membrane trafficking pathways, consistent with impaired synaptic and circuit maturation, whereas the cerebral cortex exhibits progressive metabolic and mitochondrial adaptations. These findings suggest that impaired creatine-dependent energy buffering disrupts distinct developmental programs across brain regions, potentially contributing to cognitive dysfunction by hindering early hippocampal circuit maturation.

DOI: https://doi.org/10.1523/JNEUROSCI.2010-25.2026
CNS Neurosci Ther. 2026 Jun;32(6): e70984

CYP46A1-Targeted Treatment Alleviates Long-Term White Matter Injury Following Traumatic Brain Injury by Promoting Cholesterol Metabolic Clearance and Remyelination.

Lin Li, You Shi, Qing Luo, Peiwen Guo, Taotao Jin, Xufang Ru, Zhouyang Jiang, Yin Niu, Wenyan Li, Yujie Chen, Zhi Chen.

   AIM: Cholesterol plays a critical role in repairing white matter injury (WMI) following traumatic brain injury (TBI). The enzyme cholesterol 24-hydroxylase (CYP46A1) regulates the removal of cholesterol by converting it into 24(S)-hydroxycholesterol (24OHC). Although CYP46A1 has neuroprotective effects on various central nervous system disorders, its effect on WMI remains unclear.
METHODS: Adult male C57BL/6 mice underwent controlled cortical impact to model TBI. Experiments using the CYP46A1 activator efavirenz and CYP46A1-/- mice were utilized to elucidate the function of CYP46A1. Neurological function, WMI, and cholesterol metabolism were evaluated, and the mechanisms through which CYP46A1 affects these processes were explored.
RESULTS: Efavirenz markedly improved outcomes and preserved white matter structure after TBI by increasing microglial phagocytic activity and myelin debris clearance, along with promoting oligodendrocyte precursor cell remyelination. Furthermore, efavirenz promoted cholesterol export by increasing 24OHC levels and activating liver X receptors (LXR). However, these neuroprotective effects of Efavirenz were partially diminished when CYP46A1 was knocked down or when LXR activity was blocked.
CONCLUSION: Efavirenz administration promotes functional neurological recovery and sustains white matter integrity in TBI through the regulation of cholesterol homeostasis and the promotion of remyelination processes.

Keywords:  CYP46A1; White matter injury; cholesterol metabolism; liver X receptor; traumatic brain injury

DOI:  https://doi.org/10.1002/cns.70984
Commun Biol. 2026 Jun 19.

Sex-dependent neurobiological and metabolic dysfunction in an aged rat model of post-traumatic stress disorder.

Yubo Hu, Wentao Hu, Yueru Zhong, Yu Liu, Peng Xiao.

The neurobiological underpinnings of post-traumatic stress disorder (PTSD) in the elderly remain poorly characterized, particularly regarding sex-dependent vulnerabilities. This study systematically investigated sex-specific behavioral and metabolic alterations in 15-month-old rats using a single prolonged stress and footshock (SPS + FS) paradigm. A multimodal approach integrating behavioral analysis, 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography (FDG-PET) imaging, plasma endocrine profiling, and brain transcriptomics was employed to assess PTSD-related dysfunction. Behavioral assessments revealed that female rats exhibited more severe PTSD-like manifestations, indicating a higher susceptibility compared to males. Macroscopically, FDG-PET imaging identified prominent sex-specific alterations in glucose metabolism within the core fear circuitry, including the prefrontal cortex (PFC), hippocampus (Hipp), and amygdala (Amyg). In females, these metabolic shifts were more pronounced and strongly correlated with behavioral phenotypes. Dynamic PET further confirmed a general decline in the cerebral metabolic rate of glucose (CMRglu) across PTSD groups. Transcriptomic analysis validated these observations, revealing a systemic reprogramming of central metabolic networks in core brain regions. These neuroenergetic shifts appeared potentially associated with the dysregulation of key metabolic signaling networks, primarily the insulin and AMPK pathways, which exhibited notable sex-dependent spatial heterogeneity. These findings elucidate sex-specific metabolic and molecular abnormalities in aged PTSD models, advancing our understanding of elderly pathophysiology.

DOI: https://doi.org/10.1038/s42003-026-10536-x
Imaging Neurosci (Camb). 2026 ;pii: IMAG.a.1275. [Epub ahead of print]4

Glucose metabolism echoes long-range temporal correlations in the human brain.

Massimiliano Facca, Anna Ridolfo, Miriam Celli, Claudia Tarricone, Ilaria Mazzonetto, Tommaso Volpi, Andrei G Vlassenko, Manu S Goyal, Maurizio Corbetta, Alessandra Bertoldo.

  Intrinsic brain activity is characterized by pervasive long-range temporal correlations. While these scale-invariant dynamics are a fundamental hallmark of brain function, their implications for individual-level metabolic regulation remain poorly understood. Here, we address this gap by integrating resting-state functional Magnetic Resonance Imaging (fMRI) and dynamic [18F]FDG Positron Emission Tomography (PET) data acquired from the same cohort of participants. We uncover a systematic relationship between long-range temporal correlations, quantified via the Hurst exponent, and glucose metabolism. Our findings reveal that persistent temporal dependencies are associated with a measurable metabolic cost, with brains exhibiting higher long-range temporal correlations incurring greater energetic demands. Full kinetic modeling of the [18F]FDG PET data traces this association specifically to intracellular glucose phosphorylation, pointing to a direct link with neuronal energy metabolism. Beyond glucose metabolism, we also show that these dynamics are likely supported by continuous biosynthetic processes, such as protein synthesis, which are critical for neural circuit maintenance and remodeling. Overall, our results suggest that a significant fraction of the brain's so-called "Dark Energy" may be linked to spontaneous long-range temporal correlations.

Keywords:  PET; criticality; fMRI; glucose metabolism; hurst exponent; long-range temporal correlations

DOI:  https://doi.org/10.1162/IMAG.a.1275
Exp Neurol. 2026 Jun 17. pii: S0014-4886(26)00245-1. [Epub ahead of print]404 115880

Proteomics reveal PTEN as a critical mediator of sustained mitochondrial dysfunction during chronic spinal cord injury.

Samir P Patel, Carlos A Gartner, Mudjgiwa Patience, Jaydeepbhai Patel, Victoria K Slone, Dylan E Capes, Krithika Iyer, Maria F Zapata-Jaramillo, Vamshi Kota, Michael T Hash, Jocelyn Salazar, Michael P Chatterton, Maya O Tree, Eric D Petersen, Calvin P Vary, Andrew N Stewart.

  Activity of the phosphatase and tensin homologue protein (PTEN) remains elevated in neurons chronically after spinal cord injury (SCI) and suppresses tissue repair. However, PTEN may also disrupt other neuronal functions not directly related to regeneration. To better understand the role of PTEN on neuronal functions in chronic SCI, neuronal-specific PTEN-KO was induced using spinal injections of retrogradely-transported AAVs (AAVrg) immediately after contusion SCI in mice. Spinal cords were harvested at 6 weeks post-injury and untargeted total proteomics was performed. Bioinformatics analyses revealed a downregulation of mitochondrial-associated proteins in chronic SCI that was reversed after PTEN-KO. We replicated the experimental conditions to validate the effects of chronic SCI ± PTEN-KO on mitochondrial functions using ex vivo respiratory testing on whole-spinal cord mitochondrial isolates. Mitochondrial respiratory capacity was reduced in chronic SCI and was restored after PTEN-KO. Next, we evaluated the extent to which chronic SCI specifically affects neuronal mitochondria and whether PGC1α upregulation can restore respiratory capacity. We designed an AAVrg vector to enable a magnetic bead pulldown approach to isolate neuron-specific mitochondria with, or without, concurrent PGC1α upregulation. AAVrg vectors were delivered into the spinal cord at 15-weeks post-injury, and neuron-specific mitochondria were isolated 6-weeks later. Neuronal mitochondria present a ∼ 50% loss of respiratory capacity in chronic SCI that was restored with PGC1α upregulation. Collectively, we demonstrate that mitochondrial respiratory abilities are significantly repressed chronically after SCI, that PTEN is a major contributor to sustained mitochondrial dysfunction, and that PGC1α upregulation can restore mitochondrial bioenergetic abilities during chronic SCI. SIGNIFICANCE STATEMENT: Chronic spinal cord injury (SCI) is hallmarked by sustained motor and sensory dysfunction with little potential for repair. The chronic SCI environment limits the excitability of spared neural circuits and significantly reduces the regenerative potential of exogenously applied therapeutics. Through a series of experiments, we have derived a novel and significant observation that neuronal mitochondria exhibit a ∼ 50% loss of respiratory abilities chronically after SCI in mice. Moreover, by knocking out PTEN, a protein known to be chronically hyperactive after SCI, we demonstrate the ability to restore mitochondrial respiratory abilities. Our discoveries highlight a novel and vital pathological mechanism that is sustained chronically after SCI that is mediated by neuronal PTEN activity.

Keywords:  Chronic spinal cord injury; Metabolism; Neuron-specific mitochondria; Proteomics

DOI:  https://doi.org/10.1016/j.expneurol.2026.115880
J Neuroinflammation. 2026 Jun 17.

Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.

Jing Yin, Yan Li, Yu-Lu Miao, Xue-Fang Song, Yao Cheng, Yu-Jie Zhai, Jia Ren, Cai-Hong Yang, Hui-Feng Zhang, Xiang-Nan Zhang, Li-Jun Yang, Yan-Ying Fan.

  Lipid droplet (LD) accumulation in microglia results in a dysfunctional and proinflammatory state after ischemic stroke and worsens neurological outcomes; yet how this accumulation is regulated remains unclear. Interferon regulatory factor 7 (IRF7) is an immune regulatory factor whose role in lipid metabolism and autophagy has been increasingly studied in peripheral tissues. However, the role of IRF7 in microglial lipophagy (a selective autophagic process that targets LDs) and poststroke functional recovery remains unexplored. In this study, using a mouse photothrombotic ischemia (PTI) model, we observed that microglia in the peri-infarct region displayed persistent lipophagy impairment and LD accumulation for up to 21 days. Reanalysis of the single-cell RNA sequencing (scRNA-seq) dataset revealed that an Irf7high microglial MG1 subcluster (disease-associated microglia) was significantly associated with autophagy and lipid metabolism poststroke. Furthermore, microglial Irf7 conditional knockout (Irf7 cKO) mice exhibited a significant rescue of lipophagy impairment and an alleviation of the ensuing LD accumulation in microglia, accompanied by enhanced synaptic plasticity and motor functional recovery during the subacute phase poststroke. Consistently, in the 15-month-old distal middle cerebral artery occlusion (dMCAO) model, Irf7 cKO mice also displayed similar improvements. Similar results were also observed in vitro. Mechanistically, Gnai2 was identified as a positively regulated transcriptional target of IRF7. In BV2 cells and primary microglia, Gnai2 knockdown mitigated lipopolysaccharide (LPS)-induced lipophagy impairment, thereby reducing LD accumulation. This treatment also increased the level of phosphatidylcholine (PC), a key lipid for stabilizing small LDs as well as promoting autophagosome formation and autophagic flux. Consistently, microglial Irf7 deletion or knockdown attenuated stroke- or LPS-induced PC reduction both in vivo and in vitro. Furthermore, exogenous supplementation with CDP-choline, an intermediate in PC synthesis, alleviated LD accumulation and lipophagy impairment, thereby improving motor function. Additionally, delayed administration of an inhibitor of stimulator of interferon genes (STING, an upstream target of IRF7) replicated the beneficial effects observed in Irf7 cKO mice, and its effects were not further enhanced by microglial Irf7 deletion. Taken together, these novel findings reveal that persistent impairment of microglial lipophagy is a key contributor to poststroke LD accumulation, and that IRF7 is involved in this process through direct transcriptional activation of Gnai2, which reduces the PC levels. Suppressing IRF7 with a STING inhibitor is a potential strategy for modulating microglial lipid metabolism and promoting functional recovery following stroke.

Keywords:  IRF7; Lipid droplet; Lipophagy impairment; Microglia; STING; Stroke

DOI:  https://doi.org/10.1186/s12974-026-03902-3
Metab Brain Dis. 2026 Jun 17. pii: 137. [Epub ahead of print]41(1):

PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.

Shreya Sood, Shareen Singh, Thakur Gurjeet Singh.

  Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer's disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.

Keywords:  Alzheimer’s Disease; Cholesterol; Dysregulation; Neurodegeneration; Neurogenesis; Neurotoxicity; PCSK9

DOI:  https://doi.org/10.1007/s11011-026-01900-1
Mol Neurobiol. 2026 Jun 17. pii: 699. [Epub ahead of print]63(1):

Focused Ultrasound Modulation of PGC-1α Pathways in Neurological Disease: Mechanistic Rationale and Translational Opportunities.

Yu Ning, Yan Gao.

  The brain's disproportionate energy demand creates an enduring bioenergetic imperative where mitochondrial performance directly determines synaptic resilience and neuronal survival. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has emerged as a master transcriptional regulator orchestrating mitochondrial biogenesis, antioxidant defenses, proteostasis, and neuroplasticity, with dysregulation of this axis representing a convergent pathogenic mechanism across Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and neuropsychiatric disorders. Despite compelling preclinical evidence, conventional pharmacological PGC-1α activators confront fundamental translational barriers including poor blood-brain barrier penetration, inadequate bioavailability, and off-target metabolic effects. This review synthesizes mechanistic evidence suggesting that focused ultrasound may provide a noninvasive platform for regionally precise modulation of PGC-1α pathways. In this review, focused ultrasound is presented as a proposed upstream modulator of the PGC-1α axis. Existing studies support its ability to induce membrane tension, engage mechanosensitive channels such as Piezo1 and TRAAK, and trigger downstream kinase signaling, but the full ultrasound → PPARGC1A → neuroprotection chain in brain tissue remains a working hypothesis rather than a demonstrated therapeutic mechanism. Indirect priming through reversible blood-brain barrier opening, hemodynamic augmentation, and glial immunomodulation may further facilitate this model. We integrate emerging concepts including the mitochondrial synapse, PGC-1α isoform diversity, and theranostic architectures combining functional ultrasound mapping with targeted sonication. By defining mechanistic opportunities, disease-specific therapeutic strategies, and the sonogenetics frontier, this review proposes a hypothesis-generating roadmap for ultrasonic modulation of PGC-1α-dependent neuroprotection, a drug-free, focal approach that converts acoustic energy into a testable mitonuclear rescue framework requiring direct experimental validation.

Keywords:  Focused ultrasound; Mechanotransduction; Mitochondrial biogenesis; Neuroprotection; PGC-1α

DOI:  https://doi.org/10.1007/s12035-026-06005-5
Transl Pediatr. 2026 May 31. 15(5): 179

Detection of elevated levels of taurine and creatine in the brain of hypoxic-ischemic newborn rat using a magnetic resonance spin echo full intensity acquired localization sequence.

Jieqiong Chen, Zhiwei Shen, Mei Li, Meini Wu, Dan Wang, Zijie Zhong, Lihua Chen, Dongping Deng.

   Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major perinatal neurological disorder with limited objective early diagnostic markers, while conventional point resolved selective spectroscopy (PRESS)-based 1H-magnetic resonance spectroscopy (1H-MRS), though widely used, is suboptimal for detecting short-T2 metabolites critical to early brain injury assessment. This study aimed to investigate the feasibility of spin echo full intensity acquired localization (SPECIAL) spectra on newborn rat brain with HIE model, and to explore the reliable metabolic markers in rat brain and compare the spectra acquired by magnetic resonance (MR) SPECIAL spectra and PRESS spectra.
Methods: Six male newborn rats were used for making HIE model induced by unilateral common carotid artery ligation followed by hypoxia. Hippocampal damage in the HIE model rat was confirmed by hematoxylin and eosin (HE) staining. T2-weighted anatomical images and 1H-MRS, including SPECIAL sequence and PRESS sequence, were performed with an animal 7-T MR scanner. Absolute concentrations of metabolites, including N-acetylaspartate (NAA), creatine + phosphocreatine (Cr + PCr), inositol (Ins), taurine (Tau), glycerophosphocholine + phosphocholine (GPC + PCh), glutamine + glutamate (Glu + Gln), lactate + macromolecule methyl at 1.4 ppm + lipid methyl at 1.3 ppm (Lac + MM14 + Liq13) on lateral and contralateral hippocampal and thalamic regions, were quantified. The possible differences of metabolites concentration between the brain area corresponding to the ligation side and the contralateral side were compared. Meanwhile, full width at half maximum (FWHM), signal-to-noise ratio (SNR), and fitting error [standard deviation (SD)] of metabolites acquired from the two kinds of spectra in bilateral brain regions were also compared. Finally, the relationship of metabolites from the two kinds of spectra was explored and compared.
Results: SPECIAL MR spectra are feasible in newborn HIE rat brain corresponding to the ligation side with higher spectral resolution compared with PRESS spectra. Elevated levels of Tau and Cr + PCr were found in the right hippocampus by SPECIAL spectra (P<0.05), and increased levels of Cr + PCr, Lac + MM14 + Liq13, and decreased NAA were observed by PRESS spectra (P<0.05). More correlations between metabolites were found from SPECIAL spectra than PRESS spectra, including Tau and Cr + PCr (r=0.7, P<0.01), Glu + Gln and Cr + PCr (r=0.75, P<0.01), GPC + PCh and Cr + PCr (r=0.63, P<0.01), and Lac + MM14 + Liq13 and Cr + PCr (r=0.54, P=0.03).
Conclusions: The use of SPECIAL sequences could provide more information on metabolic changes in the HIE rat brain, and Tau and Cr + PCr may be considered as reliable metabolic markers for earlier and accurate assessments of the damage of hypoxic-ischemic.

Keywords:  Hypoxic-ischemic encephalopathy (HIE); magnetic resonance spectroscopy (MRS); metabolism; spin echo full intensity acquired localization (SPECIAL); taurine (Tau)

DOI:  https://doi.org/10.21037/tp-2026-1-0074
iScience. 2026 Jun 19. 29(6): 116299

Genetic dissection of the role of Piga and Pgap2 in the embryonic mouse brain.

Jennifer L Watts, Jesus M Leal, Rolf W Stottmann.

  Glycosylphosphatidylinositol (GPI) anchors are a post-translational modification made to over 150 proteins. These GPI-anchored proteins are enriched in lipid rafts in the plasma membrane and serve a variety of functions. Human pathogenic variants in GPI biosynthesis pathway enzymes are collectively called inherited GPI deficiencies and lead to several brain anomalies, but we still lack a deep understanding of GPI-anchor functions in brain development. PIGA and PGAP2 are two enzymes in the GPI-anchor biosynthesis pathway. A Nestin-Cre mediated deletion of Piga in the mouse led to early postnatal death and significant structural brain malformations. There are no studies on Pgap2 loss of function in the brain to date. We extended these studies with a series of genetic ablations to further determine the role of Piga and Pgap2 in the forebrain, oligodendrocytes, and cerebellum. We find Piga expression in the hindbrain is absolutely required for survival while Pgap2 ablations were much less deleterious.

Keywords:  molecular biology; molecular genetics; neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.116299
Mol Neurobiol. 2026 Jun 18. pii: 702. [Epub ahead of print]63(1):

Unraveling Aberrant Metabolic Patterns in Alzheimer's Disease Subtypes: From Perturbed Metabolic Pathways to Candidate Drug Targets.

Hatice Büşra Lüleci, Attila Jones, Ryan A Neff, David A Bennett, Bin Zhang, Tunahan Çakır, Madhav Thambisetty.

  Alzheimer's Disease (AD) is characterized by multiple metabolic abnormalities that differ between individuals. In this study, we aimed to elucidate metabolic dysregulations associated with five distinct molecular subtypes of AD, defined in a recent report, based on brain transcriptome data from two autopsy-derived datasets with approximately 550 AD patients. We mapped transcriptome data from each individual on a human genome-scale metabolic network to create personalized metabolic models. We identified aberrant metabolic patterns common across AD subtypes as well as those specific to each AD subtype. More than 20 metabolic pathways were found to be dysregulated in both datasets, with a majority of these pathways unidentified by a conventional subtype-agnostic approach. Among these, fatty acid metabolism was found to be dysregulated commonly in all subtypes while inositol phosphate metabolism and nucleotide metabolism were among the subtype-specific perturbed pathways. These results were independently validated through analyses of metabolome data available in one of the datasets. Moreover, upregulated secretion of pregnenolone and N-acetylneuraminate and therapeutic targeting of ALDH18A1 and SLC6A12 were among the subtype-specific candidate metabolite biomarkers and drug targets, respectively, predicted by our metabolic modeling approach, with available literature support. Subtype-specific metabolic abnormalities catalogued in our study may provide novel insights for understanding biological mechanisms implicated in AD pathogenesis as well as precision-guided treatments targeting dysregulated metabolism in AD.

Keywords:  AD-subtypes; Candidate drug targets; Genome-scale metabolic modeling; Metabolic dysfunction

DOI:  https://doi.org/10.1007/s12035-026-05978-7
Mol Neurobiol. 2026 Jun 17. pii: 697. [Epub ahead of print]63(1):

Glycogen Synthase Kinase-3β Inhibition Ameliorates Synaptic and Mitochondrial Dysfunction in a Sporadic Alzheimer's Disease-Like Model.

Ya-Han Wang, Peng-Li Ding, Hao Qin, Kai-Xin Zhang, Jin-Wen Ge, Da-Hua Wu, Le Xie, Kun Liang.

  Abnormal glucose metabolism in the central nervous system is a major cause of sporadic Alzheimer's disease (SAD). We hypothesize that glycogen synthase kinase 3β (GSK3β) mediates cognitive impairment by inhibiting the Wnt/β-catenin pathway, which in turn induces abnormal glucose metabolism, synaptic damage, and mitochondrial dysfunction. To test this hypothesis, we injected streptozotocin bilaterally into the lateral ventricles of 100 male C57BL/6 J mice to establish in vivo models of SAD, and into HT22 cells to establish in vitro models of SAD. GSK3β expression was knocked down via adeno-associated virus (AAV) injection into the hippocampal CA1 region in vivo and via lentiviral transfection in vitro. We assessed cognitive function using the Morris water maze, Y-maze, and novel object recognition tests (n = 10). Glucose metabolism was evaluated by 18F-FDG PET imaging (n = 3), while synaptic and myelin sheath ultrastructure was examined using transmission electron microscopy (n = 6). Cell viability, mitochondrial function, and key protein expression were measured using CCK-8 assays, Seahorse analysis, and molecular biology techniques, respectively (n = 3, n = 6). In both in vivo and in vitro STZ-induced SAD models, GSK3β knockdown significantly reduced amyloid-β (1-42) deposition and tau hyperphosphorylation, activated the Wnt/β-catenin pathway, enhanced glucose metabolism, reversed glycolytic inhibition and mitochondrial dysfunction, and repaired synaptic and myelin sheath damage, ultimately improving cognitive deficits. Our findings demonstrate that GSK3β knockdown ameliorates STZ-induced SAD-like pathologies by restoring Wnt/β-catenin signaling and normalizing glucose metabolism, highlighting GSK3β as a potential therapeutic target for SAD.

Keywords:  GSK3β/Wnt/β-catenin; Glucose Metabolism; Mitochondria; Sporadic Alzheimer's disease; Synapse

DOI:  https://doi.org/10.1007/s12035-026-05970-1
Autophagy. 2026 Jun 18.

Dysregulation of a novel autophagosome-mitochondria contact contributes to tauopathy-related neurodegeneration by disrupting autophagy.

Nuo Jia, Yantao Zuo, Hongyuan Guan, Gavesh Rajapaksha, Qian Cai.

  Beyond their role in energy production, mitochondria also interact with other organelles through forming membrane contacts that serve as central hubs of cellular metabolism and signaling. Aberrant mitochondria-organelle communication has been implicated in various neurodegenerative diseases, but the underlying mechanisms and their pathological consequences remain poorly understood. Here, we reveal that tauopathy synapses exhibit excessive tethering of autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contacts, driven by mitochondrial bioenergetic deficit-induced hyperactivity of adenosine monophosphate-activated protein kinase (AMPK) that results in accelerated turnover of the contact release factor TBC1D15. Such defects consequently disrupt autophagy-mediated clearance of MAPT/tau by preventing AV retrograde transport. Strikingly, elevating TBC1D15 levels normalizes AV-Mito contact dynamics and restores autophagy activity, thereby mitigating MAPT/tau pathology and ameliorating neurodegeneration and cognitive impairment in tauopathy mice. Together, these findings establish bioenergetic deficits and the resulting AV-Mito hyper-tethering as a critical mechanism driving autophagy dysfunction and pathological MAPT/tau buildup in tauopathy neurons and highlight TBC1D15-modulated AV-Mito contact release and autophagy as promising therapeutic targets for tauopathies, including Alzheimer disease.

Keywords:  AMPK; Alzheimer; TBC1D15; autophagosome-mitochondria contact; autophagy; mitochondrial bioenergetics; retrograde transport; tauopathy

DOI:  https://doi.org/10.1080/15548627.2026.2692613
J Biochem Mol Toxicol. 2026 Jun;40(6): e70924

Posttranscriptional Regulation of Metabolism in Glioblastoma: A Multipathway Review.

Suleiman Ibrahim Mohammad, Asokan Vasudevan, Favian Bayas Morejón, Bobur Abduvoyitov, Tina Saeed Basunduwah, Zahraa Khudhair Abbas Al-Khafaji, Basma Mohammed Abdulhussein, Ahmed Hjazi, Khetam Habeeb Rasool, Majid S Jabir.

  Glioblastoma (GBM) is the most aggressive and lethal form of primary brain tumor. A hallmark of GBM metabolism is the Warburg effect, whereby tumor cells preferentially utilize aerobic glycolysis despite oxygen availability, producing ATP inefficiently but supporting anabolic processes. Concurrently, the pentose phosphate pathway (PPP), amino acid metabolism, lipid biosynthesis, and nucleotide synthesis are rewired to meet the energetic and biosynthetic demands of GBM cells. Recent discoveries underscore the role of microRNAs (miRNAs) as master regulators orchestrating these metabolic rewiring events. Acting posttranscriptionally, miRNAs target key transporters, enzymes, and signaling molecules involved in glycolysis, glutaminolysis, lipid biosynthesis, and oxidative metabolism. This review explores how miRNA networks modulate metabolic plasticity in GBM. Specific miRNAs, such as miR-153, miR-451, miR-940, and miR-200b, suppress glutamine metabolism, regulate glucose transporters (e.g., GLUT1/3), inhibit lactate dehydrogenase, and disrupt mitochondrial folate metabolism. Others, such as miR-29 and miR-183, control lipid and nucleotide metabolism via the SREBP1 and IDH2 pathways. Furthermore, regulatory interactions among miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), such as the XIST/miR-126 or circ-CREBBP/miR-375 axes, create complex feedback loops that fine-tune metabolic pathways and enhance tumor survival under stress. We also discuss therapeutic strategies targeting these miRNA-metabolism circuits, including nanoparticle delivery, dietary restriction, and combination therapies that re-sensitize tumors to temozolomide and radiation. Understanding and therapeutically exploiting these networks presents a powerful approach to overcoming GBM's metabolic resilience, thereby opening new avenues for precision oncology.

Keywords:  glioblastoma; glycolysis; metabolic reprogramming; microRNAs; therapeutics

DOI:  https://doi.org/10.1002/jbt.70924
Biophys Rev. 2026 Apr;18(2): 511-526

Insight into the metabolism of gliomas by MRI and MRS.

Samishtha Pandey, Neha Yadav, Vivek Tiwari, Naranamangalam R Jagannathan.

  Gliomas are biologically and metabolically heterogeneous brain tumors whose clinical behavior is strongly influenced by lineage-defining genomic alterations such as isocitrate dehydrogenase (IDH1/2) mutation, 1p/19q-codeletion, ATRX loss, TERT promoter mutation, etc. Conventional magnetic resonance imaging (MRI) and tumor tissue biopsy are the clinical standards for diagnosis, tumor grading, and treatment planning. The conventional MRI/ magnetic resonance spectroscopy (MRS) identifies structural and vascular changes, and easy-to-measure high concentration metabolites. However, conventional MRS method suffers from spectral overlap and fails to provide a pure resonance, thus, it has limited application for estimation of difficult-to-identify and clinically relevant metabolic pool and flux changes in the tumors. Metabolic imaging using in vivo molecule tailored MRS provides a quantitative, highly precise non-invasive approach to measure tumor biochemistry in real time for ascertaining clinically relevant signatures for tumor diagnostication and prognostication. Recent developments in spectroscopic editing methods have provided quantitative MRS approaches to measure challenging metabolites such as glycine (Gly), glutamine (Gln), glutamate (Glu), 2-hydroxyglutarate (2HG), cystathionine and glutathione (GSH), in addition to routine MRS based measurements of metabolites, such as N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lactate (Lac), etc. The pool of 2HG reflects epigenetic and redox remodeling in IDH-mutant tumors, whereas elevated glycine is associated with increased nucleotide demand and proliferative activity. Furthermore, molecule tailored MRS provide insights into cysteine-centered transsulfuration, antioxidant reprogramming and GSH-mediated radioresistance. Notably, these metabolic alterations often precede visible changes seen on anatomical MRI. Thus, metabolic profiling using molecule tailored MRS helps to find early tumor biomarkers for better diagnosis, along with the MRI. Future directions should include standardizing MRS protocols across imaging platforms, integrating metabolic markers with radio-genomics and machine-learning frameworks. Further, multi-center clinical trials and incorporating metabolic endpoints are necessary for adaptive therapy strategies. Together, MRI and MRS provide a comprehensive view of glioma biology that supports precision diagnosis, risk stratification, and individualized treatment planning, thereby advancing the goal of routine clinical adoption of metabolic imaging in neuro-oncology.

Keywords:  Glioma; In vivo; MRI; MRS; Metabolic Reprogramming

DOI:  https://doi.org/10.1007/s12551-026-01416-z
Fluids Barriers CNS. 2026 Jun 13. pii: 81. [Epub ahead of print]23(1):

Characterization of blood-brain barrier L-arginine uptake using in situ brain perfusions in a female mouse model.

Olivia C Milam, Cullen P Wolford, Geoffrey L Pecar, Joshua J Applegate, Maxine E Casto, Dominic J Gabriele, Austin S Nestor, Paul R Lockman.

   BACKGROUND: L-arginine is a critical determinant of central nervous system (CNS) function through nitric oxide (NO) production. Its uptake from plasma into brain is dependent on carrier-mediated transport across the blood-brain barrier (BBB). Transport kinetics of L-arginine BBB uptake have been assessed in rat models, but saturation constants such as maximal transport rate (Vmax), half-saturation constant (KM), and diffusion constant (KD) in mice remain unknown. The aim of this study was to determine the transporter responsible for L-arginine BBB transport and to provide a complete kinetic profile, including whole brain and regional saturation kinetics of its transport, in a female mouse model.
METHODS: BALBc mice were perfused with 3H-L-arginine using the in situ brain perfusion technique. Linear and unidirectional uptake was determined by perfusion at increasing timepoints (15-60s). Saturation kinetics were identified regionally and in whole brain by adding unlabeled L-arginine to buffer and perfusing for 45s. Sodium sensitivity was evaluated by decreasing sodium levels with replacement of cesium to maintain physiologic osmolarity. Dependence of transport on hydrogen ions was determined across ranges of pH (5.5-8) by addition of hydrochloric acid or sodium hydroxide. The transport system responsible for L-arginine BBB transport was assessed by adding inhibitors such as harmaline, N-methylmaleimide (NMM), L-homoarginine, cimetidine, and 2-amino-2-norbornanecarboxylic acid (BCH), and was further evaluated for affinity to other cationic amino acids, including L-lysine and L-ornithine. Inhibitory constants (Ki) were calculated to assess the affinity of inhibitors at the transporter.
RESULTS: BBB arginine uptake showed both saturable and nonsaturable components, with a whole brain Kin, KM and Vmax of 0.25 ± 0.02 × 10-2 mL/s/g, 55 ± 10 µM and 5.9 ± 0.3 nmol/min/g, respectively. Whole brain diffusion constant, KD, was 2.7 ± 1.0 × 10-4 mL/s/g. Furthermore, regional data showed cerebellar Vmax was significantly higher than in cortical tissue (5.5 ± 0.6 vs. 9.3 ± 0.9 nmol/min/g). L-arginine transport was insensitive to sodium depletion and was not inhibited at pH levels 7, 7.4, or 8, but was significantly inhibited at pH 5.5. Its transport was not significantly inhibited by BCH, harmaline, NMM, or cimetidine, but was sensitive to inhibition by L-homoarginine and other cationic amino acids, including lysine and ornithine.
CONCLUSION: The results indicate that mice predominantly use the y+ system, a cationic amino acid transporter, to transport L-arginine across the BBB. Our work supports previous characterization of BBB carrier-mediated transport of L-arginine yet extends the data by assessing complete Michaelis-Menten transport kinetics across regions and in whole brain in a female mouse model. Data further suggest species can influence BBB L-arginine transport function and there is differential need for L-arginine between brain regions. This data serves as a baseline for studies involving alterations in cationic amino acid homeostasis or altered L-arginine metabolism such as in cases of arginine auxotrophy.

Keywords:  Amino acid brain transport; Amino acid homeostasis; Blood-brain barrier; L-arginine; Nitric oxide; Transport kinetics

DOI:  https://doi.org/10.1186/s12987-026-00832-3
Mol Ther Adv. 2026 Jun 11. 34(2): 201760

In vivo adenine base editing rescues brain biochemistry and improves motor deficits in a common phenylketonuria variant.

Megan K Gautier, Kaitlyn King, Yongseok Han, Hooda Said, Mohamad-Gabriel Alameh, Xiao Wang, Xinying Hong, Kiran Musunuru, Rebecca C Ahrens-Nicklas.

  Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. Patients are unable to convert the amino acid phenylalanine (Phe) into tyrosine (Tyr), leading to neurotoxic Phe accumulation. Chronically elevated Phe results in intellectual disability, psychiatric disorders, motor impairments, and epilepsy in affected children. Although there are interventions that focus on reducing plasma Phe levels, no curative therapies exist for PKU. Utilizing an adenine base editor (ABE), we demonstrate efficient in vivo corrective editing of hepatocytes in humanized PKU mice homozygous for the common P281L (c.842C>T) variant of PAH. Delivery of the ABE via lipid nanoparticles (LNPs) at four weeks of age resulted in significant reductions in Phe levels in plasma and cortex, as well as increases in cerebral amino acid and neurotransmitter concentrations. Behavioral assessment post-treatment revealed improvements in abnormal motor phenotypes. These data provide increased support for the viability of ABE-based therapeutics as a durable treatment for patients with monogenic metabolic disorders.

Keywords:  PAH; PKU; base editing; in vivo gene therapy; inborn error of metabolism; lipid nanoparticle; mRNA; neurotransmitter; phenylalanine; rotarod

DOI:  https://doi.org/10.1016/j.omta.2026.201760