Journal Of Neurochemistry[JOURNAL]
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200 papers
LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models.
Baumart GJ, Rodrigues MS, Sholl JN … +13 more , de Sousa AC, Weber AF, Costa-Beber LC, Farias HR, Costa MV, Peres AM, de Camargo PR, Fróes FT, Bast RK, de Bem AF, Figueiró F, Guma FTCR, de Oliveira J
J Neurochem · 2026 Mar · PMID 41821217 · Full text
Astrocytes are the primary antioxidant defense cells of the brain, protecting the central nervous system (CNS) through a controlled inflammatory response and acting as metabolic suppliers to neurons. These cells exhibit...
Astrocytes are the primary antioxidant defense cells of the brain, protecting the central nervous system (CNS) through a controlled inflammatory response and acting as metabolic suppliers to neurons. These cells exhibit morphological, functional, and molecular changes in pathological conditions, such as neurodegenerative diseases. Previous studies have demonstrated a link between hypercholesterolemia, especially elevated levels of low-density lipoprotein (LDL) cholesterol, and brain disorders, including hippocampal astrogliosis. In this context, this study aimed to investigate how LDL cholesterol modulates astrocyte biology. In vitro, high-passage rat C6 astroglial cells were exposed to human LDL cholesterol (50 or 300 μg/mL) for 24 or 48 h. We evaluated lipid accumulation, cholesterol metabolism-related gene expression, astrocyte-related gene expression, reactive species production, antioxidant activity, redox-related gene expression, fatty acid and glucose uptake, cell proliferation, and metabolic activity - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. LDL exposure increased intracellular lipid content and downregulated LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and sterol regulatory element-binding transcription factor 1 (SREBF1) gene expression. LDL exposure altered astrocytic marker expression, as evidenced by increased glial fibrillary acid protein (GFAP) messenger RNA (mRNA) levels at 24 h with 300 μg/mL LDL and at 48 h with 50 μg/mL LDL. LDL cholesterol decreased long-chain fatty acids (LCFA) uptake and superoxide dismutase (SOD) activity at 24 h and increased cluster of differentiation 36 (CD36), also known as fatty acid translocase levels, at 48 h. Nuclear factor erythroid 2-related factor 2 (NRF2) expression was significantly increased after 48 h of incubation with 300 μg/mL LDL. The MTT reduction assay did not indicate decreased cell viability; instead, it revealed increased metabolic activity after 24 h of incubation with 300 μg/mL LDL, with no changes observed in glucose uptake. In vivo, hippocampal astrocytes from young (3-month-old) and middle-aged (14-month-old) LDL receptor knockout (LDLr-/-) and wild-type C57BL/6 mice were analyzed by immunofluorescence and quantitative reverse transcription polymerase chain reaction (RT-qPCR). In the hippocampal Cornu Ammonis 3 (CA3) region, 14-month-old LDLr-/- mice showed an increase in the number of processes compared to 3-month-old wild-type C57BL/6 mice. Aging and genotype influenced astrocyte morphology and expression of genes such as S100 calcium-binding protein B (S100B) and aquaporin-4 (AQP4). Our findings demonstrate that LDL cholesterol induces morphological, metabolic, and molecular changes in astrocytes, both in vitro and in vivo, suggesting that astroglial cells are sensitive to lipid imbalance and may play a role in the brain consequences of hypercholesterolemia.
Lack of Structural Change in Olfactory Circuitry Following Fecal Microbiome Transplant From Donors Subjected to Diet-induced Obesity.
Loeven AM, Pacheco FA, Brown AN … +1 more , Fadool DA
J Neurochem · 2026 Mar · PMID 41817170 · Full text
Obesity and fatty diets are known to damage the structure and function of chemosensory systems. Consumption of a moderately high-fat diet (MHF) induces loss of olfactory sensory neurons (OSNs) and reduces the density of...
Obesity and fatty diets are known to damage the structure and function of chemosensory systems. Consumption of a moderately high-fat diet (MHF) induces loss of olfactory sensory neurons (OSNs) and reduces the density of associated axonal projections to the olfactory bulb that are central in the coding of odor information. Previous work has demonstrated reduced alpha diversity, as well as signature changes in microbiome composition when mice are challenged with a MHF diet that precipitates diet-induced obesity. Herein, we tested the hypothesis that a dysbiotic gut microbiome is sufficient to induce olfactory damage. Male and female donor mice were randomly assigned to a control-fat (CF) or MHF diet for 5 months duration, followed by baseline measurements of body weight, body composition (EchoMRI), glucose tolerance, and metabolic phenotyping via indirect calorimetry. We next performed fecal microbiome transplantation (FMT) from these donors to CF-maintained recipient mice. After 8 weeks post FMT, we observed no difference in body weight, glucose clearance, body composition, or fat pad weights as a consequence of transfer from MHF-maintained donors. Following FMT, recipient male mice exhibited increased Erysipelotrichaceae abundance and decreased Lactobacillaceae abundance, similar to MHF-fed donors. Recipient brains were processed for tissue clearing using immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) and then imaged using high resolution light sheet microscopy. The volume of olfactory glomeruli expressing Olfr160 odor receptors could be visualized using genetic reporters; the FMT from MHF-maintained donors failed to evoke structural changes to these defined olfactory synapses. We conclude that diet-induced obesity, associated adiposity, and metabolic dysfunctions drive functional loss and structural changes to the olfactory system, but that gut microbiome dysbiosis alone is not sufficient to yield olfactory circuitry deficits.
Pre-Stress Trait Anxiety Levels Shape Hippocampal Responses to Acute Stress in High Anxiety Male Mice.
Papageorgiou MP, Nussbaumer M, Samiotaki M … +1 more , Filiou MD
J Neurochem · 2026 Mar · PMID 41817165 · Publisher ↗
Stress is a major risk factor for neuropsychiatric disorders. However, how stress influences highly anxious populations and how pre-stress anxiety-related behavior variability mediates stress-elicited molecular responses...
Stress is a major risk factor for neuropsychiatric disorders. However, how stress influences highly anxious populations and how pre-stress anxiety-related behavior variability mediates stress-elicited molecular responses remain elusive. Here, we investigated the effects of acute stress on the hippocampus in high anxiety-related behavior (HAB) male mice and explored how pre-stress high anxiety-related behavior shapes hippocampal and peripheral molecular signatures following acute stress. We first exposed HAB male mice to acute restraint stress (ARS) and investigated ARS effects on hippocampal proteome. We extensively characterized the pre-stress behavior of HAB mice, ranked them in high and low anxiety HAB subpopulations according to their pre-stress anxiety-related profiles and assessed whether divergent high anxiety-related behavior levels influence molecular stress responses. We found that ARS exerts imperceptible hippocampal proteome effects in HAB mice. However, when we compared high versus low anxiety HAB subpopulations following ARS, we observed profound stress-induced molecular changes in low anxiety ARS versus low anxiety control HAB mice, but not in high anxiety ARS versus high anxiety control HAB mice, predominantly impacting mitochondrial translation. When further exploring pre-stress anxiety variability effects in the presence and absence of stress, we observed that high versus low anxiety HAB subpopulations display divergent molecular profiles only after ARS, but not in its absence, leading to changes in RNA metabolism along with altered mitochondrial dynamics players. Taken together, our data showcase that individual behavioral variability largely shapes molecular stress responses in HAB male populations through modulating mitochondrial pathways.
A High-Resolution Transcriptomic Atlas of Cell Types in the Ventral Visual Thalamus.
Stebbins K, Jalil M, Khaksar P … +3 more , Webster AN, Campbell J, Fox MA
J Neurochem · 2026 Mar · PMID 41814933 · Full text
Axons from retinal ganglion cells (RGCs) convey visual information from the retina to distinct regions within the mammalian brain, including several nuclei within the visual thalamus. In rodents, the visual thalamus cont...
Axons from retinal ganglion cells (RGCs) convey visual information from the retina to distinct regions within the mammalian brain, including several nuclei within the visual thalamus. In rodents, the visual thalamus contains three primary retinorecipient regions: the dorsal lateral geniculate nucleus (dLGN), the ventral LGN (vLGN), and the intergeniculate leaflet (IGL). While principal retinorecipient neurons in dLGN are excitatory thalamocortical relay cells (TRCs), most neurons in vLGN are GABAergic, including GABAergic projection neurons. Previous studies suggest that both dLGN and vLGN neurons may be specified into parallel visual pathways for processing and transmitting to select cortical and subcortical brain regions, respectively. While dLGN neurons have been studied extensively, prior studies suggest that additional cell types remain to be identified and characterized in vLGN. Here, we used transcriptomic profiling to generate the first comprehensive and high-resolution atlas for cell types in the mouse vLGN. This atlas was generated based on a single nucleus-sequencing (snRNA-Seq) dataset that contained data from over 16 500 nuclei. We systematically analyzed neuronal and non-neuronal cell types across vLGN based on gene expression. The results revealed the identity of 20 potential types of neurons in the mouse vLGN, including at least two excitatory neuronal types. This comprehensive transcriptomic atlas of mouse vLGN establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of an essential nucleus of the mammalian visual system.
Emerging Role of Liquid Chromatography-Mass Spectrometry in the Clinical Laboratory Evaluation of Chronic Autonomic Failure.
Goldstein DS, Sullivan P, Holmes C … +2 more , Kema I, van Faassen M
J Neurochem · 2026 Mar · PMID 41814889 · Publisher ↗
Liquid chromatography with electrochemical detection (LC-ED) after batch alumina extraction has been the mainstay for assaying levels of catecholamines and related 3,4-dihydroxy compounds (catechols) as part of the clini...
Liquid chromatography with electrochemical detection (LC-ED) after batch alumina extraction has been the mainstay for assaying levels of catecholamines and related 3,4-dihydroxy compounds (catechols) as part of the clinical laboratory workup of patients with neurogenic orthostatic hypotension, especially in the setting of the autonomic synucleinopathies Parkinson disease with orthostatic hypotension (PD + OH), pure autonomic failure (PAF), and multiple system atrophy (MSA). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is faster and measures catechols and non-catechol metabolites simultaneously but has not yet been validated sufficiently against LC-ED or used to assess catechol vs. non-catechol neurochemical abnormalities in autonomic synucleinopathies. We measured plasma catechols by LC-MS/MS and LC-ED in patients with PAF, PD + OH, or MSA and healthy controls. Cardiac sympathetic neuroimaging by F-dopamine positron emission tomography (PET) was used to indicate myocardial norepinephrine (NE) content in the same subjects. Across 41 participants (12 PAF, 9 PD + OH, 10 MSA, 10 controls) individual values for plasma 3,4-dihydroxyphenylglycol (DHPG), NE, and 3,4-dihydroxyphenylalanine (DOPA) by LC-MS/MS correlated positively with values by LC-ED (r = 0.97, 0.98, and 1.00, p < 0.0001 each). The PAF group had low mean NE, DHPG, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, epinephrine, and metanephrine compared to the PD + OH group, while cardiac PET did not separate the 2 groups. We therefore conclude that LC-MS/MS validly assays plasma catechols. Several catechol and non-catechol biomarkers of generalized catecholamine deficiency separate PAF from PD + OH but not PD + OH from MSA, while F-dopamine PET separates PAF and PD + OH from MSA but not PAF from PD + OH. Combining LC-MS/MS with cardiac sympathetic neuroimaging efficiently differentiates among these conditions.
Engram Synapses and Synapse Dynamics in Memory Processing.
Sung Y, Lee C, Jung H … +1 more , Kaang BK
J Neurochem · 2026 Mar · PMID 41814882 · Full text
Synaptic plasticity is believed to underlie a range of cognitive functions, including learning and memory. Numerous studies have shown that memory formation not only modifies the strength of existing synapses but also al...
Synaptic plasticity is believed to underlie a range of cognitive functions, including learning and memory. Numerous studies have shown that memory formation not only modifies the strength of existing synapses but also alters the dynamics of synaptic turnover. The dynamics of the synaptic landscape reflect brain-wide genetic changes and the activation of molecular mechanisms that mediate pre- and postsynaptic structural plasticity. The activity-dependent nature of these mechanisms leads to an intriguing possibility that synapses between engram neurons across multiple brain regions, or "engram synapses," may act as a hub for such synaptic changes. This review aimed to highlight the close relationship between the dynamics of synapse turnover and memory storage and summarize the underlying molecular mechanisms involved. The analysis highlights the need for more systematic investigation into how engram-specific synapses form and are eliminated across different brain regions.
Prefrontal Cortex Dysfunction as a Precipitating Factor for Schizophrenia and Depression.
Uliana DL, Grace AA
J Neurochem · 2026 Mar · PMID 41808329 · Full text
The prefrontal cortex (PFC) is critical for regulating stress responses through top-down control over limbic and subcortical structures. The PFC undergoes a prolonged developmental process that only reaches maturation du...
The prefrontal cortex (PFC) is critical for regulating stress responses through top-down control over limbic and subcortical structures. The PFC undergoes a prolonged developmental process that only reaches maturation during adulthood, causing it to be highly sensitive to environmental insults during neurodevelopment, such as adolescence. During this critical period, synaptic pruning, the maturation of inhibitory GABAergic interneurons, and the refinement of dopaminergic transmission collectively establish the excitatory-inhibitory balance necessary for adaptive behavior. Impairment of the PFC due to developmental disruptions increases susceptibility to maladaptive stress responses. These responses can, in turn, contribute to the development of major depressive disorder and schizophrenia. In depression, a dysfunctional PFC fails to effectively inhibit the amygdala, which contributes to hyperactivity in stress-related circuits, hypodopaminergic states, and anhedonia. In schizophrenia, a neurodevelopmental PFC dysfunction would precipitate hippocampal circuit disruption driven by stress. The inability of an immature PFC to regulate the amygdala response to stress would trigger an increased excitatory drive to the ventral hippocampus, which is proposed to underlie the excessive limbic drive, hippocampal hyperactivity, and a hyperdopaminergic state. In addition, the activation of the mesocortical dopaminergic system by stress facilitates the PFC response to stress, both during adulthood and adolescence. A dopamine (DA)-induced unregulated stress response disrupts the excitatory and inhibitory transmission within the PFC, which plays a critical role in its function. Understanding the interplay between stress and PFC activity/maturation to regulate the circuit toward adaptive or maladaptive outcomes offers critical insights for early intervention and prevention. Early changes in the PFC could underlie vulnerability to unregulated stress response and its consequent effect in contributing to schizophrenia and depression. In this way, early intervention may limit the impact and prevent further circuit dysregulation leading to pathological states.
Dysregulated Plasticity in Serotonin, Galanin, and Opioid Systems Contributes to Limbic Seizure Recruitment in Wistar Audiogenic Rat.
Camilo TA, Valentim-Lima E, de Oliveira JAC … +4 more , Garcia-Cairasco N, Reis LC, Nani JV, Mecawi AS
J Neurochem · 2026 Mar · PMID 41797229 · Full text
The Wistar Audiogenic Rat (WAR) strain is a genetically selected model of reflex epilepsy, susceptible to mesencephalic and, following chronic stimulation, limbic seizures. In this study, we examined the molecular underp...
The Wistar Audiogenic Rat (WAR) strain is a genetically selected model of reflex epilepsy, susceptible to mesencephalic and, following chronic stimulation, limbic seizures. In this study, we examined the molecular underpinnings of this seizure progression by assessing gene expression profiles of pre-synaptic serotonergic components in Dorsal Raphe Nucleus (DRN) and post-synaptic receptors in the Basolateral Amygdala (BLA), Central Amygdala (CeA), and Hippocampus (HIP). Concurrently, we evaluated mRNA expression of Galanin (Gal) and Prodynorphin (Pdyn) in the Supraoptic Nucleus (SON) and their respective receptors in the BLA, CeA, and HIP. WARs and control Wistar rats underwent a ten-day audiogenic kindling (AK) protocol, involving twice-daily exposure to a high-intensity acoustic stimulus to induce seizures. WARs were sub-grouped based on their behavioral phenotype (seizure scales) into limbic-recruited seizures (LiR) and non-limbic-recruited (n-LiR). Quantitative PCR analysis of brain micropunches revealed a significant failure of adaptive plasticity in WARs. Unlike control rats, which showed a robust upregulation of serotonergic (5-HT-ergic) components in the DRN in response to the chronic stress of the kindling protocol, WARs had a significantly blunted pre-synaptic response. Rats that did not show limbic seizures showed compensatory upregulation of amygdala 5-HT receptors, a mechanism that failed in rats that developed chronic seizures. Furthermore, WARs showed elevated hypothalamic galanin but reduced limbic receptor expression. The opioid system was also imbalanced, with an increase in the pro-convulsant mu-opioid receptor. Critically, Pdyn expression was strongly and negatively correlated with limbic seizure severity. Collectively, these findings suggest that the progression to limbic epilepsy, already demonstrated in behavioral and EEG protocols in this model, is driven by a widespread failure of plasticity across interconnected neuromodulatory networks, rather than a single molecular defect, highlighting novel targets for therapeutic intervention.
Young Regulatory T Cell-Derived Extracellular Vesicles Improve Mitochondrial Function and Angiogenesis and Suppress Inflammation in Senescent Brain and Heart.
Cheng J, Xia Y, Ji Z … +10 more , Xu L, Gao R, Xiong Z, Huang L, Zhang X, Ding W, Sun Y, Suo S, Li B, Zhou Y
J Neurochem · 2026 Mar · PMID 41797211 · Publisher ↗
The core mechanisms underlying aging involve genomic instability, cellular senescence, mitochondrial dysfunction, and chronic inflammation, necessitating multi-dimensional therapeutic interventions. Treg-derived extracel...
The core mechanisms underlying aging involve genomic instability, cellular senescence, mitochondrial dysfunction, and chronic inflammation, necessitating multi-dimensional therapeutic interventions. Treg-derived extracellular vesicles (Treg-EVs) therapy, which circumvents the safety risks associated with live cell therapies, exhibits the potential to modulate metabolic and immune functions, offering promise for healthy aging. Here, we isolated Tregs from young male C57BL/6 mice and collected Treg-EVs. In vitro experiments demonstrated that Treg-EVs significantly attenuated cellular senescence, reduced reactive oxygen species (ROS) accumulation, and enhanced mitochondrial respiration in HL-1 and HT22 senescent cell models. In vivo experimental data revealed that young Treg-EVs promoted mitochondrial biogenesis, facilitated vascular repair and regeneration, as well as attenuated inflammatory responses, and ultimately prolonged the survival of aged male C57BL/6 mice. This study demonstrates the ability of Treg-EVs therapy to reverse multiple aging-related abnormal phenotypes, providing a promising strategy for treating aging and its associated diseases.
Astrocyte Bioenergetic Remodeling as a Central Trait of Disrupted Glucocorticoid Signaling: Mechanisms and Implications for Stress Vulnerability.
Hanus P, Frydecka D, Ślęzak M
J Neurochem · 2026 Mar · PMID 41797210 · Full text
Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasing...
Glucocorticoids (GCs) are central to the organism's adaptation to stress, coordinating systemic energy distribution and neuroendocrine signaling. While acute effects of GCs are adaptive, chronic GC exposure is increasingly recognized as an important factor contributing to the pathophysiology of neuropsychiatric disorders, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). A piling evidence points to astrocytes as a central integrator of brain response to stress hormones, including GCs. In this review, we discuss a biphasic regulation of astrocyte metabolism by GCs. According to the hypothesis, astrocytes undergo metabolic adaptations in response to GC: acute exposure leads to the enhancement of astrocyte metabolism through upregulation of glycolysis, mitochondrial activation, and glutamate clearance. In turn, prolonged GC exposure induces a metabolic shift toward branched-chain amino acid and lipid catabolism, promoting mitochondrial reactive oxygen species (ROS) production and impairing key homeostatic functions, including the astrocyte-neuron lactate shuttle and calcium signaling. Progressive disruption of astrocytes' supporting function may subsequently lead to synaptic dysregulation and energy imbalance in stress-related brain pathology. We postulate that a detailed understanding of this dynamic regulation is necessary for targeting astrocyte-specific metabolic mechanisms in neuropsychiatric disorders.
Spastin Is Required to Prevent SPAST-Related Demyelination.
Akarsu Ş, Orhan DM, Avşar T … +1 more , Karabay A
J Neurochem · 2026 Mar · PMID 41797006 · Publisher ↗
Mutations in the SPAST gene, encoding the microtubule-severing protein Spastin, cause the most common type of hereditary spastic paraplegia (HSP): SPG4, a disorder primarily characterized by length-dependent axonal degen...
Mutations in the SPAST gene, encoding the microtubule-severing protein Spastin, cause the most common type of hereditary spastic paraplegia (HSP): SPG4, a disorder primarily characterized by length-dependent axonal degeneration. Clinically, most SPG4 patients present with a pure phenotype marked by progressive spasticity in the lower extremities. It has also been reported that complex cases exhibit demyelination and cognitive deficits. Additionally, some SPAST variants have been determined in patients with multiple sclerosis (MS), indicating potential shared pathological mechanisms. Spastin is known to promote axonal regeneration by remodeling microtubules, whereas mutant Spastin disrupts microtubule dynamics and causes axonal transport defects in SPG4. However, whether Spastin dysfunction impairs regenerative processes such as myelination remains unknown. In this study, we investigated whether the SPG4-associated SPAST mutations affect axonal myelination. Using an in vitro cortical neuron-oligodendrocyte co-culture model, we found that pathogenic SPAST mutations result in a significant reduction in the myelination index. Furthermore, a cuprizone-induced demyelination mouse model revealed a decrease in Spastin protein levels in demyelinated white matter. Given Spastin's role in axonal regeneration, we hypothesized that Spastin may also protect against demyelination. Supporting this, wild-type Spastin expression protected neurons from demyelination in a cuprizone-induced cell culture demyelination model. Together, these results suggest a role for Spastin in axonal myelination, and its dysfunction may compromise myelin stability. Our findings highlight that impaired myelin stability may represent a secondary pathological feature of SPG4, contributing to disease complexity. This dual role of Spastin in axonal maintenance and myelin stability suggests its potential relevance for contributing to complex forms of SPG4.
EXPRESSION OF CONCERN: High Specificity of Widely Used Phospho-Tau Antibodies Validated Using a Quantitative Whole-Cell Based Assay.
J Neurochem · 2026 Mar · PMID 41795683 · Publisher ↗
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Deficiency of Tissue Nonspecific Alkaline Phosphatase Dysregulates Microglial Morphology and Function in a Mouse Model of Infantile Hypophosphatasia.
Elaswad K, Mashal Y, Nasser I … +3 more , Almhanaa L, Grabowski C, Zhang Z
J Neurochem · 2026 Mar · PMID 41792908 · Full text
Tissue-nonspecific alkaline phosphatase (TNAP) has emerged as a crucial regulator of neuronal circuit formation and maintenance; however, the complexities of its sex- and cell type-specific roles within microglia remain...
Tissue-nonspecific alkaline phosphatase (TNAP) has emerged as a crucial regulator of neuronal circuit formation and maintenance; however, the complexities of its sex- and cell type-specific roles within microglia remain largely unexplored. To address this critical knowledge gap, this study examined how TNAP deficiency differentially affects microglial morphology, function, and signaling in both male and female mice, and investigated its broader implications for neurodevelopment and disease susceptibility. Using Alpl (wild-type) and Alpl (TNAP knockout) mice, we conducted behavioral assessments at postnatal Days 13-14 to evaluate early neurobehavioral outcomes. Microglia were subsequently isolated for molecular, metabolic, and morphological analyses. TNAP-deficient mice of both sexes exhibited profound physiological deficits, including stunted growth and significant sensorimotor impairments, confirming effective TNAP knockout and indicating that systemic TNAP loss affects multiple cell types beyond microglia. At the cellular level, TNAP loss induced notable morphological changes in microglia, characterized by enlarged cell soma and shortened processes, hallmarks of microglial activation. Molecular profiling revealed upregulation of neuroinflammatory and phagocytic markers, implicating TNAP as a modulator of the innate immune response. Furthermore, metabolic analyses uncovered a dramatic shift in tryptophan-kynurenine metabolism, with increased quinolinic acid production signifying a transition to a neurotoxic, pro-inflammatory state. Additionally, TNAP-deficient microglia displayed extensive dysregulation in purinergic signaling pathways, exemplified by increased expression of key purinergic receptors, and acquired a senescent phenotype evidenced by elevated canonical senescence gene expression. Given the influence of TNAP deficiency on multiple cell populations, some observed microglial phenotypes may result from altered intercellular signaling or indirect effects. To delineate cell-autonomous effects, siRNA-mediated TNAP knockdown was performed in primary microglia isolated from wild-type (WT) mice. TNAP depletion modulated inflammatory responses, suggesting an intrinsic role for TNAP in microglial regulation; however, these effects may not fully recapitulate the extent of deficiency observed in vivo. Overall, TNAP emerges as a key modulator of microglial structure and function, with its dysfunction potentially increasing susceptibility to neurodevelopmental and neurodegenerative disorders. This highlights the potential of TNAP as a therapeutic target for central nervous system health and disease.
Correction to "Dissociation of the mTOR Protein Interaction Network Following Neuronal Activation Is Altered by Shank3 Mutation".
J Neurochem · 2026 Mar · PMID 41792863 · Full text
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Neuroprotective Effects of Strength Training on Behavioral Deficit, Oxidative Damage, Astrogliosis, and Neuronal Death in a Bipolar Disorder Model.
Maidana LM, da Silva Guerra JM, Souza-Pereira A … +5 more , Dahleh MMM, Godinho DB, Prigol M, Royes LFF, Rambo LM
J Neurochem · 2026 Mar · PMID 41789714 · Full text
Bipolar disorder (BD) is associated with mood dysregulation and neurobiological abnormalities such as oxidative stress, neuroinflammation, and neurodegeneration. While physical exercise shows promise in mental health, th...
Bipolar disorder (BD) is associated with mood dysregulation and neurobiological abnormalities such as oxidative stress, neuroinflammation, and neurodegeneration. While physical exercise shows promise in mental health, the mechanistic effects of strength training in BD remain poorly understood. This study aimed to investigate the impact of an 8-week strength training protocol on behavioral, oxidative, and cellular alterations in a validated rat model of BD induced by ouabain. Adult male Wistar rats were randomly assigned to sedentary or exercised groups. After the training period, animals underwent surgery for cannula implantation. Following recovery, they received either ouabain or artificial cerebrospinal fluid. Behavioral assessments were conducted during the manic- (Day 7) and depressive-like (Day 14) phases, and tissue samples were collected on Day 18 post-injection. Neurochemical assays and immunohistochemical analyses were performed in the cerebral cortex and hippocampus. Ouabain induced manic- and depressive-like behaviors, cognitive impairments along with oxidative imbalance, increased NF-κB activation, astrogliosis, and neuronal degeneration. Notably, prior strength training prevented these behavioral disturbances and significantly attenuated oxidative stress, neuroinflammation, and cell death. Physical exercise normalized antioxidant enzyme activities, reduced reactive species accumulation, prevented NF-κB activation, and decreased GFAP and Fluoro Jade-C labeling. Correlation analyses revealed significant associations among oxidative stress, inflammation, neurodegeneration, and cognitive impairment. These findings demonstrate, for the first time, that structured strength training exerts neuroprotective effects in a BD model by modulating redox homeostasis, inflammatory signaling, and neuronal integrity. Strength training emerges as a promising, low-cost, and mechanistically grounded adjunctive strategy in BD management.
Sex and Diet Biased Effect of L-DOPA on Iron Accumulation in the Ventral Midbrain.
Serpa RO, Tufano E, Palsa K … +4 more , Helmuth TB, Mills-Huffnagle S, Kant M, Connor JR
J Neurochem · 2026 Mar · PMID 41787920 · Full text
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, a region within the ventral midbrain known to accumulate iron. While L-3,4-d...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, a region within the ventral midbrain known to accumulate iron. While L-3,4-dihydroxyphenylalanine (L-DOPA) remains the gold standard treatment for PD, its impact on brain iron homeostasis, particularly under varying systemic iron conditions, remains poorly understood. In this study, we investigate how dietary iron status and anti-PD treatments influence brain iron accumulation and regulation in the ventral midbrain, with a focus on sex-specific differences. Male and female Long-Evans rats were placed on iron-adequate (IA), iron-deficient (ID), or iron-repletion (IR) diets from postnatal day (PND) 21 for eight weeks. In the final three weeks, animals received daily subcutaneous injections of L-DOPA, selegiline, or vehicle. Our findings revealed that L-DOPA treatment in IR males significantly increased brain iron levels in the ventral midbrain, whereas females showed no such effect. This sex-specific accumulation was accompanied by the upregulation of iron uptake protein transferrin receptor 1 (TfR1), increased ferroportin (FPN1), and reduced expression of the iron storage protein ferritin heavy chain (FTH1), indicating disrupted iron homeostasis. Furthermore, L-DOPA-treated males on the IR diet exhibited elevated glial fibrillary acidic protein (GFAP) and lipocalin-2 (LCN2), suggesting enhanced oxidative stress and astrocyte activation. Consistent with this, antioxidant enzymes catalase (CAT) and superoxide dismutase 2 (SOD2) were significantly decreased in L-DOPA-treated males on the IR diet, highlighting increased vulnerability to oxidative damage. In contrast, selegiline did not significantly alter brain iron levels or iron-regulatory protein expression, regardless of diet or sex. These findings demonstrate that systemic iron repletion after deficiency sensitizes the male brain to L-DOPA-induced iron accumulation, potentially increasing susceptibility to neurodegeneration. This study highlights the importance of considering that both dietary iron status and biological sex may impact PD treatment strategies.
Iron Depletion in the Substantia Nigra of Children With Prenatal Alcohol Exposure.
Alves F, Fazollahi A, Kalinowski P … +6 more , Anderson P, Muggli E, Kelly C, Ponsonby AL, Thompson D, Ayton S
J Neurochem · 2026 Mar · PMID 41787772 · Publisher ↗
Prenatal alcohol exposure (PAE) occurs in 10%-60% of pregnancies and can contribute to fetal alcohol spectrum disorders (FASD). FASD presents with diverse cognitive, behavioral, and motor impairments. Animal studies sugg...
Prenatal alcohol exposure (PAE) occurs in 10%-60% of pregnancies and can contribute to fetal alcohol spectrum disorders (FASD). FASD presents with diverse cognitive, behavioral, and motor impairments. Animal studies suggest PAE disrupts fetal iron homeostasis, but direct evidence in the human brain is lacking. Because iron is essential for neurodevelopmental processes including myelination, neurotransmitter synthesis, and energy metabolism, perturbations in iron deposition may represent a modifiable mechanism linking PAE to adverse outcomes. The aim of this study was to explore whether PAE is associated with brain iron levels at age 7 years, assessed using quantitative susceptibility mapping MRI. Children were recruited from the Asking Questions about Alcohol in Pregnancy (AQUA) prospective longitudinal cohort. Participants were categorized as unexposed (no PAE, n = 5), exposed in the first trimester only (PAE T1, n = 14), or exposed across the first to third trimester (PAE T1-3, n = 6). Quantitative susceptibility mapping (QSM), an MRI modality sensitive to iron, was used to estimate regional brain iron across 38 cortical and subcortical regions. Linear models assessed the effects of alcohol exposure and timing of exposure on brain iron, adjusting for age and sex. Compared with unexposed children, those with any PAE had significantly lower QSM in the substantia nigra (β = -18.93, p = 0.011). Stratified analyses revealed that substantia nigra QSM was lower even after first-trimester-restricted exposure (T1 β = -22.63 95% CI [-37.35, -7.91]; p = 0.004). Cortical analyses showed regionally variable alterations, with reductions in the superior parietal cortex (β = -1.33, p = 0.011), insula (β = -1.33, p = 0.051), and pars opercularis (β = -0.926, p = 0.078), and elevations in the postcentral gyrus (β = 2.82, p = 0.003) in those with any PAE compared with unexposed. PAE is associated with region-specific disruptions in brain iron, inferred by QSM, with early exposure particularly affecting the substantia nigra and extended exposure linked to broader cortical and subcortical changes. These exploratory findings provide the first evidence in humans that PAE alters brain iron homeostasis, highlighting iron metabolism as a potentially modifiable pathway contributing to the neurodevelopmental burden of FASD.
Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.
Kaya Y, Kırboğa KK
J Neurochem · 2026 Mar · PMID 41782322 · Publisher ↗
Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in di...
Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.
Neuroprotection From Intracerebral Hemorrhage Following Pharmacological Inhibition of GSK3β Depends on HFE Gene Status.
Helmuth TB, Palsa K, Sahu AP … +5 more , Neely EB, Kumari R, Slagle-Webb B, Simon SD, Connor JR
J Neurochem · 2026 Mar · PMID 41772831 · Full text
Iron release from hemoglobin breakdown following an intracerebral hemorrhage (ICH) is a key mediator in stroke-induced cytotoxicity. We have previously demonstrated that mice carrying the H67D mutation in the homeostatic...
Iron release from hemoglobin breakdown following an intracerebral hemorrhage (ICH) is a key mediator in stroke-induced cytotoxicity. We have previously demonstrated that mice carrying the H67D mutation in the homeostatic iron regulatory gene (HFE) experience marked neuroprotection following ICH. This improvement is likely due to an endogenous upregulation in the Nrf2 antioxidant system. Prior studies in H67D mice discovered decreased activity in GSK3β, a kinase that functions to break down Nrf2. Interestingly, pharmacological inhibition of GSK3β has been shown to vastly improve outcomes in ICH animal models. However, it remains unclear whether this pathway is responsible for the enhanced antioxidant response in H67D animals. In this study, H67D and WT mice received daily injections of intraperitoneal SB216763, a selective inhibitor of GSK3β, 14 days prior to ICH. The functional motor recovery of each animal was assessed by rotarod and neurodegeneration was measured using Fluorojade-B. Immunoblotting assessed the antioxidant response and GSK3β activity through Nrf2, GPX4, FTH1, and β-Catenin. At 3 days post-ICH, SB216763-treated WT mice display enhanced functional recovery, decreased degenerated neurons, and increased brain levels of Nrf2 and GPX4 compared to WT-Vehicle-Controls. Further, SB216763 treatment in H67D mice did not result in any significant changes in measured outcomes compared to H67D-Vehicle-Controls. In conclusion, WT mice benefit from GSK3β inhibition following ICH whereas H67D animals do not. This suggests that the regulation of the antioxidant response may have reached its biological limit in H67D animals. Importantly, these data suggest that clinical trials aimed towards improving ICH outcomes, especially through GSK3β inhibition, must take into account HFE genotype as this mutation, present in nearly 20% of individuals worldwide, may alter ICH recovery regardless of therapy.
Integrated Bioinformatics Analysis of Screen Mitochondrial Autophagy-Related Core Genes and Construct Diagnostic Model for Alzheimer's Disease.
Gao Z, Wang Y, Ren Y … +1 more , Lyu J
J Neurochem · 2026 Feb · PMID 41731906 · Publisher ↗
Identify mitochondrial autophagy genes associated with Alzheimer's disease (AD) and elucidate its underlying pathogenesis and explore potential therapeutic targets. Alzheimer's disease related gene expression data were o...
Identify mitochondrial autophagy genes associated with Alzheimer's disease (AD) and elucidate its underlying pathogenesis and explore potential therapeutic targets. Alzheimer's disease related gene expression data were obtained from the Gene Expression Omnibus database. Mitochondrial autophagy-related genes with a relevance score > 1 were screened based on the GeneCards database. We identified differentially expressed genes using R, followed by functional enrichment and immune cell infiltration analyses. A protein-protein interaction network was constructed based on the STRING database, and key genes were identified by Cytoscape software. A diagnostic model for Alzheimer's disease was subsequently developed based on these key genes. Nine key genes were identified for Alzheimer's disease. Gene Ontology enrichment analysis revealed that the differentially expressed genes (DEGs) were primarily involved in mitochondrial function and nucleotide metabolism. Immune infiltration analysis showed negative correlations between YWHAG and VPS35 expression and M1 macrophage abundance, while RTN4 expression positively correlated with follicular helper T cell abundance. Using logistic regression analysis, a diagnostic model for AD was constructed based on three of the key genes. The model was validated by independent external samples, where area under the curve (AUC) demonstrated its robust and excellent diagnostic performance. The nine key genes identified in this study provide new insights and potential therapeutic targets for elucidating how mitochondrial autophagy influences Alzheimer's disease. The established diagnostic model provides a theoretical basis for personalized diagnosis and treatment of Alzheimer's disease.
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