bims-medebr 2025-03-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–03–02
33 papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Glycogen-Its Metabolic Role in Neuronal Health and Neurological Disorders-An Extensive Narrative Review.
Awake brain MRSI reveals anesthetic sensitivity and regional aging effects on [13C]bicarbonate metabolism in mice.
The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.
An unraveled mystery: What's the role of brain sphingolipids in neurodegenerative and psychiatric disorders.
Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.
Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.
Astrocyte-Neuron Metabolic Crosstalk in Ischaemic Stroke.
Neuronal polyunsaturated fatty acids are protective in ALS/FTD.
Impaired mitochondrial integrity and compromised energy production underscore the mechanism underlying CoASY protein-associated neurodegeneration.
Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
Glutamate uptake is transiently compromised in the perilesional cortex following controlled cortical impact.
Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform.
Nicotinamide adenine dinucleotide alleviates neuroinflammation in rats with traumatic brain injury.
Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer's Disease in Down Syndrome.
Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.
Deuterium Metabolic Imaging of the Brain Using 2-Deoxy-2-[2H2]-d-glucose: A Non-ionizing [18F]FDG Alternative.
Enhanced visualization of endocannabinoids spatial distribution in mouse brain via MALDI-2 mass spectrometry imaging.
Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.
L-Lactate Administration Improved Synaptic Plasticity and Cognition in Early 3xTg-AD Mice.
Neuronal guidance signaling in neurodegenerative diseases: key regulators that function at neuron-glia and neuroimmune interfaces.
Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.
Mitochondrial Dysfunction in Neurodegenerative Diseases.
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
Plasma lipidomic and metabolomic profiles in high-grade glioma patients before and after 72-h presurgery water-only fasting.
Imaging lipid rafts reveals the principle of ApoE4-induced Aβ upregulation in human neurons.
Changes in glycosphingolipid levels in plasma and cerebrospinal fluid of individuals with Lysosomal Free Sialic Acid Storage Disorder.
mRNA therapy as primary and bridge therapy for inborn errors of metabolism.
Monitoring Cellular Energy Balance in Single Cells Using Fluorescent Biosensors for AMPK.
25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer's disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition.
Prenatal Valproic Acid Exposure Impairs Offspring Cognition Through Disturbing Interneuron Development.
Sensing of Long-Chain Fatty Acyl-CoA Esters by AMPK.
Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
A miniaturized iodine value assay for quantifying the unsaturated fatty acid content of lipids, lipid mixtures, and biological membranes.

Metabolites. 2025 Feb 13. pii: 128. [Epub ahead of print]15(2):

Brain Glycogen-Its Metabolic Role in Neuronal Health and Neurological Disorders-An Extensive Narrative Review.

Ana Isabel Beltran-Velasco.

  Background: Brain glycogen is imperative for neuronal health, as it supports energy demands and metabolic processes. This review examines the pathways involved in glycogen storage and utilization in the central nervous system, emphasizing their role in both physiology and pathology. It explores how alterations in glycogen metabolism contribute to neurological disorders, including neurodegenerative diseases, epilepsy, and metabolic conditions while highlighting the bidirectional interaction between neurons and glia in maintaining brain homeostasis. Methods: A comprehensive search of articles published between 2015 and 2025 was conducted using the following databases: ScienceDirect, Scopus, Wiley, Web of Science, Medline, and PubMed. The selection of relevant studies was based on their focus on brain glycogen metabolism and its role in neurological conditions, with studies that did not meet the inclusion criteria being excluded. Results: The metabolic processes of brain glycogen are subject to rigorous regulation by astrocyte-neuron interactions, thereby ensuring metabolic homeostasis and energy availability. The dysregulation of glycogen storage and mobilization has been implicated in the development of synaptic dysfunction, excitotoxicity, and neurodegeneration in a variety of disorders. For instance, aberrant glycogen accumulation in diseases such as Lafora disease has been associated with severe neurodegeneration, while impaired glycogen mobilization has been shown to exacerbate energy deficits in Alzheimer's and epilepsy. Conclusions: Targeting brain glycogen metabolism represents a promising approach for therapeutic intervention in neurological disorders. However, the translation of these strategies to human models remains challenging, particularly with regard to the long-term safety and specificity of glycogen-targeted therapies.

Keywords:  brain glycogen; enzyme modulation; epilepsy; glucose metabolism; glycogen metabolism; neurodegenerative diseases; neuroglia; neuronal health; therapeutic strategies

DOI:  https://doi.org/10.3390/metabo15020128
Front Neuroimaging. 2025 ;4 1506126

Awake brain MRSI reveals anesthetic sensitivity and regional aging effects on [13C]bicarbonate metabolism in mice.

Maiko Ono, Rena Kono, Kosei Hirata, Keita Saito, Motonao Nakao, Yoichi Takakusagi, Rikita Araki, Akira Sumiyoshi, Yuhei Takado.

  Abnormalities and alterations in the glycolytic pathway in the pathology of neurodegenerative diseases and brain aging have received much attention, as clinical applications of proton-based magnetic resonance spectroscopy (MRS) have recently illuminated the elevation of lactate concentrations in the brains of patients with neurodegenerative diseases, including Alzheimer's disease. Hyperpolarized [1-13C]pyruvate MRS has shown promise for neurological applications because it enables the real-time in vivo detection of glycolysis and oxidative phosphorylation flux. In studies of the mouse brain using hyperpolarized [1-13C]pyruvate, there are few reports that the signal of [13C]bicarbonate, a product of oxidative phosphorylation metabolized from [1-13C]pyruvate, was detected using MR spectroscopic imaging (MRSI) that allows spatial mapping of metabolism, although there have been reports of [13C]bicarbonate signals being detected by pulse-acquire sequences in the entire brain. In the present study, we compared hyperpolarized [1-13C]pyruvate metabolism between the brains of awake and isoflurane-anesthetized mice using a custom-made awake mouse restraint device with MRSI. Although the signal for [1-13C]lactate, a product of glycolysis metabolized from [1-13C]pyruvate, was detectable in multiple brain regions that include the orbitofrontal cortex and hippocampus in both awake and anesthetized mice, the signal for [13C]bicarbonate metabolized from [1-13C]pyruvate was only detectable in the brains of awake mice. Moreover, a comparison of hyperpolarized [1-13C]pyruvate metabolism in young and aged mouse brains using awake MRSI detected age-related decreases in oxidative phosphorylation flux in brain regions that include the hippocampus with variations in the extent of these changes across different brain regions. These results demonstrate that hyperpolarized [1-13C]pyruvate MRSI under awake conditions is useful for the spatial detection of abnormalities and alterations in glycolysis and oxidative phosphorylation flux in the brains of mice. Thus, the use of hyperpolarized [1-13C]pyruvate MRSI has potential in pathological and mechanistic studies of brain diseases and brain aging.

Keywords:  aging; awake condition; bicarbonate; carbon-13 MRS; chemical shift imaging; hyperpolarized [1-13C]pyruvate; mouse brain

DOI:  https://doi.org/10.3389/fnimg.2025.1506126
Curr Issues Mol Biol. 2025 Feb 11. pii: 115. [Epub ahead of print]47(2):

The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms.

Ilinca Savulescu-Fiedler, Luiza-Roxana Dorobantu-Lungu, Serban Dragosloveanu, Serban Nicolae Benea, Christiana Diana Maria Dragosloveanu, Ana Caruntu, Andreea-Elena Scheau, Constantin Caruntu, Cristian Scheau.

  Cholesterol is an essential element for the development and normal function of the central nervous system. While peripheral cholesterol is influenced by liver metabolism and diet, brain cholesterol metabolism takes place in an isolated system due to the impermeability of the blood-brain barrier (BBB). However, cross-talk occurs between the brain and periphery, specifically through metabolites such as oxysterols that play key roles in regulating cholesterol balance. Several neurodegenerative conditions such as Alzheimer's disease or Parkinson's disease are considered to be affected by the loss of this balance. Also, the treatment of hypercholesterolemia needs to consider these discrete interferences between brain and peripheral cholesterol and the possible implications of each therapeutic approach. This is particularly important because of 27-hydroxycholesterol and 24-hydroxycholesterol, which can cross the BBB and are involved in cholesterol metabolism. This paper examines the metabolic pathways of cholesterol metabolism in the brain and periphery and focuses on the complex cross-talk between these metabolisms. Also, we emphasize the regulatory role of the BBB and the need for an integrated approach to cholesterol management.

Keywords:  24-hydroxycholesterol; 27-hydroxycholesterol; PCSK9i; brain; cholesterol; metabolism; peripheral metabolism; physiology; physiopathology; preoperative management; statins

DOI:  https://doi.org/10.3390/cimb47020115
Neurobiol Dis. 2025 Feb 20. pii: S0969-9961(25)00068-3. [Epub ahead of print]207 106852

An unraveled mystery: What's the role of brain sphingolipids in neurodegenerative and psychiatric disorders.

Xintian Bie, Maoxing Zhang, Qingyu Wang, Ying Wang.

  Sphingolipids are a class of lipids highly expressed in brain, especially in the myelin sheath of white matter. In recent years, with the development of lipidomics, the role of brain sphingolipids in neurological disorders have raised lots of interests due to their function in neuronal signal transduction and survival. Although not thoroughly investigated, some previous studies have indicated that sphingolipids homeostasis are closely linked to the etiology and development of some neurological disorders. For example, disrupted sphingolipids level have been found in clinic patients with neurological disorders, such as neurodegeneration and psychiatric disorders. Conversely, intervention of sphingolipids metabolism by modulating activity of related enzymes also could result in pathological deficits identified in neurological disorders. Moreover, the alteration of sphingolipids catabolic pathway in the brain could be partly represented in cerebrospinal fluid and blood tissues, which show diagnostic potential for neurological disorders. Therefore, our review aims to summarize and discuss the known contents of bioactive sphingolipid metabolism with their related studies in neurodegenerative and psychiatric disorders, to help understand the potential mechanism underlying sphingolipid regulation of neural function and provide possible directions for further study. The new perspectives in this promising field will open up new therapeutic options for neurological disorders.

Keywords:  Metabolites; Neurodegenerative disorder; Psychiatric disorder; Sphingolipids

DOI:  https://doi.org/10.1016/j.nbd.2025.106852
Mol Neurobiol. 2025 Feb 22.

Glucose Metabolic Reprogramming in Microglia: Implications for Neurodegenerative Diseases and Targeted Therapy.

Mengqi Fang, Yuan Zhou, Keren He, Yangyuxiao Lu, Fangfang Tao, Hong Huang.

  As intrinsic immune cells in the central nervous system, microglia play a crucial role in maintaining brain homeostasis. Microglia can transition from homeostasis to various responsive states in reaction to different external stimuli, undergoing corresponding alterations in glucose metabolism. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglial glucose metabolic reprogramming is widespread. This reprogramming leads to changes in microglial function, exacerbating neuroinflammation and the accumulation of pathological products, thereby driving the progression of neurodegeneration. This review summarizes the specific alterations in glucose metabolism within microglia in AD, PD, ALS, and MS, as well as the corresponding treatments aimed at reprogramming glucose metabolism. Compounds that inhibit key glycolytic enzymes like hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), or activate regulators of energy metabolism such as AMP-activated protein kinase (AMPK), have shown significant potential in the treatment of various neurodegenerative diseases. However, current research faces numerous challenges, including side effects and blood-brain barrier (BBB) penetration of compounds. Screening relevant drugs from natural products, especially flavonoids, is a reliable approach. On the one hand, longtime herbal medical practices provide a certain degree of assurance regarding clinical safety, and their chemical properties contribute to effective BBB permeability. On the other hand, the concurrent anti-tumor and anti-neuroinflammatory activities of flavonoids suggest that regulation of glucose metabolism reprogramming might be a potential common mechanism of action. Notably, considering the dynamic nature of microglial metabolism, there is an urgent need to develop technologies for real-time monitoring of glucose metabolism processes, which would significantly advance research in this field.

Keywords:  Glycolysis; Metabolism Reprogramming; Microglia; Neurodegenerative Diseases; Oxidative Phosphorylation; Pentose Phosphate Pathway

DOI:  https://doi.org/10.1007/s12035-025-04775-y
bioRxiv. 2025 Feb 16. pii: 2025.02.12.637879. [Epub ahead of print]

Cholesterol depletion activates trafficking-coupled sphingolipid synthesis.

Yeongho Kim, Jan Parolek, Christopher G Burd.

Within cellular membranes, sphingomyelin is associated with cholesterol and this complex facilitates homeostatic regulation of membrane viscosity. Acute cholesterol depletion increases the synthesis of very-long-chain (VLC) sphingomyelin, but a link between lipid sensing and sphingolipid synthesis is lacking. Using sphingolipid metabolic flux analysis, we observed that VLC-ceramide, the precursor to VLC complex sphingolipids that are produced in the Golgi apparatus, was rapidly consumed after cholesterol depletion, while synthesis of long-chain sphingolipids was unaffected. Sphingolipid trafficking assays showed that cholesterol depletion enhances VLC-Ceramide trafficking from the endoplasmic reticulum to the Golgi apparatus. Changes in the sizes of coatomer II ER exit sites were correlated with increased VLC-Ceramide trafficking and concomitant increase in sphingomyelin. Depletion of Sec16A, a component of the COPII network, abolished VLC-SM synthesis. This study reveals ER-to-Golgi trafficking of VLC-Ceramide as a key regulatory node in organelle membrane homeostasis pathways.
Summary: In cellular membranes, sphingomyelin is associated with cholesterol. Metabolic flux analysis of sphingolipid metabolism showed that synthesis rate of sphingomyelin, but not ceramide, was increased after depletion of cholesterol due increased rate of COPII-dependent ER-to-Golgi transport of ceramide.

DOI: https://doi.org/10.1101/2025.02.12.637879
Neurochem Int. 2025 Feb 21. pii: S0197-0186(25)00027-0. [Epub ahead of print] 105954

Astrocyte-Neuron Metabolic Crosstalk in Ischaemic Stroke.

Zi-Lin Ren, Xin Lan, Jia-Lin Cheng, Yu-Xiao Zheng, Cong-Ai Chen, Ying Liu, Yan-Hui He, Jin-Hua Han, Qing-Guo Wang, Fa-Feng Cheng, Chang-Xiang Li, Xue-Qian Wang.

  Ischemic stroke (IS) is caused by temporary or permanent obstruction of the brain's blood supply. The disruption in glucose and oxygen delivery that results from the drop in blood flow impairs energy metabolism. A significant pathological feature of IS is impaired energy metabolism. Astrocytes, as the most prevalent glial cells in the brain, sit in between neurons and the microvasculature. By taking advantage of their special anatomical location, they play a crucial part in regulating cerebral blood flow (CBF) and metabolism. Astrocytes can withstand hypoxic and ischemic conditions better than neurons do. Additionally, astrocytes are essential for maintaining the metabolism and function of neurons. Therefore, the "neurocentric" perspective on neuroenergetics is gradually giving way to a more comprehensive perspective that takes into account metabolic interaction between astrocytes and neurons. Since neurons in the core region of the infarct are unable to undergo oxidative metabolism, the focus of attention in this review is on neurons in the peri-infarct region. We'll go over the metabolic crosstalk of astrocytes and neurons during the acute phase of IS using three different types of metabolites: lactate, fatty acids (FAs), and amino acids, as well as the mitochondria. After IS, astrocytes in the peri-infarct zone can produce lactate, ketone bodies (KBs), glutamine (Gln), and L-serine, shuttling these metabolites, along with mitochondria, to neurons. This process helps maintain the energy requirements of neurons, preserves their redox state, and regulates neurotransmitter receptor activity.

Keywords:  astrocytes; energy metabolism; ischaemic stroke; neurons

DOI:  https://doi.org/10.1016/j.neuint.2025.105954
Nat Neurosci. 2025 Feb 25.

Neuronal polyunsaturated fatty acids are protective in ALS/FTD.

Ashling Giblin, Alexander J Cammack, Niek Blomberg, Sharifah Anoar, Alla Mikheenko, Mireia Carcolé, Magda L Atilano, Alex Hull, Dunxin Shen, Xiaoya Wei, Rachel Coneys, Lele Zhou, Yassene Mohammed, Damien Olivier-Jimenez, Lian Y Wang, Kerri J Kinghorn, Teresa Niccoli, Alyssa N Coyne, Rik van der Kant, Tammaryn Lashley, Martin Giera, Linda Partridge, Adrian M Isaacs.

Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in a Drosophila model of C9orf72 repeat expansion, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), and in human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD Drosophila, induced pluripotent stem (iPS) cell neurons and postmortem FTD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). Feeding C9 ALS/FTD flies PUFAs yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of C9 ALS/FTD flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor-induced neuronal death in iPS cell neurons of patients with both C9 and TDP-43 ALS/FTD. These data implicate neuronal fatty acid saturation in the pathogenesis of ALS/FTD and suggest that interventions to increase neuronal PUFA levels may be beneficial.

DOI: https://doi.org/10.1038/s41593-025-01889-3
Cell Mol Life Sci. 2025 Feb 22. 82(1): 84

Impaired mitochondrial integrity and compromised energy production underscore the mechanism underlying CoASY protein-associated neurodegeneration.

Yuzhuo Shao, Jiaxin Hu, Kunhao Yan, Keke Zheng, Wenchi Sha, Jinlong Wang, Jiarui Wu, Yunpeng Huang.

  Coenzyme A (CoA) is a crucial metabolite involved in various biological processes, encompassing lipid metabolism, regulation of mitochondrial function, and membrane modeling. CoA deficiency is associated with severe human diseases, such as Pantothenate Kinase-Associated Neurodegeneration (PKAN) and CoASY protein-associated neurodegeneration (CoPAN), which are linked to genetic mutations in Pantothenate Kinase 2 (PANK2) and CoA Synthase (CoASY). Although the association between CoA deficiency and mitochondrial dysfunction has been established, the underlying molecular alterations and mechanisms remain largely elusive. In this study, we investigated the detailed changes resulting from the functional decline of CoASY using the Drosophila model. Our findings revealed that a reduction of CoASY in muscle and brain led to degenerative phenotypes and apoptosis, accompanied by impaired mitochondrial integrity. The release of mitochondrial DNA was notably augmented, while the assembly and activity of mitochondrial electron transport chain (ETC) complexes, particularly complex I and III, were diminished. Consequently, this resulted in decreased ATP generation, rendering the fly more susceptible to energy insufficiency. Our findings suggest that compromised mitochondrial integrity and energy supply play a crucial role in the pathogenesis associated with CoA deficiency, thereby implying that enhancing mitochondrial integrity can be considered a potential therapeutic strategy in future interventions.

Keywords:   Drosophila ; ATP; CoASY; Coenzyme A; Mitochondria

DOI:  https://doi.org/10.1007/s00018-025-05576-1
Nat Commun. 2025 Feb 26. 16(1): 1982

Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.

Ge Gao, Yong Shi, Han-Xiang Deng, Dimitri Krainc.

Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.

DOI: https://doi.org/10.1038/s41467-025-57142-9
Cereb Cortex. 2025 Feb 05. pii: bhaf031. [Epub ahead of print]35(2):

Glutamate uptake is transiently compromised in the perilesional cortex following controlled cortical impact.

Jacqueline P Garcia, Moritz Armbruster, Mary Sommer, Aliana Nunez-Beringer, Chris G Dulla.

  Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), is regulated by the excitatory amino acid transporters glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST). Following traumatic brain injury, extracellular glutamate levels increase, contributing to excitotoxicity, circuit dysfunction, and morbidity. Increased neuronal glutamate release and compromised astrocyte-mediated uptake contribute to elevated glutamate, but the mechanistic and spatiotemporal underpinnings of these changes are not well established. Using the controlled cortical impact model of TBI and iGluSnFR glutamate imaging, we quantified extracellular glutamate dynamics after injury. Three days postinjury, glutamate release was increased, and glutamate uptake and GLT-1 expression were reduced. Seven and 14 days postinjury, glutamate dynamics were comparable between sham and controlled cortical impact animals. Changes in peak glutamate response were unique to specific cortical layers and proximity to injury. This was likely driven by increases in glutamate release, which was spatially heterogeneous, rather than reduced uptake, which was spatially uniform. The astrocyte K+ channel, Kir4.1, regulates activity-dependent slowing of glutamate uptake. Surprisingly, Kir4.1 was unchanged after controlled cortical impact and accordingly, activity-dependent slowing of glutamate uptake was unaltered. This dynamic glutamate dysregulation after traumatic brain injury underscores a brief period in which disrupted glutamate uptake may contribute to dysfunction and highlights a potential therapeutic window to restore glutamate homeostasis.

Keywords:  astrocyte glutamate uptake; controlled cortical impact; excitatory amino acid; iGluSnFR imaging; transporters; traumatic brain injury

DOI:  https://doi.org/10.1093/cercor/bhaf031
J Alzheimers Dis. 2025 Feb 24. 13872877251317732

Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform.

Joshua L Milstein, Joshua A Kulas, Aria Kamal, An B Lo, Heather A Ferris.

   BACKGROUND: Lipids synthesized in astrocytes are distributed to other brain cells in high-density lipoprotein-like ApoE particles. ApoE, which is a powerful genetic risk factor for developing Alzheimer's disease, is secreted differently depending on genotype. Secretion of ApoE from mouse astrocytes is regulated by the mevalonate pathway.
OBJECTIVE: We aimed to understand if the regulation of ApoE secretion from astrocytes by the mevalonate pathway was the same between mouse ApoE and ApoE from humanized mice, and if this is impacted by ApoE isoform.
METHODS: Astrocyte-enriched glial cultures from wild-type and humanized ApoE targeted-replacement mice were treated with pharmacological inhibitors of various steps along the mevalonate pathway and ApoE in the conditioned media was measured.
RESULTS: We show that statins and prenylation inhibitors, but not specific cholesterol inhibitors, reduce extracellular ApoE lipoparticle levels in astrocyte-enriched glial cultures, and that this occurs in cells harboring either the mouse ApoE or any of the three human ApoE genotypes to a similar extent. We find that geranylgeranylation modulates ApoE release from astrocytes, and it does so independent of ApoE genotype.
CONCLUSIONS: Our results suggest that prenylation broadly regulates ApoE secretion from astrocytes regardless of ApoE genotype, and that this is mediated specifically by geranylgeranylation. Therefore, our data implicates geranylgeranylation as a general mechanism modulating ApoE release from astrocytes, but likely is not responsible for the reported baseline differences in ApoE secretion seen in vivo and in vitro across genotypes.

Keywords:  Alzheimer's disease; apolipoprotein E; cholesterol; geranylgeranylation; glia; prenylation

DOI:  https://doi.org/10.1177/13872877251317732
Neurosci Lett. 2025 Feb 22. pii: S0304-3940(25)00066-7. [Epub ahead of print] 138178

Nicotinamide adenine dinucleotide alleviates neuroinflammation in rats with traumatic brain injury.

Huancheng Wu, Mengli Jin, Jiandong Hu, Fenge Li.

   OBJECTIVE: To characterize the pathology and pathophysiological processes within 6 h after Traumatic brain injury (TBI) in rats, elucidate the neuroprotective effects and the underlying mechanisms of Nicotinamide Adenine Dinucleotide (NAD) in the early stage of TBI to explore the feasibility and clinical benefits of applying NAD directly to the localized injury after TBI.
MATERIAL AND METHODS: 54 male Sprague-Dawley (SD) rats aged 6-8 weeks were randomly assigned equally to three groups, sham-operated surgery (SO) with saline treatment (SO + Saline), TBI with saline treatment (TBI + Saline), and TBI with 10 μM NAD treatment (TBI + NAD). The whole brain tissues were collected at 1, 3, and 6 h following the procedure. Levels of biomarkers for TBI including S100β, TNF-α, occludin, PPARβ/δ were measured.
RESULTS: Significant neuroinflammation was observed in the rat brains after TBI, which peaked at 3 h following injury. Significant changes in S100β, TNF-α, PPARβ/δ, and occluding were also observed. Treatment with NAD significantly alleviated neuroinflammation at 1 h following TBI.
CONCLUSIONS: TBI caused severe neuroinflammation in rat brains, which peaked at 3 h following injury. Treatment with NAD alleviated neuroinflammation in TBI rats.

Keywords:  NAD; Occludin; PPARβ/δ; S100β; TNF-α; Traumatic brain injury (TBI)

DOI:  https://doi.org/10.1016/j.neulet.2025.138178
Brain Sci. 2025 Jan 28. pii: 130. [Epub ahead of print]15(2):

Mitochondrial Dysfunction Correlates with Brain Amyloid Binding, Memory, and Executive Function in Down Syndrome: Implications for Alzheimer's Disease in Down Syndrome.

Jessica A Beresford-Webb, Catherine J McAllister, Alison Sleigh, Madeleine J Walpert, Anthony J Holland, Shahid H Zaman.

  Background/Objectives: Mitochondrial dysfunction is increasingly recognized as a central contributor to neurodegenerative diseases and age-related cognitive decline. Individuals with Down syndrome (DS) are at high risk of neurodegeneration due to Alzheimer's disease (AD). This study aims to explore the relationship between mitochondrial dysfunction, brain amyloid-beta (Aβ) deposition, and cognitive decline in this population. Methods: We investigated mitochondrial function, brain amyloid-beta burden, and cognitive performance in a pilot study of a cohort of 10 eligible adults with DS selected from a sample of 28 individuals with DS. Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) was used to assess mitochondrial function in skeletal muscle using a post-exercise paradigm, while positron emission tomography using 11C-Pittsburgh compound B (PiB-PET) measured brain Aβ deposition. Cognitive performance was evaluated using the Cambridge Cognitive Examination adapted for individuals with Down syndrome (CAMCOG-DS) and executive function batteries. Results: Significant correlations were observed between slowed phosphocreatine (PCr) recovery in muscle and increased Aβ deposition in key brain regions, particularly the striatum. Cognitive performance inversely correlated with mitochondrial function, with pronounced deficits in memory and executive function tasks. Notably, an individual carrying the APOE-ε4 allele exhibited the poorest mitochondrial function, highest Aβ burden, and most severe cognitive impairment, suggesting a potential interaction between genetic risk and mitochondrial health. Conclusions: These findings highlight the role of mitochondrial dysfunction in DS-associated AD (DSAD) and its impact on cognition in adults. The results support targeting mitochondrial pathways as a potential therapeutic strategy to mitigate AD progression in DS populations. Further research with larger cohorts and longitudinal designs is needed to clarify causative mechanisms and develop effective interventions.

Keywords:  Alzheimer’s disease; Down syndrome; dementia; mitochondria

DOI:  https://doi.org/10.3390/brainsci15020130
Biomolecules. 2025 Feb 03. pii: 223. [Epub ahead of print]15(2):

Advances in the Development of Mitochondrial Pyruvate Carrier Inhibitors for Therapeutic Applications.

Henry Politte, Lingaiah Maram, Bahaa Elgendy.

  The mitochondrial pyruvate carrier (MPC) is a transmembrane protein complex critical for cellular energy metabolism, enabling the transport of pyruvate from the cytosol into the mitochondria, where it fuels the citric acid cycle. By regulating this essential entry point of carbon into mitochondrial metabolism, MPC is pivotal for maintaining cellular energy balance and metabolic flexibility. Dysregulation of MPC activity has been implicated in several metabolic disorders, including type 2 diabetes, obesity, and cancer, underscoring its potential as a therapeutic target. This review provides an overview of the MPC complex, examining its structural components, regulatory mechanisms, and biological functions. We explore the current understanding of transcriptional, translational, and post-translational modifications that modulate MPC function and highlight the clinical relevance of MPC dysfunction in metabolic and neurodegenerative diseases. Progress in the development of MPC-targeting therapeutics is discussed, with a focus on challenges in designing selective and potent inhibitors. Emphasis is placed on modern approaches for identifying novel inhibitors, particularly virtual screening and computational strategies. This review establishes a foundation for further research into the medicinal chemistry of MPC inhibitors, promoting advances in structure-based drug design to develop therapeutics for metabolic and neurodegenerative diseases.

Keywords:  MPC (mitochondrial pyruvate carrier); MPC inhibitors; drug design; energy metabolism; medicinal chemistry; metabolic disorders (e.g., diabetes, obesity, and cancer); neurodegenerative disorders; pyruvate transport; therapeutic target; virtual screening

DOI:  https://doi.org/10.3390/biom15020223
JACS Au. 2025 Feb 24. 5(2): 571-577

Deuterium Metabolic Imaging of the Brain Using 2-Deoxy-2-[2H2]-d-glucose: A Non-ionizing [18F]FDG Alternative.

Xiao Gao, Kai Qiao, David M Wilson, Myriam M Chaumeil, Jeremy W Gordon.

The positron emission tomography (PET) tracer 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) is widely used to study diseases where glucose metabolism is dysregulated, including cancer and neurodegenerative disorders. Here we investigate the hypothesis that the 2-position deuterium-enriched analogue 2-deoxy-2-[2H2]-d-glucose (2-DG-d2) can also map glucose uptake using deuterium metabolic imaging (DMI) without ionizing radiation. To accomplish this, we used a spectrally selective multiband radiofrequency pulse and balanced steady-state free procession (bSSFP) technique, enabling rapid 2H imaging with high specificity and sensitivity to 2-DG-d2. Both in vitro and in vivo validations demonstrated the sequence's ability to suppress endogenous water signal. Mapping of 2-DG-d2 with high spatial resolution was achieved in healthy mouse brains, comparable to what might be obtained using [18F]FDG PET. The numerous applications of [18F]FDG PET, as well as recent clinical translation of the natural abundance 2-deoxy-d-glucose (2-DG) parent sugar, suggest that DMI using 2-DG-d2 may be applied to patients in the future.

DOI: https://doi.org/10.1021/jacsau.4c00888
Talanta. 2025 Feb 23. pii: S0039-9140(25)00301-7. [Epub ahead of print]290 127811

Enhanced visualization of endocannabinoids spatial distribution in mouse brain via MALDI-2 mass spectrometry imaging.

Emanuela Salviati, Francesca Guida, Danila La Gioia, Fabrizio Merciai, Sabatino Maione, Vincenzo Di Marzo, Pietro Campiglia, Fabiana Piscitelli, Eduardo Sommella.

  Endocannabinoids (eCBs) are endogenous lipid messengers that primarily bind cannabinoid receptors CB1/CB2 and together with the enzymes that regulate their biosynthesis and degradation define the endocannabinoid system. The eCB signaling system plays a key role in the central nervous system, and results often altered in neurological disorders. The analysis of eCBs is challenging due to their low concentration in biospecimens, and this is exacerbated in Mass Spectrometry Imaging (MSI) where low sensitivity and tissue dependent ion suppression obscure their spatial visualization. In this work we address this limitation by the application of laser-induced post-ionization (MALDI-2) approach. Herein we demonstrate that MALDI-2 boosts the detection of 2-arachidonylglycerol (2-AG) and N-acylethanolamines (AEA, PEA, OEA) with respect to MALDI, and that eCBs can be visualized in brain at physiological concentration only by MALDI-2-MSI. Root-mean-square (RMS), Total ion count (TIC) and internal standards (I.S.) normalization were evaluated, with I.S. normalization providing improved pixel to pixel variation and more uniform distribution for 2-AG and PEA in specific brain regions. Furthermore, high spatial resolution up to 5 μm pixel size was evaluated, resulting in the detection of all eCBs and confirming the MALDI-2 potential even reducing the ablated tissue amount. As proof of concept, the method was applied to map eCBs in a mouse model of mild traumatic brain injury, the APP-SWE mice, highlighting differences in the modulation of eCBs in Cortex, Hippocampus and Hypothalamus, suggesting the ability to reveal valuable biological insights for neuropharmacology.

Keywords:  Brain; Endocannabinoids; MALDI-2; Mass spectrometry imaging; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.talanta.2025.127811
Biomedicines. 2025 Jan 31. pii: 327. [Epub ahead of print]13(2):

Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.

Kai Meng, Haocheng Jia, Xiaoqing Hou, Ziming Zhu, Yuguang Lu, Yingying Feng, Jingwen Feng, Yong Xia, Rubin Tan, Fen Cui, Jinxiang Yuan.

  Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.

Keywords:  mitochondrial dynamics; mitochondrial energy metabolism; mitochondrial homeostasis imbalance; mitophagy; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biomedicines13020327
Int J Mol Sci. 2025 Feb 11. pii: 1486. [Epub ahead of print]26(4):

L-Lactate Administration Improved Synaptic Plasticity and Cognition in Early 3xTg-AD Mice.

Yaxin Wang, Jinfeng Zhao, Li Zhao.

  Synaptic plasticity impairment and behavioral deficits constitute classical pathological hallmarks in early-stage Alzheimer's disease (AD). Emerging evidence suggests these synaptic dysfunctions may stem from metabolic dysregulation, particularly impaired aerobic glycolysis. As a key product of astrocyte-mediated aerobic glycolysis, lactate serves dual roles as both an energy substrate and a signaling molecule, playing a critical regulatory role in synaptic plasticity and long-term memory formation. This study investigated whether exogenous L-lactate supplementation could ameliorate synaptic dysfunction and cognitive deficits in early-stage AD models. Our findings reveal significant reductions in hippocampal lactate levels in experimental AD mice. Systemic administration of L-lactate (200 mg/kg) effectively restored physiological lactate concentrations in both hippocampal tissue and cerebrospinal fluid (CSF). Chronic L-lactate treatment significantly improved spatial learning and memory performance in behavioral assessments. Electrophysiological recordings demonstrated that either acute bath application of L-lactate (2 mM) to hippocampal slices or chronic intraperitoneal administration enhanced high-frequency stimulation (HFS)-induced long-term potentiation (LTP) magnitude in 3xTg-AD mice. Ultrastructural analysis revealed that L-lactate treatment enhanced synaptic density and improved morphological features of hippocampal synapses. At the molecular level, L-lactate administration upregulated synaptic marker synaptophysin (SYP) expression while downregulating activity-regulated cytoskeletal-associated protein (ARC) levels in AD mice. These multimodal findings demonstrate that exogenous L-lactate supplementation effectively restores synaptic plasticity and cognitive function in early-stage 3xTg-AD mice through concurrent improvements at behavioral, structural, and molecular levels.

Keywords:  AD; L-lactate; cognition; synaptic plasticity

DOI:  https://doi.org/10.3390/ijms26041486
Neural Regen Res. 2025 Feb 24.

Neuronal guidance signaling in neurodegenerative diseases: key regulators that function at neuron-glia and neuroimmune interfaces.

Junichi Yuasa-Kawada, Mariko Kinoshita-Kawada, Masaki Hiramoto, Satoru Yamagishi, Takayasu Mishima, Shin'ichiro Yasunaga, Yoshio Tsuboi, Nobutaka Hattori, Jane Y Wu.

ABSTRACT: The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-01330
Front Aging Neurosci. 2024 ;16 1454735

Study insights in the role of PGC-1α in neurological diseases: mechanisms and therapeutic potential.

Mi-Bo Tang, Yi-Xuan Liu, Zheng-Wei Hu, Hai-Yang Luo, Shuo Zhang, Chang-He Shi, Yu-Ming Xu.

  Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which is highly expressed in the central nervous system, is known to be involved in the regulation of mitochondrial biosynthesis, metabolic regulation, neuroinflammation, autophagy, and oxidative stress. This knowledge indicates a potential role of PGC-1α in a wide range of functions associated with neurological diseases. There is emerging evidence indicating a protective role of PGC-1α in the pathogenesis of several neurological diseases. As such, a deeper and broader understanding of PGC-1α and its role in neurological diseases is urgently needed. The present review provides a relatively complete overview of the current knowledge on PGC-1α, including its functions in different types of neurons, basic structural characteristics, and its interacting transcription factors. Furthermore, we present the role of PGC-1α in the pathogenesis of various neurological diseases, such as intracerebral hemorrhage, ischemic stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and other PolyQ diseases. Importantly, we discuss some compounds or drug-targeting strategies that have been studied to ameliorate the pathology of these neurological diseases and introduce the possible mechanistic pathways. Based on the available studies, we propose that targeting PGC-1α could serve as a promising novel therapeutic strategy for one or more neurological diseases.

Keywords:  PGC-1α; mitochondria; neuroinflammation; neurological diseases; oxidative stress

DOI:  https://doi.org/10.3389/fnagi.2024.1454735
Cells. 2025 Feb 13. pii: 276. [Epub ahead of print]14(4):

Mitochondrial Dysfunction in Neurodegenerative Diseases.

Han-Mo Yang.

  Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.

Keywords:  mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative disease; oxidative stress

DOI:  https://doi.org/10.3390/cells14040276
Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.21203/rs.3.rs-5961609/v1
Mol Oncol. 2025 Feb 24.

Plasma lipidomic and metabolomic profiles in high-grade glioma patients before and after 72-h presurgery water-only fasting.

Iris Divé, Lisa Hahnefeld, Katharina J Wenger, Donat Kögel, Joachim Steinbach, Gerd Geisslinger, Michael W Ronellenfitsch, Irmgard Tegeder.

  Glioblastoma (GB) is the most aggressive primary brain tumor with poor prognosis despite multimodal therapy. Calorie-restricted diets have emerged as putative strategies to augment anticancer therapies. We employed UHPLC-high-resolution mass spectrometry analyses of plasma lipids and polar metabolites to assess the systemic metabolic effects of a 72-h preoperative fasting period in IDH-wild-type glioma patients (n = 9 GB and n = 1 diffuse pediatric-type high-grade H3/IDH-wildtype) who participated in the prospective ERGO3 trial (NCT04461938). Fasting reduced lysophosphatidylcholines (LPC, LPC-O), lysophosphatidylethanolamines (LPE, LPE-O), and increased free fatty acids and carnitines. Triglyceride (TG) profiles shifted from short-chain TGs (42-48 C-atoms) to very long-chain TGs (58-60 C-atoms) indicating an exploitation of neutral lipid stores. Branched-chain amino acids, aminobutyric acid, and uric acids were increased, and glucose reduced after fasting. The effects of fasting were comparable in men and women. To our knowledge, this is the first study that evaluated the effects of fasting on systemic lipid/metabolite levels in GB patients. Our results may hold promise for integrating fasting interventions as a component of a potential metabolic tumor therapy.

Keywords:  fasting; glioblastoma; lipidomic; lysophosphatidylcholines; metabolomic; plasma

DOI:  https://doi.org/10.1002/1878-0261.70003
iScience. 2025 Feb 21. 28(2): 111893

Imaging lipid rafts reveals the principle of ApoE4-induced Aβ upregulation in human neurons.

Se-In Lee, Heejin Lim, Na Yeon Kim, Jichang Yu, Joonho Cho, Hyein Lee, Dae Won Moon, Jinsoo Seo.

  Lipid rafts in plasma membranes are thought to provide a platform for regulating signaling pathways by increasing the expression or proximity of proteins in the same pathway. Despite this understanding, the absence of direct, simultaneous observations of lipid rafts and their affiliated proteins has hindered a comprehensive assessment of their roles across various biological contexts. Amyloid-β (Aβ), a hallmark of Alzheimer's disease (AD), is generated from the sequential cleavage of amyloid precursor proteins (APPs) by β- and γ-secretases, primarily within endosomes after APP endocytosis by canonical clathrin-mediated endocytosis in neurons. In this study, we developed a protocol for imaging APP on lipid rafts using time-of-flight secondary ion mass spectrometry (ToF-SIMS) and found that astrocyte ApoE4 contributes to an increase in APP localization on lipid rafts, subsequently elevating Aβ42 synthesis in a clathrin-independent manner in neurons.

Keywords:  Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience; Techniques in neuroscience

DOI:  https://doi.org/10.1016/j.isci.2025.111893
Rare. 2025 ;pii: 100065. [Epub ahead of print]3

Changes in glycosphingolipid levels in plasma and cerebrospinal fluid of individuals with Lysosomal Free Sialic Acid Storage Disorder.

Marya S Sabir, Lynne Wolfe, David R Adams, Carla Ciccone, Forbes D Porter, William A Gahl, Marjan Huizing, Frances M Platt, May Christine V Malicdan.

  Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem disease caused by biallelic pathogenic variants in SLC17A5, encoding the lysosomal transmembrane sialic acid exporter, sialin. Defective sialin function leads to sialic acid accumulation in lysosomes, contributing to neurodegeneration. While glycosphingolipid (GSL) metabolism is altered in other lysosomal storage disorders, its role in FSASD remains poorly understood, especially due to the restricted availability of biospecimens. This study investigated GSL levels in FSASD plasma and cerebrospinal fluid (CSF) using two normal-phase high-performance liquid chromatography assays. In plasma, GM1a was significantly elevated, while GM2 was decreased, with no significant alterations in other GSL species. In CSF, total GSLs, GM1a, GM3, GD3, GD1a, and GD1b were significantly elevated compared to comparison samples. These results reveal dysregulated GSL metabolism and suggest the potential of gangliosides as biomarkers. Further research is warranted to elucidate the biological implications of these alterations and their contributions to FSASD pathogenesis.

Keywords:  Salla disease; gangliosides; glycosphingolipids; leukodystrophy; lipid metabolism; sialin

DOI:  https://doi.org/10.1016/j.rare.2025.100065
Mol Ther. 2025 Feb 21. pii: S1525-0016(25)00100-5. [Epub ahead of print]

mRNA therapy as primary and bridge therapy for inborn errors of metabolism.

Jerry Vockley.

DOI: https://doi.org/10.1016/j.ymthe.2025.02.010
Methods Mol Biol. 2025 ;2882 47-79

Monitoring Cellular Energy Balance in Single Cells Using Fluorescent Biosensors for AMPK.

Nicholaus DeCuzzi, Nont Kosaisawe, Michael Pargett, Markhus Cabel, John G Albeck.

  5'-Adenosine monophosphate-activated protein kinase (AMPK) senses cellular metabolic status and reflects the balance between ATP production and ATP usage. This balance varies from cell to cell and changes over time, creating a need for methods that can capture cellular heterogeneity and temporal dynamics. Fluorescent biosensors for AMPK activity offer a unique approach to measure metabolic status nondestructively in single cells in real time. In this chapter, we provide a brief rationale for using live-cell biosensors to measure AMPK activity, survey the current AMPK biosensors, and discuss considerations for using this approach. We provide methodology for introducing AMPK biosensors into a cell line of choice, setting up experiments for live-cell fluorescent microscopy of AMPK activity, and calibrating the biosensors using immunoblot data.

Keywords:  AMPKAR; Biosensors; Fluorescent protein reporters; Forster resonance energy transfer (FRET); Live-cell microscopy; Metabolic signaling; Single cell

DOI:  https://doi.org/10.1007/978-1-0716-4284-9_3
J Neuroinflammation. 2025 Feb 25. 22(1): 50

25-Hydroxycholesterol modulates microglial function and exacerbates Alzheimer's disease pathology: mechanistic insights and therapeutic potential of cholesterol esterification inhibition.

Hayoung Choi, Haeng Jun Kim, Sang-Eun Lee, Hyun Ho Song, Jieun Kim, Jihui Han, June-Hyun Jeong, Do Yup Lee, Sunghoe Chang, Inhee Mook-Jung.

  This study investigates the role of 25-hydroxycholesterol (25HC), a metabolite produced by cholesterol hydroxylase encoded by the Ch25h gene, in modulating microglial function and its potential implications in Alzheimer's disease (AD) pathology. We demonstrated that 25HC impairs microglial surveillance, reduces phagocytic capacity, and increases the production of pro-inflammatory cytokines. In vivo two-photon microscopy revealed that 25HC administration diminishes microglial response to brain lesions, while flow cytometry confirmed reduced phagocytosis in both in vivo and in vitro models. Additionally, amyloid-beta (Aβ) was shown to upregulate Ch25h expression and elevate 25HC levels in microglia, exacerbating these functional impairments. Mechanistically, 25HC was found to enhance cholesterol esterification, disrupt cell membrane dynamics, and further reduce microglial mobility and phagocytosis. Treatment with Avasimibe, a cholesterol esterification inhibitor, restored membrane dynamics and microglial function, leading to attenuated AD pathology in a 5XFAD mouse model. These findings suggest that 25HC-induced changes in microglial function contribute to AD progression, and targeting cholesterol metabolism could offer therapeutic potential.

Keywords:  25HC; Avasimibe; Aβ; Cholesterol; Disease-associated microglia; Microglia

DOI:  https://doi.org/10.1186/s12974-025-03357-y
CNS Neurosci Ther. 2025 Feb;31(2): e70303

Prenatal Valproic Acid Exposure Impairs Offspring Cognition Through Disturbing Interneuron Development.

Kaiyuan Shen, Yandong Zhang, Yunyun Huang, Yunli Xie, Jing Ding, Xin Wang.

   AIMS: Valproic acid (VPA) exposure during the gestational period has been found to impair the cognition of the offspring. The study aimed to investigate whether VPA leads to offspring cognitive impairment through disturbing interneuron development.
METHODS: Pregnant mice were injected with VPA peritoneally to establish the prenatal VPA exposure model. Cortical interneurons were labeled with Rosa26-EYFP/- reporter mice activated by Nkx2.1-Cre. Interneuron subtypes both in the cortex and the hippocampus were detected by immunofluorescence. A battery of behavioral tests was conducted on postnatal Day 28 to assess the cognition and anxiety of the offspring. RNA-Seq analysis was performed to investigate the underlying molecular mechanisms.
RESULTS: We found that after the exposure to VPA, all the groups of the male offspring exerted anxiety. When VPA injection was performed on gestational Day 12.5, the memory of the offspring was impaired. Mechanistically, the distribution of cortical interneurons was disrupted. The distribution of interneuron subtypes was abnormal both in the cortex and hippocampus after the VPA exposure, which affected the somatostatin-positive neurons but not the parvalbumin-positive neurons, indicating the effects of VPA were subtype specific. Biological processes related to ion homeostasis were greatly changed after VPA exposure.
CONCLUSION: Prenatal VPA exposure during the neurogenic period impaired the cognition of the offspring by disrupting interneuron migration and differentiation. The study provides a novel perspective on the influence of VPA over neurodevelopment.

Keywords:  antiseizure medication; cognition; neurodevelopment; pregnancy with epilepsy

DOI:  https://doi.org/10.1111/cns.70303
Methods Mol Biol. 2025 ;2882 121-137

Sensing of Long-Chain Fatty Acyl-CoA Esters by AMPK.

Eric M Desjardins, Emily A Day, John W Scott, Gregory R Steinberg.

  Fatty acids are utilized to maintain cellular energy/adenine nucleotide balance under times of energetic stress such as during endurance exercise or fasting. It has long been recognized that fatty acids stimulate their own oxidation through a mechanism involving allosteric inhibition of acetyl-CoA carboxylase (ACC) and reductions in malonyl-CoA. We have recently described a parallel pathway by which long-chain fatty acid-CoAs bind to and activate the AMP-activated protein kinase (AMPK) at the allosteric drug and metabolic (ADaM) binding site. Increases in AMPK activity lead to the phosphorylation and inhibition of ACC which is essential for fatty acids to stimulate fatty acid oxidation. Here, we describe the methods to detect fatty acyl-CoA-induced activation of AMPK in cell-free assays, primary mouse hepatocytes, and in the liver of mice. These methodologies will be useful to allow further investigations into the importance of this fatty acid sensing axis in regulating metabolism and provide a framework for future studies investigating whether there may be other natural ligands targeting the ADaM binding site of AMPK.

Keywords:  AMPK; Cell-free assay; Fat oxidation; Fatty acid sensing; Fatty acyl-CoA; Hepatocytes; In vitro; In vivo; Intralipid; Liver extraction; Methods; Palmitate; Phosphorylation

DOI:  https://doi.org/10.1007/978-1-0716-4284-9_6
Nat Commun. 2025 Feb 24. 16(1): 1910

Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.

Alzheimer’s Disease Neuroimaging Initiative

Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.

DOI: https://doi.org/10.1038/s41467-025-57032-0
Lipids. 2025 Feb 23.

A miniaturized iodine value assay for quantifying the unsaturated fatty acid content of lipids, lipid mixtures, and biological membranes.

Maria Monserrat Roman-Lara, Katie J Chong, Roslyn M Bill, Alan D Goddard.

  Various methods exist for identifying and quantifying lipid unsaturation, including mass spectrometry and Raman spectroscopy. A disadvantage of these existing approaches is the need for sophisticated equipment and software, placing them beyond the means of many laboratories. The iodine value (IV) is a colorimetric unsaturation index; however, it uses iodine monochloride, a hazardous chemical, and considerable amounts of sample. Here, we demonstrate the first use of a miniaturized IV method that requires only milliliter quantities of hazardous chemicals and sample sizes such that it is feasible to assay biological membranes. Briefly, lipids are exposed to iodine monochloride, resulting in the replacement of unsaturated bonds with di-halogenated single bonds. Potassium iodide then reacts with unreacted iodine monochloride forming I2, which is quantified through titration with sodium thiosulfate. To demonstrate the biological relevance of our assay, membrane lipids of Escherichia coli grown at 30, 37, and 42°C were analyzed, with IV increasing as temperature decreased, as would be expected. Importantly, multiple samples could be rapidly and simultaneously analyzed in a reproducible assay that did not require sophisticated equipment or data analysis methods. Our miniaturized IV assay will benefit laboratories with limited access to sophisticated equipment and enable the rapid determination of lipid unsaturation in milligram-scale samples.

Keywords:  Iodine Value; Wijs reagent; cell membrane; colorimetry; lipid unsaturation

DOI:  https://doi.org/10.1002/lipd.12438