bims-medebr 2026-05-31 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2026–05–31
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University

Pentose Phosphate Pathway Is Critical for Providing Energy by Bypassing 6-Phosphofructo-1-Kinase (PFK1) During Increased Neuronal Activity.
Diet, Metabolism and Synaptic Function: Integrating Evidence Across Models in Neurodegeneration Research.
ROS-HIF1α-driven glycolytic reprogramming sustains ATP production in Huntington's disease.
Blocking β-alanine synthesis triggers widespread perturbations of energy and lipid metabolism in the brain.
Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.
Hippocampal CA1 and CA2 dendritic compartment-specific differences in mitochondrial form and function.
Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.
Aspartate-Glutamate Carrier 1 (SLC25A12) Deficiency: Malate-Aspartate Shuttle Failure, Neurodevelopmental Epileptic Encephalopathy, and Ketone-Based Metabolic Therapy.
The impact of lactate and lipid metabolism in microglia upon cognitive impairment following radiation-induced brain injury.
Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain.
Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.
Oxysterol Signaling Within the Microbiome-Regulated Gut-Liver-Brain Axis: Implications for Metabolic Homeostasis and Neurodegeneration.
Uncovering the causal link between cerebral glucose metabolism and cognitive function in Alzheimer's disease.
Metabolic modelling and time-resolved mapping of glucose oxidative metabolism in the rat brain by indirect deuterium detection with 1H-FID-MRSI at 9.4 T.
Cerebral metabolic trajectories alterations in multiple system atrophy: A longitudinal FDG-PET study.
Glycogen drives the sensory activation of POMC neurons.
Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.
A high-throughput screening platform to facilitate treatment development in Rett syndrome.

Metabolites. 2026 May 12. pii: 321. [Epub ahead of print]16(5):

Pentose Phosphate Pathway Is Critical for Providing Energy by Bypassing 6-Phosphofructo-1-Kinase (PFK1) During Increased Neuronal Activity.

Tibor Kristian, Jaylyn Waddell, Mary C McKenna.

  Glycolysis and the pentose phosphate pathway (PPP) are two metabolic pathways that play crucial roles in brain energy metabolism. The glycolytic pathway is differentially regulated in neurons compared to astrocytes. In neurons, the flux directly through the glycolytic pathway is reduced due to compromised ability to activate the key glycolytic enzyme 6-phosphofructo-1-kinase (PFK1). Consequently, potential increases in neuronal glucose metabolic flux can occur through the PPP, leading to the generation of NADPH, which is essential for the antioxidant defense system in these cells. Additionally, the PPP can supply glycolysis with intermediates downstream of PFK1, resulting in the production of pyruvate, which is used by mitochondria for oxidative phosphorylation and ATP production. In this review, we propose that during increased activity, neurons will preferentially metabolize glucose through the PPP. This allows them to support their antioxidant defense mechanisms and maintain bioenergetic metabolism by bypassing the limiting PFK1 enzyme and still forming pyruvate for mitochondrial oxidation.

Keywords:  astrocytes; glucose metabolism; glycolysis; neurons; pentose-phosphate pathway; pyruvate

DOI:  https://doi.org/10.3390/metabo16050321
Biomedicines. 2026 May 12. pii: 1089. [Epub ahead of print]14(5):

Diet, Metabolism and Synaptic Function: Integrating Evidence Across Models in Neurodegeneration Research.

Imogen L Targett, John T Hancock, Tim J Craig.

  The brain has a higher energy demand per unit weight than any other organ in the body; however, links between metabolism, diet and neurological function have historically been underexplored. This partly stems from early assumptions that brain metabolism is primarily dependent on glucose and ketone bodies, whereas more recent evidence indicates broader metabolic flexibility and complex cell-type specialisation. In the past few decades, brain metabolism has become increasingly recognised as relevant to neurological and mental health, and many neurodegenerative disorders are accompanied by changes in brain energy utilisation. In parallel, epidemiological studies associate hypercaloric dietary patterns and metabolic disorders-particularly type-2 diabetes mellitus-with increased risk of later cognitive decline and sporadic Alzheimer's disease, although causal pathways remain difficult to establish in humans. In this narrative review, we summarise selected findings linking "unhealthy" diets to synaptic function, focusing on synaptic plasticity, neuroinflammation and adult hippocampal neurogenesis, and we distinguish between evidence from human observational studies and mechanistic insights from animal and cellular models. We also discuss candidate mechanisms-including insulin resistance-linked signalling changes, lipid-driven inflammatory amplification, oxidative stress, and altered lipid handling-that may contribute to synaptic vulnerability. Finally, we outline translational considerations and key knowledge gaps (including physiological exposure levels and heterogeneity of experimental paradigms) that currently limit inference from preclinical models to clinical intervention.

Keywords:  brain metabolism; diabetes; fatty acids; high-fat diet; high-sugar diet; neurodegeneration; neurogenesis; neuroinflammation

DOI:  https://doi.org/10.3390/biomedicines14051089
Neurobiol Dis. 2026 May 25. pii: S0969-9961(26)00204-4. [Epub ahead of print]226 107459

ROS-HIF1α-driven glycolytic reprogramming sustains ATP production in Huntington's disease.

Ching-Wen Wu, Ching-Pang Chang, Dennis W Hwang, Yu-Wen Chen, Yan Hua Lee, Jian Jing Siew, Hui-Mei Chen, Yijuang Chern.

  Huntington's disease (HD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and impaired energy metabolism contribute to disease pathogenesis. Surprisingly, we find that ATP levels are not diminished but instead elevated in the striatum of R6/2 HD mice despite impaired TCA cycle intermediates and mitochondrial deficits. Integrative metabolomics, gene expression profiling, and pharmacological perturbation reveal that increased reactive oxygen species stabilize hypoxia-inducible factor-1α (HIF1α), driving enhanced glucose uptake and glycolytic flux. In vivo dynamic glucose-enhanced (DGE) MRI further supports altered glucose handling in the living R6/2 brain. Inhibition of either glycolysis or HIF1α abolishes ATP elevation, suggesting that HIF1α-dependent glycolysis compensates for mitochondrial impairment. Single-nucleus RNA sequencing further uncovers coordinated metabolic reprogramming across neuronal and glial populations. These findings reveal an oxidative stress-triggered metabolic switch that sustains ATP production in HD, redefining bioenergetic adaptation in neurodegenerative diseases.

Keywords:  Energy metabolism; Glucose uptake; Glycolysis; HIF1α; Huntington's disease; Metabolic resilience; Oxidative stress

DOI:  https://doi.org/10.1016/j.nbd.2026.107459
Mol Metab. 2026 May 23. pii: S2212-8778(26)00067-0. [Epub ahead of print] 102383

Blocking β-alanine synthesis triggers widespread perturbations of energy and lipid metabolism in the brain.

Selina Cannon Homaei, Elaheh Mahootchi, Aashish Srivastava, Mahima Sanjay Gomladu, Oda Caspara Krokengen, Anne Baumann, Jan Haavik.

   BACKGROUND: Glutamate decarboxylase-like 1 (GADL1) decarboxylates aspartic acid to β-alanine in several mammalian tissues, particularly in the brain and skeletal muscle. β-alanine is a precursor to the antioxidant and osmoregulatory dipeptide carnosine (β-alanyl-l-histidine), as well as pantothenic acid and coenzyme A. Deletion of GADL1 reduces carnosine and anserine levels in multiple tissues, but the consequences for brain metabolism remain unclear. This study aimed to explore sex-specific metabolic and cellular effects of GADL1 and β-alanine depletion in different areas of the brain.
METHODS AND RESULTS: We conducted a metabolomic screening of seven mouse tissues, followed by a detailed transcriptomic, proteomic, and metabolomic analysis of cerebrum, cerebellum, and olfactory bulb tissues from male and female GADL1 knockout and wild-type mice to explore sex-, age-, and region-specific molecular alterations. Loss of GADL1 induced distinct, sex-dependent metabolic responses across brain regions. Metabolomic data showed increased oxidative stress and possible synaptic remodeling in the cerebrum of mature females, whereas males exhibited massive lipid accumulation in multiple tissues. A similar pattern appeared in the developing olfactory bulb, where both sexes displayed lipid accumulation, but only males showed signs of inflammatory activation and altered energy metabolism, as supported by transcriptomic and proteomic analyses.
CONCLUSIONS: GADL1 loss and consequent β-alanine depletion trigger widespread metabolic remodeling in brain tissue. Even modest β-alanine reduction leads to region, age, and sex-specific perturbations of energy metabolism and cellular homeostasis. These findings highlight the multifaceted biochemical roles of β-alanine and suggest that its physiological and therapeutic effects may differ by tissue, sex, and developmental stage.

Keywords:  Carnosine; Energy homeostasis; Fatty acid synthesis; Glutamate decarboxylase-like 1 (GADL1); Multi-omics; β-alanine metabolism

DOI:  https://doi.org/10.1016/j.molmet.2026.102383
Front Immunol. 2026 ;17 1815719

Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.

Tingting Li, Kanglin Guo, Yongxia Ma, Jianjun Zhao, Yanchun Cao, Run Zhang, Xiang Li, Jing Wei, Yufang Ma, Zongxia Zhu, Dongrong Zhao.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau pathology, and sustained neuroinflammation. Increasing evidence indicates that dysregulated lipid metabolism is not merely a metabolic disturbance but a critical modulator of inflammatory responses driving AD pathogenesis. The brain, one of the most lipid-enriched organs, relies on tightly controlled lipid homeostasis to maintain neuronal function and synaptic integrity. Alterations in fatty acid composition, apolipoprotein E (ApoE) isoforms, lipoprotein lipase activity, and lipid-derived signaling mediators profoundly reshape microglial activation states and inflammatory cascades. Obesity, insulin resistance, and gut microbiota dysbiosis further exacerbate systemic and central lipid imbalance, amplifying neuroinflammatory signaling through cytokine networks and blood-brain barrier disruption. Notably, polyunsaturated fatty acids and lipid mediators exert dual immunomodulatory effects, influencing β-amyloid aggregation, oxidative stress, and microglial polarization. This review synthesizes recent advances in understanding how lipid metabolism modulates neuroinflammation and microglia-neuron crosstalk in AD, highlighting emerging therapeutic strategies targeting lipid-inflammation axes as promising avenues for disease modification.

Keywords:  Alzheimer’s disease; apolipoprotein E (APOE); fatty acids; gut–brain axis; lipid metabolism; metabolic dysregulation; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1815719
Prog Neurobiol. 2026 May 26. pii: S0301-0082(26)00057-2. [Epub ahead of print] 102931

Hippocampal CA1 and CA2 dendritic compartment-specific differences in mitochondrial form and function.

Mayd Alsalman, Lucy Turner, Katy Pannoni, Renesa Tarannum, Rutvi Desai, Sharon A Swanger, Shannon Farris.

  Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found that CA2 dendritic mitochondria were larger than in CA1. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for MFF and OPA1, which showed a general enrichment in distal relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerability to disease.

Keywords:  calcium; dendrite; entorhinal cortex; heterogeneity; hippocampus; mitochondria

DOI:  https://doi.org/10.1016/j.pneurobio.2026.102931
Mol Neurodegener. 2026 May 28.

Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.

Dezhen Tu, Yuxiao Zheng, Pingping Ding, Miao Shen, Wangyang Tang, Bin Wei, Hongyan Wang.

  Cholesterol metabolites are abundant in the central nervous system (CNS) that regulate cell membrane fluidity, signal transduction, and inter- and intracellular vesicular transport, as well as cell proliferation/cell death or migration. Brain cholesterol synthesis and metabolism are tightly coupled to the functional homeostasis of neurons, glial cells or microglia, and dysregulation of these processes has been strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review provides a comprehensive overview of how cholesterol synthesis, esterification, efflux, uptake, and oxidation affect the CNS function, highlighting the function of key enzymes or metabolites in distinct brain cell types during neurodegeneration. Based on single-cell/nucleus RNA sequencing data from the brains of AD, PD, and HD patients, we summarize cell-type-specific genes in cholesterol metabolism pathways, shedding new light to understand cellular heterogeneity. The role of cholesterol-derived neurosteroids in neurodegenerative diseases is also discussed. Furthermore, how cholesterol metabolites modulate the formation, aggregation, and degradation of amyloid-β (Aβ), α-synuclein and huntingtin, as well as Tau protein phosphorylation are outlined. Finally, future research directions are proposed that aim to understand neurodegenerative diseases with new angle.

Keywords:  Astrocyte; Cholesterol metabolism; Microglia; Neurodegeneration; Neuron; Oligodendrocyte

DOI:  https://doi.org/10.1186/s13024-026-00951-3
Int J Mol Sci. 2026 May 15. pii: 4455. [Epub ahead of print]27(10):

Aspartate-Glutamate Carrier 1 (SLC25A12) Deficiency: Malate-Aspartate Shuttle Failure, Neurodevelopmental Epileptic Encephalopathy, and Ketone-Based Metabolic Therapy.

Manuela Murano, Giorgia Natalia Iaconisi, Magnus Monné, Amer Ahmed, Giuseppe Fiermonte, Loredana Capobianco, Vincenza Dolce.

  Aspartate-glutamate carrier 1 (AGC1) deficiency is a rare neurometabolic disorder caused by biallelic pathogenic variants in SLC25A12. Clinically, it is characterized by early-onset developmental and epileptic encephalopathy, often associated with hypomyelination and reduced brain N-acetylaspartate. AGC1 loss reduces malate-aspartate shuttle flux, limiting cytosolic NAD+ regeneration and impairing neuronal redox coupling, ATP supply, and aspartate-dependent biosynthesis during brain development. We integrate human genetics with mechanistic evidence from mammalian, Drosophila melanogaster, and Saccharomyces cerevisiae models to describe conserved transport principles and species-specific regulation underlying selective central nervous system vulnerability. We review the management of AGC1 deficiency, focusing on ketogenic therapy. Published reports show reproducible seizure reduction and, in some patients, improved myelination and N-acetylaspartate. However, these responses are heterogeneous and appear to depend on the timing, duration, and stability of ketosis. Preclinical evidence suggests that β-hydroxybutyrate may contribute to metabolic support in AGC1 deficiency. Prospective studies should test disease modification using standardized endpoints plus MRI/1H-MRS and ketosis measures.

Keywords:  N-acetylaspartate (NAA); SLC25A12; aspartate/glutamate carrier 1 (AGC1); epilepsy; ketogenic diet; myelination

DOI:  https://doi.org/10.3390/ijms27104455
J Transl Med. 2026 May 26.

The impact of lactate and lipid metabolism in microglia upon cognitive impairment following radiation-induced brain injury.

Zeyuan Li, Yu Lin, Yi Lu, Lijing Zeng, Hongdan Guan, Fenghao Huang, Xianyi Zeng, Qiwei Yao, Rong Zheng.

   BACKGROUND: Radiation-induced brain injury (RIBI) is a serious complication that occurs after cranial radiotherapy. The main manifestations are delayed radiation effects characterized by neuroinflammation and damage to neural stem cell populations. Microglia, the resident immune cells of the central nervous system (CNS), have become key mediators in the pathological process of RIBI. This review aims to systematically elucidate how metabolic reprogramming of lactate and lipid pathways in microglia contributes to chronic neuroinflammation and cognitive impairment following RIBI, and to evaluate the therapeutic potential of targeting these metabolic pathways.
MAIN BODY: Ionizing radiation (IR) triggers intense activation of microglia, which initiates and maintains a chronic neuroinflammatory state characterized by the release of cytotoxic mediators and changes in phagocytic function. Changes in lactate and lipid metabolism within microglia are crucial in their response to neuroinflammation and neurodegeneration. Activated microglia typically change their metabolism from oxidative phosphorylation (OXPHOS), which uses oxygen to generate energy, to a process called aerobic glycolysis, which leads to increased lactate production. This metabolic shift, combined with the role of lactate as a signaling molecule and a substrate for epigenetic modifications (lactylation), can significantly influence the inflammatory outcome. Additionally, dysregulation of lipid metabolism, such as accumulation of lipid droplets (LDs), represents a pro-inflammatory, dysfunctional state known as lipid droplet accumulation-type microglia (LDAM), and is associated with impaired phagocytosis and persistent inflammation. This article summarizes the pathological mechanisms of RIBI, with a focus on the complex roles of lactate and lipid metabolism in microglia. It explores how radiation induces microglial activation and metabolic transformation. The article also discusses the dual role of lactate, the effects of lipid dysregulation, and potential interactions between metabolic pathways. Finally, it highlights how these factors commonly relate to impaired inflammatory responses and disruptions in neural repair processes, such as neurogenesis and oligodendrocyte generation.
CONCLUSIONS: By studying how changes in microglial metabolism lead to neuronal dysfunction and cognitive decline in RIBI, this review provides a new perspective for regulating microglial metabolic pathways to alleviate radiation-induced cognitive impairment.

Keywords:  Cognitive impairment; Lactate metabolism; Lipid metabolism; Metabolic reprogramming; Microglia; Neuroinflammation; Radiation-induced brain injury

DOI:  https://doi.org/10.1186/s12967-026-08309-5
Mol Neurobiol. 2026 May 26. pii: 651. [Epub ahead of print]63(1):

Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain.

Enso O Torres Alegre, Diana E Mora Jiménez.

  Chronic pain is traditionally framed as a consequence of neuroinflammation and maladaptive synaptic plasticity, with activated microglia releasing cytokines, chemokines, and growth factors that sensitize nociceptive circuits in the spinal dorsal horn. However, microglial activation is also accompanied by profound metabolic reprogramming-including a glycolytic shift, altered mitochondrial dynamics, and increased demand for biosynthetic intermediates-that has received comparatively little attention in pain neurobiology. Here, we propose that metabolic competition between activated microglia and neighboring neurons may constitute an underexplored mechanism contributing to persistent pain states. We argue that shifts in local energy allocation-particularly glucose, lactate, and nicotinamide adenine dinucleotide (NAD+) availability-could modulate neuronal excitability and sustain central sensitization even when classical inflammatory signaling is no longer dominant. Drawing on advances in immunometabolism, emerging single-cell/spatial metabolomics, and in vivo biosensor imaging, we integrate neuroimmunology with metabolic neurobiology to generate experimentally testable predictions. If validated, this framework could reposition cellular metabolism as a tractable therapeutic dimension for chronic pain management.

Keywords:  Astrocyte–neuron lactate shuttle; Central sensitization; Chronic pain; Dorsal horn; Glycolysis; Immunometabolism; Metabolic reprogramming; Microglia; Mitochondrial dysfunction; Warburg effect

DOI:  https://doi.org/10.1007/s12035-026-05952-3
Antioxid Redox Signal. 2026 May 28. 15230864261455714

Mitochondrial NAD+ Transport Alleviates Cerebral Ischemia/Reperfusion Injury via Enhancement of Mitochondrial Function.

Xiaorong Wang, Yuxin Li, Jinhua Tan, Xiaona Sun, Qidi Zhou, Rui Xu, Xiaoqi Song, Yu Cui, Zhaolong Zhang.

   AIMS: Cerebral ischemia-reperfusion (I/R) injury is a leading cause of neurological disability and is characterized by mitochondrial dysfunction and oxidative stress. Although depletion of nicotinamide adenine dinucleotide (NAD+) is a hallmark of ischemic injury, therapeutic strategies aimed at NAD+ replenishment have shown limited efficacy. Whether impaired mitochondrial NAD+ import contributes to neuronal vulnerability after I/R remains poorly understood.
RESULTS: We found that cerebral I/R disrupts the balance of NAD+ distribution between the cytoplasm and mitochondria in the cortex due to upregulated expression of SLC25A51. Augmenting SLC25A51 expression restored mitochondrial NAD+ pools, improved mitochondrial respiratory function, reduced oxidative lipid damage, and attenuated neuronal injury. In contrast, SLC25A51 deficiency exacerbated mitochondrial dysfunction and heightened susceptibility to I/R stress. These effects occurred independently of global NAD+ biosynthesis, indicating that mitochondrial NAD+ transport rather than NAD+ availability per se is a critical determinant of neuronal survival.
INNOVATION: This study reveals the subcellular distribution change of NAD+-mediated by SLC25A51 and its neuroprotective effects via modulating mitochondrial function after cerebral I/R injury.
CONCLUSION: This study identifies defective mitochondrial NAD+ import as a previously underrecognized mechanism of cerebral I/R injury. By establishing SLC25A51-dependent NAD+ trafficking as a key regulator of mitochondrial redox balance and neuronal resilience, our findings shift the therapeutic paradigm from NAD+ supplementation to restoration of subcellular NAD+ distribution, highlighting mitochondrial NAD+ transport as a promising target for ischemic brain injury. Antioxid. Redox Signal. 00, 000-000.

Keywords:  NAD+; SLC25A51; ischemic-reperfusion injury; mitochondria; neurons; oxidative stress

DOI:  https://doi.org/10.1177/15230864261455714
Compr Physiol. 2026 06;16(3): e70181

Oxysterol Signaling Within the Microbiome-Regulated Gut-Liver-Brain Axis: Implications for Metabolic Homeostasis and Neurodegeneration.

Nila Ganamurali, Sarvesh Sabarathinam.

  The gut-liver-brain axis integrates metabolic and inflammatory signals that influence systemic homeostasis and cognitive function. While current models emphasize short-chain fatty acids and bile acids, they do not fully explain lipid-driven neurodegenerative processes. Oxysterols, oxidized derivatives of cholesterol, are emerging as key signaling molecules that bridge peripheral metabolism and brain function. Generated at the gut-liver interface through enzymatic and oxidative pathways, oxysterols regulate lipid and glucose metabolism via nuclear receptors, including liver X receptors and farnesoid X receptor. Importantly, specific oxysterols cross the blood brain barrier, enabling bidirectional communication between the periphery and central nervous system. By modulating neuroinflammation and synaptic function, oxysterols provide a mechanistic link between metabolic dysfunction and cognitive decline.

Keywords:  Good Health and Well‐being; cholesterol metabolism; cognitive decline; gut–brain axis; metabolic dysfunction; neuroinflammation; oxysterols

DOI:  https://doi.org/10.1002/cph4.70181
J Alzheimers Dis. 2026 May 25. 13872877261452181

Uncovering the causal link between cerebral glucose metabolism and cognitive function in Alzheimer's disease.

Catarina Tristão-Pereira, Marta Casquero-Veiga, Vincent Malotaux, Yakeel T Quiroz.

  Cerebral glucose metabolism is distinctly disrupted in Alzheimer's disease (AD), though its role in downstream cognitive decline remains unclear. Ueda et al. leverage Mendelian Randomization by integrating genetics, imaging and cognitive data to demonstrate that cerebral glucose metabolism is causally linked to cognitive performance. This approach lays the groundwork for novel therapeutic strategies by suggesting that metabolism-focused interventions may mitigate cognitive impairment in AD. Future studies should further integrate single-cell and multi-omics strategies to elucidate cellular and molecular pathways related to causal effects and explore the influence of co-pathologies and epigenetics on metabolic and cognitive performance.

Keywords:  Alzheimer's disease; Mendelian randomization; glucose metabolism; therapeutics/treatments

DOI:  https://doi.org/10.1177/13872877261452181
MAGMA. 2026 May 27.

Metabolic modelling and time-resolved mapping of glucose oxidative metabolism in the rat brain by indirect deuterium detection with 1H-FID-MRSI at 9.4 T.

Alessio Siviglia, Gianna Nossa, Brayan Alves, Fabian Niess, Anna Duguid, Zenon Starčuk, Wolfgang Bogner, Bernhard Strasser, Cristina Cudalbu, Bernard Lanz.

   OBJECT: This study exploits newly developed dynamic indirect 1H-[2H]-FID-MRSI at 9.4 T, combined with a dedicated metabolic model, to enable regional and quantitative characterization of glucose oxidative metabolism flux in the rat brain with minimal metabolic assumptions, by measuring both 2H-labelled Glx turnover and pool size along a controlled 2H-Glc infusion protocol.
MATERIALS AND METHODS: Seven rats underwent dynamic 2D 1H-FID-MRSI during a 2-h infusion of [6,6'-2H₂] glucose. Consecutive 13-min acquisitions quantified Glx-C4 1H-signal decay, converted to 2H-Glx concentrations using baseline metabolite pool sizes. A four-pool kinetic model including 2H-label loss was fitted to regional turnover curves to estimate oxidative flux (Vgt) and pyruvate dilution (Kdil). Model performance and parameter robustness were assessed with Monte-Carlo simulations.
RESULTS: In vivo 2H-Glx turnover showed a saturated exponential rise (~ 60 min), with a labelling plateau higher in striatum (1.85 μmol/g) than hippocampus (1.55 μmol/g). Metabolic modelling provided region-specific oxidative fluxes: Vgt = 0.53 ± 0.15 μmol/g/min (hippocampus) and Vgt = 0.81 ± 0.12 μmol/g/min (striatum), with consistent Kdil across regions. Simulations confirmed a good model robustness in retrieving Vgt over a large range of experimental conditions.
DISCUSSION: This work shows the potential of indirect dynamic 1H-[2H]-FID-MRSI for quantitative metabolic flux mapping of cerebral glucose oxidative metabolism.

Keywords:  Brain; Deuterium; Glucose oxidative metabolism; Magnetic Resonance Spectroscopic Imaging; QELT; Rats

DOI:  https://doi.org/10.1007/s10334-026-01363-6
J Parkinsons Dis. 2026 May 28. 1877718X261455593

Cerebral metabolic trajectories alterations in multiple system atrophy: A longitudinal FDG-PET study.

Yixin Zhao, Huamei Lin, Xinyi Li, Qi Shen, Jing Wang, Chuantao Zuo, Jian Wang, Jingjie Ge, Feng-Tao Liu.

  Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder with different metabolic patterns in parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes, but their longitudinal changes are not well understood. To characterize longitudinal changes of glucose metabolism and network connectivity in MSA using 18F-FDG-PET for early diagnosis and disease progression tracking, we retrospectively analyzed 29 MSA patients (17 MSA-P, 12 MSA-C) and 28 healthy controls. Regional glucose uptake was assessed as standardized uptake value ratios (SUVR). We examined inter-regional connectivity via correlation analysis and modeled metabolic decline using nonlinear mixed-effects models. Clinical progression was measured using the Unified Multiple System Atrophy Rating Scale (UMSARS). MSA-P displayed progressive hypometabolism in the putamen, cerebellum, and frontal cortex, while MSA-C showed declines primarily in the cerebellum and frontal regions. Longitudinal modeling indicated a faster putaminal decline in MSA-P (β = -0.015 ± 0.006) than in MSA-C (β = 0 ± 0.011), whereas cerebellar metabolism declined over time in both groups with overlapping slopes in MSA-P (β = -0.022 ± 0.006) and MSA-C (β = -0.022 ± 0.011). Regional metabolic reductions correlated with UMSARS progression (putamen in MSA-P: r = -0.59, p < 0.001; cerebellum in MSA-C: r = -0.62, p < 0.001). Significant connectivity disruptions were noted in frontal, basal ganglia, and cerebellar-parietal circuits. Longitudinal FDG-PET reveals distinct metabolic decline patterns in MSA subtypes-putamen in MSA-P and cerebellum in MSA-C-linked to clinical severity. These findings may inform clinical practice and trial design, supporting the use of FDG-PET for biological staging, monitoring disease progression, and potentially evaluating treatment responses.

Keywords:  18F-fluorodeoxyglucose (18F-FDG); Multiple system atrophy; cerebral metabolism; positron emission tomography

DOI:  https://doi.org/10.1177/1877718X261455593
Nat Metab. 2026 May 27.

Glycogen drives the sensory activation of POMC neurons.

Alicia G Gómez-Valadés, David Meseguer, Luís Varela, Gabriele Lienhard, Uxía Fernández, Andrés Vidal-Itriago, Miriam Toledo, Elena Eyre, Berta Laudo, Francisco Díaz-Castro, Macarena Pozo, Mehdi Boutagouga Boudjadja, Júlia Fos-Domènech, Pau García-Ramón, Mariana Ferreira, Jordi Altirriba, Daniel Beiroa, Bandy Chen, Amanda Rodríguez-Díaz, Maria Milà-Guasch, Iñigo Chivite, Arnaud Obri, Sara Ramírez, Roberta Haddad-Tóvolli, Iasim Tahiri, Mathew S Gentry, Giuseppe D'Agostino, Rubén Nogueiras, Nicolas Renier, Tamas L Horvath, Joan J Guinovart, Jordi Duran, Marc Schneeberger, Marc Claret.

Hypothalamic POMC neurons modulate systemic energy balance and glucose homeostasis by sensing nutritional state signals. In addition to this classic regulatory mode, these neurons are also activated by the sensory perception of food. Here, we report that food-related sensory cues engage glycogen metabolism in POMC neurons. Genetic depletion of glycogen through various approaches renders POMC neurons unresponsive to food-associated sensory stimuli. This defective perception of food is linked to alterations in consummatory behaviour, hepatic adaptations and cephalic insulin release associated with a prediabetic phenotype that progresses into overweight and overt diabetes with a high-calorie diet or ageing. Collectively, our results posit glycogen as a decisive fuel resource for meeting the rapid and demanding energy requirements linked with sensory activation. Furthermore, our data delineate the biological function of food perception and provide support for the physiological relevance of neuronal glycogen.

DOI: https://doi.org/10.1038/s42255-026-01535-7
Alzheimers Res Ther. 2026 May 25.

Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.

Myuri Ruthirakuhan, Maya Mills, Paul Rosenberg, Norman Haughey, Jacobo Mintzer, Suzanne Craft, Nathan Herrmann, Alan J Lerner, Allan I Levey, Prasad R Padala, Anton Porsteinsson, Christopher H van Dyck, David Shade, Krista L Lanctôt.

   BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.
METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.
RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.
CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.

Keywords:  Alzheimer’s disease; Apathy; Lipidomics; Methylphenidate

DOI:  https://doi.org/10.1186/s13195-026-02055-y
Front Neurol. 2026 ;17 1759410

A high-throughput screening platform to facilitate treatment development in Rett syndrome.

Yanhong Yin, Anxin Wang, Qiping Dong, Ziyao Zhang, Qian Bu, Runfeng Wang, Qiang Chang.

  Rett syndrome (RTT) is a rare X-linked progressive neurodevelopmental disorder affecting predominantly females with no cure and a prevalence of ~1 in 10,000 female birth worldwide. Before mutations in the methyl-CpG binding protein 2 (MECP2) gene were identified to cause classic RTT, there were suggestions that RTT is a mitochondrial disease. Being an essential organelle for all eukaryotic cells, the mitochondria produce energy, buffer calcium, and regulate the generation of reactive oxygen species. Indeed, accumulated reports documented mitochondrial abnormalities in RTT patient biopsies, and animal models and human stem cell models of RTT, including reduced ATP production, altered mitochondrial structure, increased systemic oxidative stress, abnormal calcium activity, mtDNA copy number, and deficiencies in mitochondrial enzyme activity. While it remains unclear how loss of MECP2 function leads to wide-ranging mitochondrial deficits, improving mitochondrial function could still bring benefits to RTT patients. After defining the mitochondrial membrane potential deficit in astrocytes differentiated from RTT patient-specific induced pluripotent stem cells (iPSC), we established a novel high-throughput screening (HTS) platform based on the JC-10 mitochondrial membrane potential (MMP) assay, which served as a rapid primary readout. All primary hits were subsequently validated by independent functional assays to confirm their effects on mitochondrial health. Using this system, we performed a small-molecule screening of 1,134 selected US Food and Drug Administration (FDA)-approved drugs and a small interfering RNA (siRNA) screening of 336 genes upregulated in RTT astrocytes and identified candidate drugs and candidate genes that reversed the MMP deficits in RTT astrocytes. Among the candidate drug hits, isradipine, a dihydropyridine calcium-channel blocker, provided preliminary evidence of neuroprotective effects both in vitro and in vivo. Among the candidate gene hits, LRRC17, a gene encoding a secreted protein, emerged as a strong candidate mediator whose elevated levels are strongly associated with and likely contribute to various observed cellular deficits. siRNA knockdown of LRRC17 not only rescued mitochondrial dysfunction in RTT astrocytes but also reversed deficits in neurons cultured in astrocyte-conditioned media. Our study provides new insights into mitochondrial dysfunction in RTT and establishes an HTS platform for the initial identification of novel therapeutic targets for follow-up studies.

Keywords:  JC-10-based mitochondrial membrane potential (MMP) assay; Rett syndrome (RTT); high-throughput screening (HTS); human embryonic stem cells (hESCs)/induced pluripotent stem cells (iPSCs) derived neurons/astrocytes; isradipine; leucine rich repeating containing 17 (LRRC17); methyl-CpG-binding protein 2 (MECP2)

DOI:  https://doi.org/10.3389/fneur.2026.1759410