bims-medebr 2025-12-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–12–07
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University

Time-dependent biphasic alterations in brain metabolism following chronic ketamine exposure in mice.
Protective ApoE variants support neuronal function by effluxing oxidized phospholipids.
Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.
Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation.
Neuromodulatory control of energy reserves in dopaminergic neurons.
SLC44A1 deficiency impedes myelin development in the central nervous system.
Brain metabolic-functional (de)coupling from health to glioma dysfunction.
Astrocyte FABP7 Modulates Seizure Activity-Dependent Protein Expression in Mouse Brain.
Navigating the Lipid Landscape: The Role of Fatty Acid Synthase in Neural Stem Cell Fate and Central Nervous System Function.
Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.
Astrocyte MCT1 Expression Does Not Contribute to the Axonal Degenerative Phenotype Observed With Ubiquitous MCT1 Depletion.
PDK4 suppresses high glucose-induced microglial ferroptosis by restricting pro-ferroptotic PUFA biosynthesis.
Lipid Metabolic Disorders in Neurodegenerative Diseases - Role of Androgen Receptor.
Lipid dependence of connexin-32 gap junction channel conformations.
A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.
Considerations for Spatial Omics, Metabolite Analyses, and Tissue-Harvesting Artifacts.
Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
Metabolic brain networks in dementia with Lewy bodies: from prodromal to manifest disease stages.

Front Pharmacol. 2025 ;16 1629824

Time-dependent biphasic alterations in brain metabolism following chronic ketamine exposure in mice.

Seo-Hyun Lim, Young-Suk Choi, Eosu Kim, Chul Hoon Kim, Ho-Taek Song.

   Background: Ketamine has attracted clinical interest for its therapeutic potential, but prolonged exposure raises concerns about dependence and its long-term effects on brain metabolism.
Materials and Methods: Male mice received daily intraperitoneal injections of ketamine (30 mg/kg) for 28 days. Brain glucose metabolism was evaluated using [18F]FDG positron emission tomography at 1 h, 1 week, and 1 month post-injection. Expression levels of glucose transporters (GLUT1), glycolytic enzymes (PKM2, HK1), NMDA receptor subunits (NR2B), and apoptotic markers (caspase-3) were analyzed by Western blotting and RT-PCR.
Results: FDG-PET imaging suggested a biphasic metabolic pattern, with an increase in uptake at 1 h and 1 week, followed by a significant reduction by 1 month, returning toward baseline levels. GLUT1 mRNA expression gradually increased, although protein levels did not show a clear parallel change. PKM2 and HK1 remained largely unchanged. At 1 month, NR2B and caspase-3 transcripts were elevated, while protein-level changes were less evident, suggesting possible transcriptional regulation of stress-related pathways.
Discussion: These findings demonstrate that ketamine induces dynamic alterations in brain glucose metabolism accompanied by molecular adaptations. The early hypermetabolic response may reflect acute excitatory effects, whereas longer exposure could engage compensatory or stress-associated mechanisms. Metabolic imaging may provide a useful, non-invasive approach to better understand ketamine's temporal effects and support long-term safety monitoring.

Keywords:  FDG-PET; GLUT1; brain metabolism; chronic exposure; ketamine

DOI:  https://doi.org/10.3389/fphar.2025.1629824
Neuron. 2025 Dec 02. pii: S0896-6273(25)00847-5. [Epub ahead of print]

Protective ApoE variants support neuronal function by effluxing oxidized phospholipids.

Isha Ralhan, Alison D Do, Ju-Young Bae, Femke M Feringa, Wendy Cai, Jinlan Chang, Kennedi Chik, Nathanael Y J Lee, Christopher J Gerry, Rik van der Kant, Jesse Jackson, Emily L Ricq, Maria S Ioannou.

  Apolipoprotein E (ApoE) mediates the bidirectional transport of lipids between cells. In the brain, this includes the transfer of lipids from neurons to glia. ApoE4, a major risk factor for Alzheimer's disease, impairs this transport pathway, increasing risk for neurodegeneration. ApoE2 and ApoE3 Christchurch (ApoE3Ch) confer resistance to disease, yet little is known regarding how these variants affect lipid trafficking. Here, we explored how lipoprotein particles containing different ApoE isoforms affect neuronal health. We demonstrate that ApoE2 and ApoE3Ch particles protect neurons from ferroptosis by extracting oxidized unsaturated lipids through the ABCA7 transporter. ApoE4 particles, on the other hand, exacerbate the effects of these toxic lipids, leading to endolysosomal dysfunction. By reducing the oxidized lipid burden in ApoE4 neurons, ApoE2 and ApoE3Ch particles rescue endolysosomal function and restore defects in neuronal activity caused by excitotoxicity. Our findings reveal how ApoE2 and ApoE3Ch help protect neurons from neurodegeneration.

Keywords:  ABCA7; APOE3 Christchurch; ApoE2; ferroptosis; lipid peroxidation; neuron; unsaturated lipid

DOI:  https://doi.org/10.1016/j.neuron.2025.10.040
NPJ Aging. 2025 Nov 30.

Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases.

Soyoung Sung, Hui-Ju Kim, Sun Joo Cha, Minyeop Nahm, Seung Hyun Kim, Min-Soo Kwon.

Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.

DOI: https://doi.org/10.1038/s41514-025-00295-0
J Lipid Res. 2025 Nov 27. pii: S0022-2275(25)00215-9. [Epub ahead of print] 100952

Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation.

Almudena Maroto Juanes, Thomas Vogels, Sascha Koppes-den Hertog, Maarten Loos, Dieter Lütjohann, Martin Giera, Rik van der Kant.

  Mutations in microtubule-associated protein Tau (MAPT), the gene that codes for the protein Tau, cause frontotemporal lobar degeneration (FTLD) with phenotypes ranging from behavioral changes to cognitive impairment and parkinsonism. Recently, lipid changes have been heavily implicated in synucleinopathies and secondary tauopathies such as Alzheimer's Disease (AD). Whether mutations in MAPT or accumulation of hyperphosphorylated Tau (pTau) can contribute to lipid changes in primary tauopathies is unknown. Here, we examine the effect of the FTLD-associated mutation MAPT P301S on brain lipid metabolism in a Tau transgenic mouse model. We find that the MAPT P301S mutation drives increased levels of diglycerides and hexosyl- and lactosylceramides while reducing triglycerides, specifically those triglyceride species containing monounsaturated fatty acids, but does not affect cholesterol metabolism prior to pTau accumulation. Strikingly, with increasing accumulation of pTau, neutral lipids such as cholesteryl esters and triglycerides start to accumulate in the brain of mutant mice, as also reported in the AD and FTLD brain. Furthermore, with increasing buildup of pTau, we observe a decrease in cholesterol synthesis and turnover to 24S-hydroxycholesterol. Overall our data indicates that Tau mutations strongly affect brain lipid metabolism.

Keywords:  Cholesterol metabolism; Frontotemporal lobar degeneration; Lipidomics; Neutral lipids; Tau

DOI:  https://doi.org/10.1016/j.jlr.2025.100952
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2523019122

Neuromodulatory control of energy reserves in dopaminergic neurons.

Camila Pulido, Matthew S Gentry, Timothy A Ryan.

  The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease, a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics. In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons, however, the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen. We show here that in primary mid-brain dopaminergic neurons, glycogen availability is under the control of dopamine autoreceptors, such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine-derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.

Keywords:  ATP; dopamine; glycogen; synapse

DOI:  https://doi.org/10.1073/pnas.2523019122
Cell Rep. 2025 Nov 27. pii: S2211-1247(25)01389-0. [Epub ahead of print]44(12): 116617

SLC44A1 deficiency impedes myelin development in the central nervous system.

Qiang Chen, Xiang Chen, Zhenghao Li, Qi Shao, Hao Huang, Wenhao Zhou, Mengsheng Qiu, Zhida Su, Peng Liu, Cheng He.

  The axon-wrapping myelin sheath is essential for CNS function. Myelination defects occur in various neurodevelopmental disorders, but the underlying mechanism remains poorly understood. Human solute carrier 44A1 (SLC44A1) deficiency causes a new type of childhood-onset neurodegeneration with cerebellar atrophy and leukoencephalopathy that lacks effective treatment. Here, we show that SLC44A1 is enriched in oligodendrocytes and is required for myelin development in the CNS of zebrafish and rodents. In vivo time-lapse imaging of Slc44a1b-deficient zebrafish reveals impaired oligodendroglial maturation and myelinogenesis. Mechanistically, SLC44A1 deficiency disrupts the expression of genes involved in the phosphatidylcholine production pathway and subsequently inhibits phospholipid biosynthesis and disturbs the lipid composition of myelin sheaths. More importantly, supplementation with citicoline, a natural choline metabolite, restores developmental myelination in SLC44A1-deficient animals. Our findings demonstrate that SLC44A1 is essential for CNS myelination, and citicoline supplementation represents a potential therapy for developmental hypomyelination.

Keywords:  CP: developmental biology; CP: neuroscience; SLC44A1; choline metabolism; citicoline; myelination; oligodendrocyte

DOI:  https://doi.org/10.1016/j.celrep.2025.116617
Commun Biol. 2025 Dec 04.

Brain metabolic-functional (de)coupling from health to glioma dysfunction.

G Vallini, G Baron, E Silvestri, T Volpi, A G Vlassenko, M S Goyal, A Chiuso, D Cecchin, M Corbetta, A Bertoldo.

The interplay between brain metabolism and function supports the brain's adaptive capacity in cognitively demanding processes. Prior work has linked glucose metabolism to resting-state fMRI activity, but often overlooks both hemodynamic confounders in the BOLD signal and the brain's dynamic nature. To address this, we employed a novel effective connectivity decomposition, separating symmetric partial covariance, capturing "true" statistical dependencies between regions, from antisymmetric differential covariance, reflecting directional brain flow. In 42 healthy subjects, we show that partial covariance corresponds to metabolic connectivity across regions, while node directionality relates to standardized uptake value ratio, a proxy for local glucose consumption. We subsequently tested the sensitivity of detected couplings in 43 glioma patients, identifying disruptions in both local and network-level effective-metabolic interactions that varied with tumor anatomical location. Our findings provide novel insights into the coupling between brain metabolism and functional dynamics at rest, advancing understanding of healthy and pathological brain states.

DOI: https://doi.org/10.1038/s42003-025-09181-7
Neuroglia. 2025 Sep;pii: 33. [Epub ahead of print]6(3):

Astrocyte FABP7 Modulates Seizure Activity-Dependent Protein Expression in Mouse Brain.

Adam P Berg, Shahroz H Tariq, Carlos C Flores, Micah Lefton, Yuji Owada, Christopher J Davis, Thomas N Ferraro, Jon M Jacobs, Marina A Gritsenko, Yool Lee, Wheaton L Schroeder, Jason R Gerstner.

   Background/Objectives: Patients with epilepsy commonly experience patterns of seizures that change with sleep/wake behavior or diurnal rhythms. The cellular and molecular mechanisms that underlie these patterns in seizure activity are not well understood but may involve non-neuronal cells, such as astrocytes. Our previous studies show the critical importance of one specific astrocyte factor, the brain-type fatty acid binding protein Fabp7, in the regulation of time-of-day-dependent electroshock seizure threshold and neural activity-dependent gene expression in mice. Here, we examined whether Fabp7 influences differential seizure activity-dependent protein expression, by comparing Fabp7 knockout (KO) to wild-type (WT) mice under control conditions and after reaching the maximal electroshock seizure threshold (MEST).
Methods: We analyzed the proteome in cortical-hippocampal extracts from MEST and SHAM groups of WT and KO mice using mass spectrometry (MS), followed by Gene Ontology (GO) and pathway analyses. GO and pathway analyses of all groups revealed a diverse set of up- and downregulated differentially expressed proteins (DEPs).
Results: We identified 65 significant DEPs in the comparison of KO SHAM versus WT SHAM; 33 proteins were upregulated and 32 were downregulated. We found downregulation in mitochondrial-associated proteins in WT MEST compared to WT SHAM controls, including Slc1a4, Slc25a27, Cox7a2, Cox8a, Micos10, and Atp5mk. Several upregulated DEPs in the KO SHAM versus WT SHAM comparison were associated with the 20S proteasomal subunit, suggesting proteasomal activity is elevated in the absence of Fabp7 expression. We also observed 92 DEPs significantly altered in the KO MEST versus WT MEST, with 49 proteins upregulated and 43 downregulated.
Conclusions: Together, these data suggest that the astrocyte Fabp7 regulation of time-of-day-mediated neural excitability is modulated by multiple cellular mechanisms, which include proteasomal pathways, independent of its role in activity-dependent gene expression.

Keywords:  blbp; glia; lipid signaling; neural excitability; protein translation; proteomics

DOI:  https://doi.org/10.3390/neuroglia6030033
Mol Neurobiol. 2025 Dec 05. 63(1): 255

Navigating the Lipid Landscape: The Role of Fatty Acid Synthase in Neural Stem Cell Fate and Central Nervous System Function.

Reena Gupta, Abdulwahab Mahmood Abdulazeez, Monthar Kedhim, Ali G Alkhathami, Malathi H, Mayank Kundlas, Laxmidhar Maharana, Ashish Singh Chauhan, Mohammed Jawad Alnajar, Hayder Abdulhasan Hammoodi.

  Lipids play a critical role in both the brain's structure and function by serving as a primary component of cell membranes and myelin sheaths. They help impart structural stability and fluidity to neuronal membranes that are crucial to synaptic plasticity and signal transduction. Importantly, the equilibrium between lipid production and degradation dictates a stem cell's fate. Lipid metabolism is an essential controller that affects how a stem cell commits to a particular cell lineage by differentiating into a specific cell type or staying undifferentiated and self-renewing. In order to maintain an elevated level of proliferation, cancer cells frequently exhibit an increased de novo lipogenesis (DNL) flow. Most malignancies overexpress the DNL enzyme fatty acid synthase (FAS), which is essential for fatty acid synthesis. There is mounting proof suggesting that FAS has a role in various cancer-related features, which are connected to its capacity to stimulate cell proliferation through the production of membranes. Beyond structural roles, lipids act as signaling molecules, including second messengers like diacylglycerol and arachidonic acid derivatives, which modulate neurotransmitter release. Moreover, this enzyme plays a pivotal role in adult stem cells, especially in neural stem cells (NSCs). This review aimed to study the role of lipids and FAS in CNS biological functions and pathological effects. Also, we delve into the role of FAS in NSC behavior to better elucidate the effects of this enzyme on the fate of such stem cells.

Keywords:  FAS; Lipids; Metabolism; NSCs; Neurogenesis

DOI:  https://doi.org/10.1007/s12035-025-05430-2
Front Cell Dev Biol. 2025 ;13 1701406

Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.

Jia-Xuan Huai, E-E Chang, Yi-Ran Zhu, Wen-Ling Ma, Tian-Su Lv, Jing Sun, Xi-Qiao Zhou.

  Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial oxidative phosphorylation, oxidative stress and neuroinflammation caused by high blood sugar, in which excess reactive oxygen species (ROS), impairs mitochondrial integrity and leads to activation of microglia cells. The impaired mitophagy and the macrophages remove defects and cause the accumulation and energy collapse of the dysfunctional organelles. In addition, it promotes excessive glycolytic flux, lipolysis disorder, lactic acid accumulation, and ceramide-dependent synaptic damage. We further examine shared metabolic mechanisms between DE and neurodegenerative diseases such as alzheimer's disease (AD) and treatment strategies for pathological metabolic reprogramming including GLP-1 receptor agonists, NAD+ boosters, and AMPK activators. This analysis laid the foundation for new intervention measures against the development of DE.

Keywords:  GLP-1 receptor agonists; NAD⁺ boosters; brain insulin resistance; diabetic encephalopathy; glycolytic flux; metabolic reprogramming; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2025.1701406
Glia. 2026 Feb;74(2): e70113

Astrocyte MCT1 Expression Does Not Contribute to the Axonal Degenerative Phenotype Observed With Ubiquitous MCT1 Depletion.

Thomas Philips, Emily G Thompson, Olivia Spead, Balaji G Vijayakumar, Erica R Kent, Sean J Miller, Treasure Nwokeleme, Svetlana Vidensky, Mohamed Hassan Farah, Jeffrey D Rothstein.

  We recently reported that the loss of oligodendrocyte metabolic support through the lactate and pyruvate transporter Monocarboxylate Transporter 1 (MCT1) is well tolerated into adulthood. Only with advanced aging did we observe axonal degeneration and hypomyelination due to the loss of MCT1 from oligodendroglia lineage cells. MCT1 is also expressed by other glial subtypes, such as astrocytes and endothelial cells where it has been suggested to be essential for learning and memory tasks. However, the importance of MCT1 in these cell types for long-term axonal metabolic support is still unknown. We therefore addressed whether the conditional loss of MCT1 from either of these cell types would lead to widespread axonal degeneration with aging. Using a conditional null approach, similar to what was used for oligodendrocyte MCT1 depletion, we observed that the conditional knockout of MCT1 from either astrocytes or endothelial cells did not cause neuronal injury. On the other hand, inducible ubiquitous depletion of MCT1 causes late-onset axonal degeneration, comparable with what was observed in our previous study using the oligodendrocyte lineage MCT1 null mice. Notably, the loss of astrocytic MCT1 does not cause late-onset neurodegeneration. Ubiquitous MCT1 deletion, however, causes axonal degeneration, suggesting that oligodendrocytes and potentially other cells are more prominent drivers of MCT1-mediated metabolic support of neurons. In summary, we conclude that unlike oligodendrocyte MCT1, astrocyte MCT1 is not an essential driver of astrocyte-mediated axonal energy homeostasis with aging.

Keywords:  astrocyte; axon; degeneration; lactate; metabolism; monocarboxylate transporter 1

DOI:  https://doi.org/10.1002/glia.70113
Neuroreport. 2026 Jan 07. 37(1): 1-10

PDK4 suppresses high glucose-induced microglial ferroptosis by restricting pro-ferroptotic PUFA biosynthesis.

Huahua Su, Zhihui Liu, Jiahao Wei, Ying Liu, Yuke Zhong, Xi Liu, Changhong Tan, Lifen Chen.

   BACKGROUND: Diabetes significantly elevates the risk of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, indicating shared pathophysiological mechanisms. While ferroptosis is increasingly implicated in neurodegeneration, microglia - highly vulnerable to ferroptosis - may mediate this link. However, it remains unknown whether high glucose (HG) directly induces microglial ferroptosis.
METHODS: Using HG-treated BV2 microglia, we integrated multiomics profiling (RNA-seq and targeted lipidomics), functional assays, and genetic manipulation of pyruvate dehydrogenase kinase 4 (PDK4) to investigate its role in HG-associated ferroptosis.
RESULTS: HG-induced microglial ferroptosis, characterized by iron overload, elevated malondialdehyde and mitochondrial reactive oxygen species, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial damage, including loss of membrane potential and ultrastructural disintegration. This was accompanied by upregulated PDK4 expression. PDK4 overexpression attenuated ferroptosis by preserving GPX4, reducing lipid peroxidation, and maintaining mitochondrial integrity; these protective effects were reversed by n-6 polyunsaturated fatty acid (PUFA) supplementation. Conversely, PDK4 knockdown exacerbated ferroptosis via amplified n-6 PUFA synthesis and oxidative stress. Mechanistically, PDK4 acts as a metabolic gatekeeper by restricting acetyl-CoA availability for the synthesis of pro-ferroptotic PUFAs, thereby curtailing iron-dependent lipid peroxidation.
CONCLUSION: PDK4 is a critical regulator of HG-induced microglial ferroptosis, thereby bridging hyperglycemia-induced metabolic dysfunction and neurodegeneration. Our findings nominate PDK4 as a promising therapeutic target for diabetes-linked neurodegenerative diseases.

Keywords:  ferroptosis; high glucose; lipid metabolism; microglia; neurodegenerative disease; pyruvate dehydrogenase kinase 4

DOI:  https://doi.org/10.1097/WNR.0000000000002234
Eurasian J Med. 2023 Dec 29. 55(Suppl 1): S1-S8

Lipid Metabolic Disorders in Neurodegenerative Diseases - Role of Androgen Receptor.

Satvika Sharma, Avneet Saini, D Dhawan.

The challenge of managing neurodegenerative disorders is a worldwide concern, especially in the aging population. Neurodegenerative diseases are a varied group of disorders that are characterized by progressive degeneration of the structure and function of the nerve cells. Neurodegenerative diseases are increasing at an alarming rate, and hence there is an urgent need for an in-depth analysis of various metabolic malfunctions that alter the proper functioning of a cell. Lipid metabolism is a process that involves the synthesis and simultaneous degradation of lipids and encompasses a balance that is essential to maintain the structural and functional ability of a cell. Androgen receptor (AR) plays a critical role in regulating cellular functions. Recent studies have expanded our knowledge regarding direct or indirect interactions that occur among mitochondria, peroxisome, and androgen receptors, which play a crucial role in lipid homeostasis. Unusual levels of lipids and cholesterol due to receptor excitation or inhibition are associated with multiple diseases and have been a cause of concern. The androgen receptor, along with other receptors and proteins, forms an important metabolic cascade that, if altered, may cause the accumulation of lipids and result in neurodegenerative disorders. In this review, we underscore the role of the androgen receptor in regulating lipid and cholesterol levels during neurodegenerative disorders (Alzheimers, Parkinson's, multiple sclerosis, and Huntington's disease).

DOI: https://doi.org/10.5152/eurasianjmed.2023.23024
Nat Commun. 2025 Dec 05.

Lipid dependence of connexin-32 gap junction channel conformations.

Pia Lavriha, Carina Fluri, Jorge Enrique Hernández González, Volodymyr M Korkhov.

Connexin-32 (Cx32) gap junction channels (GJCs) mediate intercellular coupling in various tissues, including myelinating Schwann cells. Mutations in Cx32, such as W3S, are associated with X-linked Charcot-Marie-Tooth (CMT1X) disease. Lipids regulate Cx32 GJC permeation, although the regulatory mechanism is unclear. Here, we determine the cryo-EM structures of Cx32 GJCs reconstituted in nanodiscs, revealing that phospholipids block the Cx32 GJC pore by binding to the site formed by N-terminal gating helices. The phospholipid-bound state is contingent on the presence of a sterol molecule in a hydrophobic pocket formed by the N-terminus: the N-terminal helix of Cx32 fails to sustain a phospholipid binding site in the absence of cholesterol hemisuccinate. The CMT1X-linked W3S mutant which has an impaired sterol binding site adopts a conformation of the N-terminus incompatible with phospholipid binding. Our results indicate that different lipid species control connexin channel gating directly by influencing the conformation of the N-terminal gating helix.

DOI: https://doi.org/10.1038/s41467-025-67004-z
Nat Commun. 2025 Dec 02.

A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.

Yingying Zhang, Brianna Watson, Ajitanuj Rattan, Tyrone Lee, Smriti Chawla, Ludwig Geistlinger, Yilin Guan, Finley B Lord, Minghe Ma, Takashi Miwa, Madhu Golla, Barbara J Caldarone, Wen-Chao Song, Jeffrey R Moffitt, Michael C Carroll.

Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from late embryonic stage to adulthood. Here we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency alters molecular structure of the brain and causes working spatial memory defects, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity.

DOI: https://doi.org/10.1038/s41467-025-66048-5
J Neurochem. 2025 Dec;169(12): e70315

Considerations for Spatial Omics, Metabolite Analyses, and Tissue-Harvesting Artifacts.

Jörg Hanrieder, Ramon Sun, Shane R Ellis, Jens Pahnke, Jeffrey N Savas.

  Within the emerging field of spatial biology, novel analytical technologies are increasingly demonstrated for mapping neurochemical changes in situ. These tools comprise spatial mass spectrometry (MS imaging, MSI), spatial transcriptomics using in situ sequencing, probe-based spatial omics, as well as laser microdissection and single cell-type isolation interfaced with either mass spectrometry or next generation RNA sequencing (NGS) for single cell-type analysis. These approaches significantly exceed the neurochemical methods that are commonly used with respect to molecular specificity and spatial precision. However, despite all these advancements, close attention has still to be paid to appropriate tissue harvesting and enzyme inactivation methods to avoid degradation of neurochemicals and the generation of artifacts, and because of euthanasia or postmortem ischemia. In this editorial, we aim to present the readership with considerations in lieu of emerging analytical and spatial molecular techniques, as well as highlight the relevance of appropriate tissue preparation. Importantly, we discuss different quenching techniques and their compatibility as well as limitations for novel spatial analyses that require morphologically pristine tissues.

Keywords:  artifacts; metabolomics; morphology; neurochemical; omics; spatial biology; tissue harvesting

DOI:  https://doi.org/10.1111/jnc.70315
Acta Neuropathol Commun. 2025 Dec 03.

Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.

Eva D Ruiz-Ortega, Anna Wilkaniec, Josué Juárez, Agata Adamczyk.

  Parkinson's disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria-and particularly their membranes-as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.

Keywords:  Alpha-synuclein; Cardiolipin; Liquid‒liquid phase separation; Mitochondrial dysfunction; Parkinson’s disease

DOI:  https://doi.org/10.1186/s40478-025-02190-x
J Neurol Neurosurg Psychiatry. 2025 Dec 04. pii: jnnp-2025-336935. [Epub ahead of print]

Metabolic brain networks in dementia with Lewy bodies: from prodromal to manifest disease stages.

Alzheimer’s Disease Neuroimaging Initiative

   BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages.
METHODS: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements.
RESULTS: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB.
CONCLUSIONS: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.

Keywords:  ALZHEIMER'S DISEASE; LEWY BODY DEMENTIA; PET, FUNCTIONAL IMAGING

DOI:  https://doi.org/10.1136/jnnp-2025-336935