Journal Of Neurochemistry[JOURNAL]
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200 papers
L-Leucine Upregulates Lysosomal Biogenesis and Autophagy to Lower Plaques in 5XFAD Mouse Model of Alzheimer's Disease.
Paidi RK, Gorai S, Mondal S … +1 more , Pahan K
J Neurochem · 2026 Apr · PMID 41940752 · Full text
Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non-essential amino acids for the ability to s...
Twenty different amino acids are required for the human body for proper functioning as amino acids serve as building blocks for proteins. We screened different essential and non-essential amino acids for the ability to stimulate lysosomal biogenesis and, interestingly, found an essential amino acid L-leucine as the most potent one in stimulating lysosomal biogenesis in astrocytes. However, D-leucine remained weaker than L-leucine in terms of stimulation of lysosomal biogenesis. Accordingly, L-leucine increased autophagy in cultured brain cells and in vivo in the brain of 5XFAD mice, one of the animal models of Alzheimer's disease (AD). L-Leucine also stimulated the uptake and degradation of amyloid-β in astrocytes and reduced the plaque load and improved cognitive functions in 5XFAD mice. Although L-leucine was discovered about 200 years back, until now, no receptor has been identified for L-leucine. Here, we noticed that L-leucine binds to the ligand-binding domain of peroxisome proliferator-activated receptor α (PPARα) to activate this nuclear hormone receptor. Accordingly, L-leucine remained ineffective in increasing lysosomal biogenesis and autophagy in PPARα brain cells. Lentiviral establishment of full-length PPARα, but not Y314D-PPARα, reinstated the autophagy-stimulating effect of L-leucine in PPARα astrocytes, emphasizing the importance of leucine's interaction with the Y314 residue. Moreover, oral L-leucine decreased the plaque load and improved spatial learning and memory in 5XFAD mice, but not in 5XFAD mice (5XFAD lacking PPARα), highlighting the involvement of PPARα in the neuroprotective effects of L-leucine. These results may be beneficial for AD patients.
A Novel Mouse Model of Sympathoadrenal Catecholamine Deficiency by Ablation of the Tyrosine Hydroxylase Gene With Slc6a4-Cre.
Ogawa R, Fukumoto R, Hara S … +2 more , Hayashi N, Ichinose H
J Neurochem · 2026 Apr · PMID 41930737 · Full text
Catecholamines (CAs) play important roles not only in the central nervous system but also in the periphery. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for CA synthesis and selective Th ablation in tissues of i...
Catecholamines (CAs) play important roles not only in the central nervous system but also in the periphery. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for CA synthesis and selective Th ablation in tissues of interest is useful to investigate the physiological function of locally produced CAs. Slc6a4 encodes serotonin transporter (SERT), a membrane transporter for serotonin reuptake, which is reported to be expressed in several peripheral tissues as well as serotonin-producing cells. Here, we report a novel Th conditional knockout mouse line generated by Slc6a4-Cre. The conditional knockout mice (cKO mice) exhibited predominant depletion of adrenaline in the adrenal glands, while noradrenaline contents were preserved at approximately 70% of control levels. TH expression was largely lost, although sparsely retained, in the adrenal medulla of cKO mice contrary to unaltered expression of TH in the brain. In addition to the adrenal gland, TH expression was lost in approximately 80% of sympathetic neurons in the superior mesenteric ganglion of cKO mice. Plasma noradrenaline levels were significantly reduced, although plasma dihydroxyphenylalanine (DOPA) levels were comparable to those of controls. Bradycardia and changes in heart rate variability in cKO mice suggested impaired sympathoadrenal catecholaminergic regulation of the heart. The present data highlight the value of these cKO mice as a useful tool for elucidating the properties of the sympathoadrenal catecholaminergic system independently of the brain noradrenergic system.
Neural Stem Cells in Demyelinating Diseases: Interplay Between Lineage Potential and the Microenvironmental Constraints in Remyelination.
Byrne AJ, Pibuel MA, Lázaro-Martínez JM … +1 more , Franco PG
J Neurochem · 2026 Apr · PMID 41925088 · Publisher ↗
Failure of remyelination is a major determinant of progressive neurological decline in demyelinating disorders of the central nervous system. Although endogenous repair mechanisms are activated following injury, the gene...
Failure of remyelination is a major determinant of progressive neurological decline in demyelinating disorders of the central nervous system. Although endogenous repair mechanisms are activated following injury, the generation of fully functional myelinating oligodendrocytes is frequently insufficient to restore long-term tissue integrity. In addition to oligodendrocyte progenitor cells, neural stem cells (NSCs) residing in adult neurogenic niches represent a potential endogenous source of oligodendroglial regeneration. However, promoting effective remyelination from NSCs requires more than stimulating lineage commitment, as progenitor fate and maturation are tightly regulated by lesion-specific microenvironmental cues. Over the past decades, a wide range of experimental models-including reductionist in vitro systems, organoid platforms, toxin-induced or immune-mediated demyelination in vivo models-have provided important mechanistic insights into NSCs activation and oligodendroglial differentiation. Yet, no single model fully captures the complexity of chronic human pathology, highlighting significant translational limitations. Moreover, inflammatory signaling, glial reactivity, and extracellular matrix remodeling critically influence whether enhanced oligodendrogenesis results in effective remyelination. In this review, we analyze current experimental frameworks used to investigate NSCs-driven oligodendrogenesis and discuss how microenvironmental regulation shapes regenerative outcomes. We further examine emerging therapeutic strategies aimed at modulating endogenous NSCs and their niche, including pharmacological approaches, cell-based interventions, and nanotechnology-based platforms. By integrating experimental and translational perspectives, we propose that successful remyelination requires coordinated modulation of both progenitor competence and lesion microenvironment.
The Kappa Free Light Chains Index in Multiple Sclerosis: From Emerging Evidence to Clinical Application.
Verchere N, Roult S, Michel L … +7 more , Le Page E, Rousseau C, Messaoudi K, Hasbini R, Bendavid C, Dumontet E, Moreau C
J Neurochem · 2026 Apr · PMID 41919443 · Full text
The kappa free light chain (KFLC) index is a promising biomarker for detecting intrathecal immunoglobulin synthesis in multiple sclerosis (MS), offering a quantitative and automated alternative to oligoclonal bands (OCBs...
The kappa free light chain (KFLC) index is a promising biomarker for detecting intrathecal immunoglobulin synthesis in multiple sclerosis (MS), offering a quantitative and automated alternative to oligoclonal bands (OCBs). However, its use in clinical practice is limited by heterogeneous thresholds and a lack of standardized diagnostic algorithms. Objective to develop and validate a biological diagnostic algorithm for MS that fully integrates the KFLC-index alongside current recommended CSF biomarkers, particularly CSF-restricted OCBs. We conducted a prospective, monocentric study including 198 patients undergoing lumbar puncture for suspected neurological disease. Patients were classified as having MS (including CIS/RIS) or non-inflammatory neurological disorders. Paired cerebrospinal fluid and serum KFLC and LFLC were quantified using a turbidimetric assay (Optilite, The Binding Site). Diagnostic performance was assessed by ROC analysis. A diagnostic algorithm was developed and validated in an independent cohort. In the derivation cohort (n = 80), the KFLC-index showed excellent accuracy (AUC = 0.93). An optimal threshold of 20.27 provided 80.6% sensitivity and 100% specificity. A lower threshold of 3 increased sensitivity (96.8%) but reduced specificity (26.5%). Application of the diagnostic algorithm to the replication cohort (n = 70) confirmed the absence of false positive and false negative results for threshold values. Systematic OCBs testing enhanced interpretation in intermediate KFLC-index ranges (3-20). The algorithm's performance was consistent with previously published thresholds. The KFLC-index is a robust biomarker for MS diagnosis. Integration into a tiered algorithm offers excellent diagnostic performance, though local validation remains essential before broad clinical adoption.
Neuroscience in China: Domestic and Foreign Experts Working Together.
Montana V, Wang Y, Chen Z … +1 more , Parpura V
J Neurochem · 2026 Apr · PMID 41919402 · Publisher ↗
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Inhibition of the NLRP3 Inflammasome With MCC950 Improves Gut Health in Huntington's Disease Mice.
Sarkar SK, Ekwudo MN, Lu D … +8 more , Masson B, Kiridena P, van de Garde N, Renoir T, Vince JE, Deepagan VG, Hannan AJ, Gubert C
J Neurochem · 2026 Apr · PMID 41906693 · Full text
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder featuring abnormal cognition, psychiatric symptoms, movement, and gastrointestinal function. It is caused by a tandem-repeat gene mutation enc...
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder featuring abnormal cognition, psychiatric symptoms, movement, and gastrointestinal function. It is caused by a tandem-repeat gene mutation encoding an expanded polyglutamine tract in the huntingtin protein. Our group was the first to demonstrate gut microbial disruption in both clinical HD cohorts and validated preclinical models, supporting a role for microbiota-gut-brain axis dysfunction in HD. The NLRP3 inflammasome, a key innate immune sensor that integrates microbial, metabolic, and host-derived danger signals, has been implicated in HD pathology. However, its contribution to gut health and microbiota-linked cognitive deficits in HD remains unknown. This study addressed this critical gap by investigating whether targeting NLRP3 can restore gut and brain health in HD through modulation of the microbiota-gut-brain axis. We aimed to investigate the role of the NLRP3 inflammasome in microbiota-gut-brain axis dysfunction by targeting its inhibition. Here, we assessed whether inhibiting NLRP3 can ameliorate cognitive deficits, gut abnormalities, gut microbial alteration, and associated molecular and behavioural disturbances in HD. NLRP3 inflammasome inhibitor MCC950 was administered to R6/1 transgenic HD mice and their wild-type (WT) littermate controls from 6 to 20 weeks of age. Cognitive and behavioural performance was evaluated using validated tests, alongside assessments of general health and gut function. HD mice exhibited reduced body and brain weight, increased fluid consumption, memory impairments, motor deficits, exacerbated gastrointestinal phenotype, and altered gut microbiota. Treatment with MCC950 did not affect body or brain weight, cognitive and motor performance, and it also did not affect the gut microbial profile of HD mice. However, MCC950 significantly rescued gut health, as evidenced by increased faecal output (in females) and water content (in both males and females), improved stool consistency (in both sexes), and ameliorated macroscopic gut abnormalities. Our findings highlight a promising therapeutic avenue for addressing the significant gastrointestinal anomalies observed in HD. By targeting the NLRP3 inflammasome in R6/1 HD mice, we have identified a novel strategy to improve gut health. These results support further investigation of inflammasome inhibition as a means to alleviate central and peripheral symptoms in HD and improve overall disease management.
Schwann Cell TRPA1, a Proalgesic Ion Channel, Mediates Neuroinflammation and Fibromyalgia-Associated Behaviours in Mice.
Brum ES, Fialho MFP, de Araújo DSM … +5 more , Landini L, Marini M, De Logu F, Nassini R, Oliveira SM
J Neurochem · 2026 Apr · PMID 41906627 · Full text
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel that integrates the somatosensory system and is specialised in detecting thermal, mechanical, and chemical stimuli. It acts as both a sensor and an amplifi...
Transient receptor potential ankyrin 1 (TRPA1) is an ion channel that integrates the somatosensory system and is specialised in detecting thermal, mechanical, and chemical stimuli. It acts as both a sensor and an amplifier of reactive oxygen and nitrogen species, carbonylic species and lipid peroxidation products, which are overproduced in several painful conditions, including fibromyalgia. Studies have linked TRPA1 to heightened sensitivity to mechanical and cold pain in fibromyalgia patients. In a preclinical mouse model of fibromyalgia induced by reserpine administration, activated Schwann cells expressing TRPA1 trigger an intracellular pathway that leads to the production of reactive oxygen species (ROS) via NADPH oxidase (NOX) 1 and to the recruitment of macrophages in the mouse sciatic and trigeminal nerves. Such mechanisms contribute to mechanical and cold hypersensitivity and early anxiety- and depression-like behaviours. Future translational studies will be essential to validate whether pharmacological modulation of the Schwann cell TRPA1/NOX1 pathway could provide clinical benefit in fibromyalgia.
A Decline in Metabotropic Glutamate mGlu3 Receptor Levels Is Associated With Amyloid Plaques in Alzheimer's Disease and Is Detectable in Serum During Mild Cognitive Impairment.
Olivera E, Sáez A, Castro M … +12 more , Garaventa P, Novack G, Romero AC, Bigi M, Celaya D, Mezmezian M, Sevlever G, Saravia F, Lasaga M, Caruso C, Palumbo ML, Durand D
J Neurochem · 2026 Apr · PMID 41906597 · Publisher ↗
Subtype 3 metabotropic glutamate receptors (mGlu3R) play neuroprotective roles and are involved in superior executive functions and memory in humans. However, this target has been scarcely studied in the context of Alzhe...
Subtype 3 metabotropic glutamate receptors (mGlu3R) play neuroprotective roles and are involved in superior executive functions and memory in humans. However, this target has been scarcely studied in the context of Alzheimer's disease (AD). Our previous results showed that astroglial mGlu3R promoted the non-amyloidogenic cleavage of amyloid precursor protein and triggered amyloid-β (Aβ) clearance by astrocytes. Remarkably, mGlu3R is downregulated in hippocampi from aged PDAPP-J20 mice, whereas the truncated isoform of the receptor, mGlu3Δ4, is early accumulated. Indeed, mGlu3Δ4 inhibited mGlu3R protective function in astrocytes. In the present paper, we aimed to investigate mGlu3Δ4/mGlu3R expression in AD brains and to assess whether changes in these proteins can be detected in human biofluids during mild cognitive impairment (MCI). Bioinformatics analysis of transcriptomic data from human brains indicated that mGlu3R expression was reduced in amyloid plaque-associated areas and in AD astrocytes. At the protein level, mGlu3R immunostaining was lower within the plaque niche in hippocampal slices from PDAPP-J20 mice, whereas cultured glial cells from these mice expressed lower mGlu3R than non-transgenic mice as early as 2 months-old of age. Furthermore, mGlu3R protein levels determined by western blot inversely correlated with histopathology in human AD hippocampi. Interestingly, mGlu3R (but not mGlu3Δ4) protein was detectable by western blot in serum samples from MCI and control subjects. We showed that mGlu3R levels were significantly reduced in MCI serum compared to those of cognitively intact individuals. Moreover, its levels positively correlated with serum Aβ. Our results showed changes in mGlu3R expression in AD brains that might reflect early glial receptor dysfunction, whereas reduced serum mGlu3R levels may be associated with mild cognitive impairment that precedes AD.
Advances in hiPSC-Derived Brain Organoids as a Model to Study Neuroinflammation in Alzheimer's Disease.
Maciel EMA, Silva NC, Santos LGP … +1 more , Ribeiro FM
J Neurochem · 2026 Apr · PMID 41906426 · Full text
Neuroinflammation plays a fundamental role in several neurodegenerative diseases, including Alzheimer's disease (AD), the leading cause of dementia worldwide. As the main defense response of the central nervous system (C...
Neuroinflammation plays a fundamental role in several neurodegenerative diseases, including Alzheimer's disease (AD), the leading cause of dementia worldwide. As the main defense response of the central nervous system (CNS), neuroinflammation can be either protective or detrimental depending on the stage of the disease. The pivotal role of neuroinflammation in AD has led to increasing investigations into neuroinflammatory mechanisms, aiming to develop AD-modifying therapies. A significant advance in the field was the emergence of the human induced pluripotent stem cell (hiPSC) model, enabling the study of patient-derived cells. Moreover, the development of hiPSC-derived brain organoids, which mimic specific aspects of the human CNS, has expanded our understanding of neuroinflammation in AD. Here, we review how AD organoid models have evolved, focusing on the integration of microglia-the brain's primary immune surveillance cells. We also summarize recent findings on how glial activation and the crosstalk between microglia and other CNS cells affect AD progression. Lastly, we address the potential of hiPSC-derived organoids as a preclinical model for screening AD drugs.
Glial Plasticity and Dysfunction: Mechanistic Insights and Therapeutic Opportunities in Neurodegeneration.
Correale J
J Neurochem · 2026 Apr · PMID 41906403 · Publisher ↗
Recent advances, including single-cell transcriptomics, lineage tracing, and in vivo imaging, have unveiled the heterogeneity, plasticity, and functional versatility of astrocytes, microglia, oligodendrocytes, and Schwan...
Recent advances, including single-cell transcriptomics, lineage tracing, and in vivo imaging, have unveiled the heterogeneity, plasticity, and functional versatility of astrocytes, microglia, oligodendrocytes, and Schwann cells. These cells respond to metabolic and immune cues, participate in synaptic regulation, and provide metabolic and trophic support to neurons. Their dual roles in neuroprotection and neurodegeneration underscore the complexity of their contributions across CNS disorders. This review examines the diverse physiological and pathological roles of glia, emphasizing their involvement in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Mechanisms including metabolic dysfunction, inflammatory polarization, glial-immune crosstalk, and extracellular vesicle-mediated signaling are critically discussed. Emerging therapeutic strategies, ranging from glial reprogramming and senolytic therapies to the use of engineered extracellular vesicles and metabolic modulators, are evaluated for their potential to harness glial plasticity and mitigate disease progression. The review also outlines current challenges in translating glial biology into clinical interventions, including cellular heterogeneity, delivery barriers, and the need for specific biomarkers. A glia-centered therapeutic paradigm offers promising avenues to restore CNS homeostasis and promote regeneration in neurodegenerative diseases.
Cocaine-Induced Immediate-Early Gene Expression in the Nucleus Accumbens: Roles of Separate cAMP Sensors.
Zhang HY, Salman T, Bi GH … +6 more , Jiang SZ, Gerfen CR, Lutas A, Xu W, Xi ZX, Eiden LE
J Neurochem · 2026 Apr · PMID 41906363 · Full text
Immediate-early gene (IEG) induction guides elucidation of signaling pathways mediating neuronal plasticity underlying compulsive use of psychostimulants. IEG induction after psychostimulant administration has been attri...
Immediate-early gene (IEG) induction guides elucidation of signaling pathways mediating neuronal plasticity underlying compulsive use of psychostimulants. IEG induction after psychostimulant administration has been attributed to both PKA- and RapGEF2-dependent signaling pathways initiated by D1 receptor stimulation by dopamine. However, it is not clear how each pathway contributes individually to IEG induction, dopaminoceptive neuronal activity, and neuronal plasticity. We used Cre-LoxP technology and a novel Cre-amplifier transgene to delete RapGEF2 only in D1-MSNs, and investigate its role in cocaine-induced IEG and behavioral responses. D1-MSN-specific RapGEF2 deletion blocked cocaine-induced ERK phosphorylation and Egr-1 induction, without affecting cocaine self-administration or c-Fos induction by cocaine. Deletion of Rap1 in D1-MSNs blocked cocaine-induced p-ERK and Egr-1 expression, but not the induction of c-Fos. Like RapGEF2 deletion, Rap1 deletion from D1-MSNs had no effect on final maintenance of stable cocaine self-administration, although the rate of acquisition was significantly impaired. These results suggest that D1-dependent activation of Egr1 is not ultimately required for cocaine self-administration, although it may affect the behavioral dynamics of this process. Suppressing cAMP elevation in D1-MSNs by D1-specific expression of PDE4D3-cat greatly reduced induction of both Egr-1 and c-Fos in NAc after cocaine administration, demonstrating that induction of both IEGs requires cAMP elevation in D1-MSNs. Specific inhibition of PKA activity via PKI-alpha expression in D1-MSNs also blocked both c-Fos and Egr-1 induction. Thus, acute or chronic cocaine administration activates at least two separate cAMP effectors in D1-MSNs. PKA activation leads to c-Fos induction, likely through CREB, and to Egr1 activation via Rap1, likely through a previously reported dependence on RasGRP2. RapGEF2 activation leads exclusively to Egr1 induction. The finding that PKA activates the ERK-Egr-1 signaling pathway by convergence on Rap1, and concomitantly activates c-Fos independently of Rap1, may underlie selective effects of RapGEF2 and PKA inhibition on psychostimulant-dependent behaviors in mice.
How Glutamate and GABA «Became» Neurotransmitters: Personal Account of a 65 Years' Voyage.
Storm-Mathisen J
J Neurochem · 2026 Apr · PMID 41906358 · Publisher ↗
With 65 years in neuroscience research, I have witnessed the discovery of all of the neurotransmitters, after acetylcholine. My own contribution has been mainly on glutamate and GABA. Localisation of neurotransmitters is...
With 65 years in neuroscience research, I have witnessed the discovery of all of the neurotransmitters, after acetylcholine. My own contribution has been mainly on glutamate and GABA. Localisation of neurotransmitters is my specialty. The present account focuses on what I consider the highlights and the aspects where I have participated, with some anecdotes for flavour. We showed for the first time that GABA in the brain is synthesised selectively in inhibitory neurons (1969 -) and that glutamate uptake labels selectively putative glutamatergic nerve endings (1976 -). Then I made antibodies to amino acids (1982 -) and showed that glutamate and GABA are localised in the glutamatergic and GABAergic nerve endings, respectively, and concentrated in their synaptic vesicles (1983 Nature -). We demonstrated microscopically the metabolic compartmentation of glutamate during release from nerve terminals and recycling through astrocytes (1984 -). We also showed that glycine is the transmitter of the inhibitory neuron of a spinal motor pattern generator (1986 Nature -). I contributed to the molecular identification of the first glutamate transporter (1992 Nature -), and to delineating its localisation and function. Similarly, to the vesicular transporters (1998 -), VGAT and VGLUT1-VGLUT2-VGLUT3, and to the discovery of the new family of glutamine transporters, now known as SLC38 (1999 Cell -). The discovery (by others) of the richness of receptor proteins mediating transmitter action settled the question of whether glutamate and GABA were actually neurotransmitters. Presently, their elaborate roles in physiology and the implications for precision medicine are explored.
Loss of Kv8.2 in the Mouse Retina Is Associated With Altered One-Carbon Metabolism.
Kruth K, Baker SA
J Neurochem · 2026 Apr · PMID 41902434 · Full text
Photoreceptors are highly energy-demanding neurons, and disruption of photoreceptor signaling remodels retinal metabolism and contributes to degeneration, yet the pathways underlying these changes remain incompletely def...
Photoreceptors are highly energy-demanding neurons, and disruption of photoreceptor signaling remodels retinal metabolism and contributes to degeneration, yet the pathways underlying these changes remain incompletely defined. Kv8.2 knockout (KO) mice, a model of KCNV2 retinopathy, exhibit impaired photoreceptor ion homeostasis and slow rod degeneration, providing an opportunity to investigate metabolic adaptation during progressive dysfunction. Untargeted metabolomic profiling was performed on retinas from wildtype (WT) and Kv8.2 KO mice at 1 and 13 months of age. Principal component analysis revealed distinct profiles for aged Kv8.2 KO retinas compared with aged WT and young groups, while young WT and KO retinas were metabolically similar. The major changes in aged Kv8.2 KO retinas compared to aged WT were reduced nucleobases and nucleosides while the amino acids homocysteine, methionine, and serine were elevated. These are signature metabolites in one-carbon metabolism, a metabolic hub influencing nucleotide metabolism, epigenic regulation, and anti-oxidant defense. Supervised modeling showed that these one-carbon-related changes emerge early and progress with age in Kv8.2 KO retinas. Together, these findings implicate altered one-carbon metabolism as a key mechanism in photoreceptor vulnerability and adaptation in slow retinal degeneration.
Electrostatic Charge Shielding Effect of ATP: Implications for Therapeutic Intervention.
Park Y
J Neurochem · 2026 Apr · PMID 41902426 · Publisher ↗
Adenosine triphosphate (ATP) is recognized as the primary "energy currency" in cells, but its chemical structure, particularly the highly anionic triphosphate chain, also confers strong electrostatic properties independe...
Adenosine triphosphate (ATP) is recognized as the primary "energy currency" in cells, but its chemical structure, particularly the highly anionic triphosphate chain, also confers strong electrostatic properties independent of catalysis. ATP consists of an adenosine moiety attached to a chain of three phosphate groups. At physiological pH, these phosphates collectively carry approximately four negative charges, typically coordinated with Mg to form a Mg/ATP complex. The high charge density of the triphosphate tail enables ATP to neutralize or shield electrostatic interactions. Importantly, the cytosol maintains ATP at millimolar concentrations (~5-10 mM), far exceeding what is required for enzymatic catalysis. One proposed rationale for this unusually high abundance is that Mg/ATP electrostatically maintains protein solubility and prevents non-specific aggregation. Mg/ATP is a central electrostatic regulator in cell physiology and a potential therapeutic molecule for diseases involving aberrant biomolecular condensation. This review summarizes the electrostatic charge shielding roles of Mg/ATP in three major contexts: (1) modulation of membrane interactions and vesicle fusion, (2) stabilization of nucleic acids, and (3) inhibition of protein aggregation.
Tri-Culture System Reveals an Activation Cascade From Microglia Through Astrocytes to Neurons During Neuroinflammation.
Kobayashi H, Kato H, Taniguchi M … +1 more , Endoh-Yamagami S
J Neurochem · 2026 Mar · PMID 41859906 · Full text
Neuroinflammation is involved in various neurodegenerative diseases, with glial cells playing crucial roles. It is known that neuroinflammation is initiated by microglia, which interact with astrocytes and neurons. Howev...
Neuroinflammation is involved in various neurodegenerative diseases, with glial cells playing crucial roles. It is known that neuroinflammation is initiated by microglia, which interact with astrocytes and neurons. However, the detailed molecular mechanisms underlying intercellular interactions during neuroinflammation are not fully understood. In this study, we developed a tri-culture system of neurons, astrocytes, and microglia derived from human induced pluripotent stem cells (iPSCs) to evaluate their relationships in neuroinflammation. Microglia cocultured with the astrocytes and neurons exhibited a morphology with branched processes compared to the monoculture system, suggesting a homeostatic state. By applying lipopolysaccharide (LPS) stimulation to induce inflammation, the microglial morphology shifted to an amoeboid shape, accompanied by an increase in the expression of pro-inflammatory cytokines. Additionally, nuclear translocation of NF-κB revealed that LPS specifically activates microglia through the TLR4 receptor, which subsequently releases TNF-α, leading to the activation of astrocytes. Furthermore, activated astrocytes were shown to enhance neuronal excitability. Using the tri-culture system, we elucidated a part of the cascade involving microglia, astrocytes, and neurons during neuroinflammation and demonstrated the amplification of inflammatory signals through cell communication. This culture system will be valuable for conducting detailed investigations into the interactions between glia and neurons, advancing research on neurodegenerative diseases associated with neuroinflammation.
Dentate Gyrus Engrams in Fear and Reward: Mechanistic Principles, Critical Gaps, and Paths to Translation.
Colón LM, Famuyide OA, Eisch AJ
J Neurochem · 2026 Mar · PMID 41852277 · Full text
The hippocampal dentate gyrus (DG) has emerged as a cornerstone of engram research. While DG fear-based engrams have been extensively studied, revealing principles of allocation, consolidation, retrieval, and valence swi...
The hippocampal dentate gyrus (DG) has emerged as a cornerstone of engram research. While DG fear-based engrams have been extensively studied, revealing principles of allocation, consolidation, retrieval, and valence switching, engrams encoding context-reward associations, particularly those involving drugs of abuse, remain comparatively underexplored. This knowledge gap has critical implications for understanding addiction, depression, and other disorders involving dysfunctional reward processing. In this review, we first establish the DG's unique anatomical and functional properties that position it as an ideal model system for engram research. We then systematically examine the DG fear engram literature, documenting how decades of contextual fear conditioning studies have elucidated mechanisms of competitive allocation, molecular consolidation, competing extinction ensembles, and context-dependent discrimination versus generalization. Turning to reward engrams, we synthesize emerging evidence demonstrating that drug-context associations are encoded through sparse, distributed ensembles across multiple brain regions including the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. While these studies establish foundational principles of reward engram allocation and retrieval, critical mechanistic gaps remain, particularly regarding differences between drug-associated and natural reward memories, the neural coding of context versus valence in hippocampal circuits, and the mechanisms underlying drug associated reward memory extinction. Evidence from valence switching studies demonstrates that the DG processes and stores both fear and reward memories within overlapping circuits, exhibiting remarkable plasticity in linking contextual representations to opposing emotional outcomes, a flexibility distinguishing it from structures with hardwired valence encoding. This encoding capacity positions the DG as a promising target for interventions aimed at modifying pathological emotional associations in addiction and trauma-related disorders while preserving contextual specificity. Understanding reward engram mechanisms with the same rigor applied to fear engrams is essential for developing comprehensive frameworks of how DG circuits contribute to memory-related psychopathology and for translating engram research into therapeutic applications.
Correction to "Iron Deficiency in Drosophila melanogaster Glial Cells Impacts Behavior Through Altered Mitochondrial Dynamics".
J Neurochem · 2026 Mar · PMID 41848764 · Publisher ↗
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Neurotrophic Modulation Restores Motor and Developmental Defects in Zebrafish Models of ints11 Deficiency.
Pistocchi A, Chiricozzi E, Molteni M … +7 more , Galassi G, Mauri L, Balistreri F, Magri S, Marozzi A, Taroni F, Pezzotta A
J Neurochem · 2026 Mar · PMID 41837557 · Full text
Mutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms re...
Mutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss-of-function zebrafish model using CRISPR/Cas9 and morpholino-based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioral deficits. ints11 deficiency led to marked impairments in locomotor activity and visual motor response, consistent with the neurological manifestations reported in INTS11-mutated patients. These behavioral abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1, map2, gfap, and mag, and upregulation of the progenitor marker nestin, indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA-mediated re-expression of ints11, but also through pharmacological administration with brain-derived neurotrophic factor (BDNF) and the GM1 ganglioside-derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA-processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs.
Uncovering Hidden Phenotypes in NEX-Cre Mice: Behavioral and Cellular Alterations Demand Re-Evaluation of a Widely Used Transgenic Line.
Renken K, Masseck OA
J Neurochem · 2026 Mar · PMID 41833530 · Full text
Transgenic mouse strains are essential tools in neuroscience, enabling targeted genetic manipulations to investigate brain function and neurological diseases. The NEX-Cre mouse line, which targets glutamatergic principal...
Transgenic mouse strains are essential tools in neuroscience, enabling targeted genetic manipulations to investigate brain function and neurological diseases. The NEX-Cre mouse line, which targets glutamatergic principal neurons in the neocortex and hippocampus by expressing Cre-recombinase under the NEX (NeuroD6) promoter, has been widely used for conditional gene manipulation. Contrary to previous reports suggesting no behavioral and histological abnormalities in NEX-Cre mice, our study reveals distinct behavioral and cellular phenotypes. Behavioral analyses indicate reduced anxiety-like behavior, altered reward-related behavior, and increased locomotor activity in NEX (Cre/Cre) mice. Additionally, Support Vector Machine (SVM) analysis uncovered subtle strain-specific and genotype-specific behavioral traits across all NEX-Cre genotypes relative to the commonly used C57BL/6J mouse strain. While overt behavioral abnormalities were most prominent in NEX (Cre/Cre) mice, SVM-based analysis revealed subtle genotype- and strain-specific behavioral signatures across NEX-Cre genotypes. This underlines the importance of using littermate controls rather than independently maintained or purchased C57BL/6J animals when interpreting genotype-related effects. Histological analyses of Golgi-Cox-stained brain slices revealed alterations in dendritic spine density across key brain regions, including the caudate putamen, hippocampal CA1, nucleus accumbens core region, lateral septum, and medial prefrontal cortex. These findings highlight significant inter- and intra-strain variability, emphasizing the importance of careful characterization of transgenic models and the need for appropriate control groups and experimental designs to ensure the reliability and validity of studies utilizing Cre-Driver lines.
Time-Dependent Effect of BDNF on the Transcriptomes of Cortical Neurons: Induction of Matrix Metalloproteases by BDNF.
Kawai A, Suzuki S, Shigeto H … +4 more , Akigawa S, Ohta KI, Otabi H, Miki T
J Neurochem · 2026 Mar · PMID 41823037 · Publisher ↗
Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to m...
Brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal development and synaptic plasticity across various maturation stages. However, the extent to which BDNF modulates the neuronal transcriptome to mediate these effects, and the gene clusters most responsive at each culture stage, remain poorly understood. To address this, we investigated the time-dependent effects of BDNF on the transcriptomes of cultured cortical neurons at different culture durations. We found that the magnitude of the transcriptomic response to a 6-h BDNF treatment, relative to untreated controls, increased with longer culture duration. Furthermore, a BDNF-induced shift towards a more mature-like transcriptional state was observed specifically in neurons cultured for shorter durations, suggesting a response dependent on the length of time in culture. Specifically, matrix metalloproteinase 3 (MMP3) was robustly induced by BDNF. Single-nucleus RNA sequencing (snRNA-seq) revealed that this induction was primarily localized to Lhx6-positive inhibitory neurons. Additionally, BDNF regulated the expression of various ligand and receptor genes through a combination of cell type-specific and non-specific mechanisms. These findings provide a comprehensive view of BDNF-mediated transcriptional regulation over the course of cortical neuron culture.
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