Journal Of Neurochemistry[JOURNAL]
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200 papers
Exocytosis, Endocytosis, and Replenishment of the Immediately Releasable Pool of Secretory Vesicles. Possible Physiological Relevance in Chromaffin Cells.
Marengo FD
J Neurochem · 2026 May · PMID 42152482 · Publisher ↗
In neuroendocrine cells, the fusion of secretory vesicles to the plasma membrane is triggered by a localized increase in cytosolic Ca concentration, which occurs following the activation of voltage-dependent Ca channels....
In neuroendocrine cells, the fusion of secretory vesicles to the plasma membrane is triggered by a localized increase in cytosolic Ca concentration, which occurs following the activation of voltage-dependent Ca channels. However, there is an important heterogeneity in vesicle readiness for fusion because of differences in maturation, localization, and proximity to Ca sources. The immediately releasable pool (IRP) was first described in rat chromaffin cells as a small group of ready-to-fuse vesicles whose fusion was tightly coupled to Ca entry through voltage-dependent Ca channels. Over the last 20 years, my research group has characterized several important features of IRP in chromaffin cells, including the Ca channel subtype involved, the characteristics of channel-vesicle molecular coupling, the mechanisms of replenishing this pool, and the types of membrane retrieval activated after IRP exocytosis. We proposed that IRP's physiological importance lies in maintaining secretion during basal firing in chromaffin cells at rest. Here, I review the most important findings on IRP during the last 30 years, with the main focus on chromaffin cells.
N,N-Dimethyltryptamine (DMT) Acutely Exposed to Mouse Ventral Tegmental Area I-Negative Neurons Alters the Firing Rate and Conductance in a Sex-Dependent Manner.
Eliasen JN, Rezagholizadeh A, Jacobsen HP … +1 more , Kohlmeier KA
J Neurochem · 2026 May · PMID 42144970 · Full text
Depression and substance use disorder (SUD) affect millions globally and unfortunately, while established treatments exist, they are not always adequate. Psychedelics have emerged as a promising avenue for development of...
Depression and substance use disorder (SUD) affect millions globally and unfortunately, while established treatments exist, they are not always adequate. Psychedelics have emerged as a promising avenue for development of more effective pharmacological interventions. Dimethyltryptamine (DMT), a classic psychedelic, has shown anti-depressive and anti-addictive properties in preclinical studies, observational evaluations, and limited controlled trials; however, the exact mechanism(s) of action(s) are still unknown. In the present ex vivo study, we provide the first evaluation of the electrophysiological effects of acute DMT exposure at two concentrations in male and female I-negative neurons of the mouse ventral tegmental area (VTA). The VTA plays a central role in regulating emotion and motivated behavior, and I-negative neurons, which are putatively inhibitory, shape VTA output to downstream targets. At the lower concentration, DMT (500 nM) did not exert any effect on evaluated electrophysiological properties of female and male VTA I-negative neurons. At the highest concentration (90 μM), DMT elicited a conductance change at subthreshold potentials and an increase in action potential firing; however, these actions were seen only in female VTA. At the higher concentration, DMT increased cytosolic calcium levels in both sexes. In conclusion, DMT has actions in both male and female I-negative VTA neurons, but the alterations in firing and membrane conductance observed in females indicate activation of mechanisms beyond the calcium changes seen in males. Taken together, these findings highlight the importance of translational research to connect the cellular effects of DMT with its potential long-term therapeutic outcomes in humans, while accounting for variables such as sex and dose-dependent responses.
Dualsteric Agonist for M2 Muscarinic Receptor Causes Oxidative Stress and Mitochondrial Alteration in Human Glioblastoma Cancer Stem Cells.
Guerriero C, De Nuccio C, Petrone M … +9 more , Rinaldi T, Cirigliano A, Visentin S, Bernardo A, Conti L, Matera C, De Amici M, Dallanoce C, Tata AM
J Neurochem · 2026 May · PMID 42141821 · Full text
Glioblastoma (GB) is the most malignant form of human brain tumor, characterized by heterogeneous cell populations, including undifferentiated cells defined as GB stem cells (GSCs), responsible for initiating the neoplas...
Glioblastoma (GB) is the most malignant form of human brain tumor, characterized by heterogeneous cell populations, including undifferentiated cells defined as GB stem cells (GSCs), responsible for initiating the neoplastic process as well as recurrence. Previous studies demonstrated that the activation of M2 muscarinic acetylcholine receptor (M2 mAChR) by the orthosteric agonist arecaidine propargyl ester (APE) and the dualsteric agonist Iper-N-naphthalimide (N-8-Iper) caused a significant decrease in cell proliferation and survival in both GSCs and GB cell lines. Interestingly, N-8-Iper activates M2 mAChR with higher efficacy and at a lower concentration than APE. The work aimed to better investigate the mechanisms downstream of M2 mAChR activation by both agonists responsible for cytotoxic and pro-apoptotic effects in both U251 cell line and G166 cells (GSCs). To this end, we assessed mitochondrial function by using cell-based assays. Our results demonstrate the ability of N-8-Iper, both at the high (100 μM) and low (25 μM) dose, to induce alteration of mitochondrial morphology and activity, affecting both cellular respiration and ROS production in U251 and G166 cells. Instead, APE causes the same alterations but only in the U251 cell line. Given the relevance of lipid metabolism analysis in the study of cancer, lipid droplets (LDs) were evaluated in the presence or absence of the two M2 agonists. LDs accumulation within the cells was detected after N-8-Iper treatment in both cell lines, whereas APE produced similar effects only in the U251 cell line. No cytotoxic effects and mitochondrial alteration were detected on normal human astrocytes. These results clearly suggest that N-8-Iper has a more potent action on GSCs than APE, thus making this dual-acting agonist a promising muscarinic ligand able to better characterize the inhibitory effects of the M2 muscarinic receptor in glioblastoma cells as well as in other tumor types.
Prenatal Methyl Nutrient Availability Shapes Mesolimbic Dopaminergic Circuitry and Systemic Inflammation in Wistar Rat Offspring of Both Sexes.
Di Pierdomenico C, Cook WJJ, Dong J … +4 more , Shelp GV, Poole EM, Burns SE, Cho CE
J Neurochem · 2026 May · PMID 42141807 · Full text
The dopaminergic system constitutes a principal element of the reward neurocircuitry and is responsive to influences encountered early in life. Methylation potential, shaped by nutrients involved in one-carbon metabolism...
The dopaminergic system constitutes a principal element of the reward neurocircuitry and is responsive to influences encountered early in life. Methylation potential, shaped by nutrients involved in one-carbon metabolism, intersects with immune signaling and dopaminergic receptor, creating a broader metabolic network through which early life nutrition may alter neurobehavioral outcomes. We have shown that methyl nutrient imbalance between folic acid and choline during pregnancy produces offspring with higher body weight and perturbed methylation potential. However, whether these effects reflect disruptions in the dopaminergic receptor expression and systemic inflammation, and the capacity of betaine (a direct methyl donor) to modify responses across different nutritional contexts remain unknown. To address this, primiparous Wistar rats were randomly assigned to either a recommended vitamin or high folic acid/low choline diet, with or without betaine supplementation during pregnancy, then switched to a control diet during lactation. One female and one male offspring from each dam were followed for 12 weeks post-weaning under an obesogenic environment. Prenatal micronutrient composition produced distinct patterns of activity in offspring across the light-dark cycle, revealing behavioral signatures of both imbalance and betaine supplementation. Betaine alone reduced body weight and food intake, and provided partial protection against the metabolic consequences of the imbalanced micronutrient diet. Dopaminergic receptor gene expression was responsive to prenatal micronutrient exposure, with treatment sex interactions restricted to the ventral tegmental area (VTA) and betaine modifying receptor patterns across both the VTA and nucleus accumbens. Catechol-O-methyltransferase expression was altered consistent with changes in S-adenosylmethionine and the S-adenosylmethionine: S-adenosylhomocysteine ratio across groups. Higher C-reactive protein concentrations occurred under micronutrient imbalance, but remained unchanged with betaine supplementation. In conclusion, gestational intake of high folic acid and low choline disturbs dopaminergic, metabolic and immune outcomes in offspring, whereas betaine may serve as a potential modulator capable of mitigating these effects.
A High-Throughput Assay for Monitoring and Quantifying Amyloid-β Accumulation and Clearance in Alzheimer's Disease Cell Models.
Ariyath A, Arigo FD, Fyfe A … +3 more , Fernando WMADB, Martins R, Bharadwaj P
J Neurochem · 2026 May · PMID 42141806 · Full text
Amyloidogenic proteins, such as amyloid-β (Aβ), self-assemble into cross-β fibrils whose accumulation is central to Alzheimer's disease (AD). Measuring Aβ aggregation and clearance in living cells remains challenging usi...
Amyloidogenic proteins, such as amyloid-β (Aβ), self-assemble into cross-β fibrils whose accumulation is central to Alzheimer's disease (AD). Measuring Aβ aggregation and clearance in living cells remains challenging using current cell-based assays, which are often low-throughput or not suited for real-time monitoring. This study aimed to (1) develop a robust, quantitative, and scalable fluorescence-based assay using Amytracker to monitor Aβ accumulation and clearance in an Aβ-producing neuronal cell model, and (2) validate its utility for mechanistic studies and therapeutic screening. We established a plate-based fluorescence assay using Amytracker in MC65 neuronal AD model expressing the Amyloid precursor protein C-terminal fragment (APP-C99) that generates Aβ. Accumulation and clearance of Aβ were quantified by measuring Amytracker fluorescence under basal conditions and after inducing Aβ clearance using a Tet-suppressible system. We utilized this assay to evaluate cell death inhibitors ferrostatin-1 and liproxstatin-1 and proteasome activator IU1. Specificity of the assay for amyloidogenic proteins was assessed by treating wild-type neuroblastoma cells with Aβ, human islet amyloid polypeptide (hIAPP), or non-aggregating Aβ controls. Validation included Aβ immunoblotting and cell viability assays. In APP-C99 expressing cells, elevated Amytracker fluorescence correlated with increased Aβ accumulation and reduced cell viability. Supplementation of ferrostatin-1, liproxstatin-1, and IU1, on these cells, markedly reduced Amytracker signal, indicating decreased Aβ burden. Furthermore, the Amytracker assay specifically detected amyloidogenic protein aggregation: wild-type cells exposed to Aβ42 or hIAPP showed high fluorescence, whereas non-aggregating Aβ16 peptide did not. The Amytracker assay provides a simple, non-toxic, and high-throughput platform for quantifying Aβ accumulation and clearance in live cell models. Its sensitivity, specificity, and compatibility with high-throughput screening make it a valuable tool for studying Aβ dynamics, interrogating mechanisms of proteostasis, and identifying therapeutic candidates targeting Aβ.
Seed Amplification Assays for Parkinson's Disease: A Review of α-Synuclein Assays in Body Fluids and Tissues.
Kong W, Satoh K, Shimamura MI … +4 more , Maeda T, Takahashi K, Kurihara M, Iwata A
J Neurochem · 2026 May · PMID 42141805 · Full text
The pathological core of Parkinson's disease and related synucleinopathies involves the misfolding and aggregation of α-synuclein. Seed amplification assays (SAAs) have revolutionized the detection of pathological α-synu...
The pathological core of Parkinson's disease and related synucleinopathies involves the misfolding and aggregation of α-synuclein. Seed amplification assays (SAAs) have revolutionized the detection of pathological α-synuclein by enabling highly sensitive and specific identification of seeding activity. Cerebrospinal fluid (CSF)-based real-time quaking-induced conversion (RT-QuIC) demonstrates exceptional diagnostic accuracy for sporadic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), with sensitivity reaching 93.3%-94.6% and pooled specificity of 94% (95% CI: 0.92-0.96), consistent with the meta-analysis of 21 core CSF studies. Alternative samples such as skin and intestinal tissues offer diagnostic accuracy up to 94.1%, providing less invasive options. These assays can distinguish conformational differences between Parkinson's disease/Lewy body dementia and multiple system atrophy (MSA), revealing potential for differential diagnosis through strain typing. In prodromal screening, SAAs show remarkable utility, with positivity rates exceeding 80% in idiopathic rapid eye movement sleep behavior disorder (iRBD) cohorts, indicating detection years before clinical diagnosis. Despite these advances, current limitations include small-sample sizes in many studies, insufficient multicenter validation, and lack of standardized protocols affecting interlaboratory consistency. Future efforts should focus on establishing standardized procedures, integrating digital biomarkers, and validating these technologies across diverse populations and disease stages to facilitate widespread clinical implementation. This study systematically evaluates the diagnostic performance of α-synuclein SAAs across biological samples, their role in differential diagnosis, and their potential in prodromal prediction and disease monitoring.
Systematic Characterisation of GLP-1R in Human Enteric Nervous System: Implications for GLP-1 as a Key Regulator of Colonic Activity.
Dontamsetti KD, Aktar R, Peiris M
J Neurochem · 2026 May · PMID 42138480 · Full text
Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis, satiety and gastrointestinal (GI) motility through interaction with its receptor (GLP-1R). While central GLP-1 pathways are well studied, the distribution an...
Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis, satiety and gastrointestinal (GI) motility through interaction with its receptor (GLP-1R). While central GLP-1 pathways are well studied, the distribution and functional role of GLP-1R within the human enteric nervous system (ENS) remain unclear. We characterised GLP-1R expression across the human GI tract, examining its anatomical localisation among distinct enteric neuronal subtypes. Non-inflamed, full-thickness human GI tissues (antrum, ileum, ascending, descending and sigmoid colon; N = 30, 5 different human samples per region) were obtained from surgical resections and analysed using immunohistochemistry, epifluorescence and confocal microscopy. Mean number of positive pixels of GLP-1R and PGP9.5 was quantified in mucosal varicosities, muscle, submucosal and myenteric plexuses. GLP-1R co-localisation with neuronal markers (PGP9.5, nNOS, ChAT, Substance P, CGRP, Calretinin, HuC/D) was assessed. Quantification used Mander's coefficient, and statistical analysis used one-way ANOVA with Tukey's post hoc test. GLP-1R was expressed abundantly in ENS structures, including mucosal varicosities, muscle, submucosal plexus and myenteric neurons throughout the lower GI tract, with significantly higher expression in the colon compared to the stomach and ileum (p < 0.05). Co-localisation analyses revealed preferential GLP-1R expression in nNOS-expressing inhibitory neurons and CGRP-expressing varicosities, moderate expression in calretinin-expressing neurons, and sparse expression in ChAT-expressing and substance P-immunoreactive excitatory neurons. Whole-mount confocal imaging confirmed GLP-1R localisation to HuC/D-immunoreactive neuronal cell bodies with punctate, membrane-associated staining. GLP-1R is differentially expressed across the human ENS, with increased expression in inhibitory neurons and putative extrinsic sensory afferents, particularly in the distal colon. This suggests that peripherally released GLP-1 acts locally within the ENS to regulate motility and sensory signalling, underpinning both its physiological functions and the gastrointestinal side effects of GLP-1-based therapies.
Muscarine, Pituitary Adenylate Cyclase Activating Polypeptide, and Angiotensin II-Evoked Secretion in Adrenal Medullary Chromaffin Cells With a Major Focus on TRPC Channels.
Inoue M, Harada K
J Neurochem · 2026 May · PMID 42138471 · Publisher ↗
Adrenal medullary chromaffin (AMC) cells secrete catecholamines in response to neuronal and humoral inputs during stress. Secreted adrenaline is crucial for organismal survival during acute and/or chronic stress, primari...
Adrenal medullary chromaffin (AMC) cells secrete catecholamines in response to neuronal and humoral inputs during stress. Secreted adrenaline is crucial for organismal survival during acute and/or chronic stress, primarily through the stimulation of adrenergic β2 receptors in various cell types. While acetylcholine and/or pituitary adenylate cyclase activating polypeptide (PACAP) are involved in neuronal transmission from the sympathetic nerve fibers, depending on the stress type, angiotensin II and decreased blood pH also act as potent humoral stimulants for catecholamine secretion. Transient receptor potential canonical (TRPC) isoforms operate as distinct molecular effectors that link specific receptors to specific modes of excitation. The present review aims to elucidate how these neuronal and humoral signals independently induce excitation in AMC cells. The discussion focuses primarily on TRPC channels and the signal transduction pathways for muscarinic, PACAP, and angiotensin II receptors.
Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies.
Gomes FCA, Matias I
J Neurochem · 2026 May · PMID 42138465 · Full text
Aging is characterized by progressive changes in the physiology of brain cells, which may contribute to cognitive decline, ultimately leading to dementia and impaired quality of life. The increase in senescent cells, inc...
Aging is characterized by progressive changes in the physiology of brain cells, which may contribute to cognitive decline, ultimately leading to dementia and impaired quality of life. The increase in senescent cells, including glial cells in the brain, is a general feature of normal aging and has been associated with age-related pathologies. Although recent evidence suggests that astrocytes undergo senescence in these conditions, little is known about the molecular, and cellular mechanisms underlying this event. This mini review, prepared as part of the special issue Neurochemistry in Latin America, provides a focused overview of astrocyte dysfunction in physiological aging and neurodegenerative conditions, integrating findings from the field alongside recent contributions from our group. We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration. Finally, we discuss emerging therapeutic strategies aimed at modulating astrocyte function, including targeting astrocyte-derived synaptogenic factors and metabolic pathways, as potential approaches to mitigate cognitive decline. Together, current evidence indicates that astrocyte dysfunction in aging reflects a complex and dynamic spectrum of cellular states that play a central role in brain vulnerability and represent promising targets for intervention in aging and neurodegenerative diseases.
Unveiling the Molecular Mechanism of Intestinal Metabolite para-Cresol in Modulating Neuroinflammation and Synaptic Dysfunction: Implications for Autism Spectrum Disorder.
Liao W, Antonioni K, Silvestri F … +7 more , Piemontese M, Bodria M, Daini E, Persico AM, Zoli M, Grabrucker AM, Vilella A
J Neurochem · 2026 May · PMID 42138450 · Full text
Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental disorders that share similar behavioral patterns. Many individuals with ASD also exhibit gastrointestinal disturbances, likely linked to alterations...
Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental disorders that share similar behavioral patterns. Many individuals with ASD also exhibit gastrointestinal disturbances, likely linked to alterations in the composition and activity of intestinal bacteria, resulting in the overproduction and release of toxic metabolites into the systemic circulation. These toxins may reach the central nervous system (CNS) and activate microglia, which release inflammatory cytokines, ultimately impairing neuronal function. This microbiota-gut-brain axis has been suggested to play a crucial role in the pathogenesis of ASD. Para-cresol (p-Cresol) is one of these intestinal metabolites and could potentially contribute to ASD, as its urinary levels are elevated in autistic children under the age of 8 and correlate with symptom severity. Here, we aim to investigate the effect of p-Cresol on various brain-cell types to speculate on their specific contributions to ASD-related synaptic dysfunctions. Immunocytochemistry assays revealed a significant decrease in excitatory (vesicular glutamate transporter VGLUT, postsynaptic density protein 95 PSD95) and inhibitory (vesicular GABA transporter VGAT) synaptic markers in p-Cresol-treated neurons during synaptogenesis. These effects were exacerbated in SH3 and multiple ankyrin repeat domains 3 (Shank3) knockdown neurons, which exhibit increased susceptibility of their synapses. p-Cresol also induced a dose-dependent inflammatory response in both astrocytes and microglia, characterized by the overexpression and release of inflammatory cytokines and chemokines such as interleukin 6 (IL6), interleukin 1β (IL1β), and C-C- motif chemokine ligand 3 (CCL3). Our results suggest that p-Cresol exerts cell-specific effects on astrocytes and microglia, and the release of inflammatory cytokines and chemokines in response to p-Cresol treatment may contribute to synaptic dysfunction, in addition to its direct effect on neurons.
Correction to "Hydroxytyrosol Mitigates Anxiety-Like Behaviors After a Traumatic Experience in Aged Mice in Parallel With Increased Neurogenesis in the Ventral and Dorsal Dentate Gyrus, and Preservation of Gut Microbiota Composition".
J Neurochem · 2026 May · PMID 42135991 · Publisher ↗
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Congratulations, JNC Turns 70!
Dringen R, Hewett SJ, Prinetti A … +3 more , Fuss B, Parpura V, Verkhratsky A
J Neurochem · 2026 May · PMID 42135972 · Publisher ↗
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Low 5HT and 5HT Receptor Neurotransmission as a Potential Link Between Cholesterol Metabolism and Suicide Risk.
Kalkman HO, Smigielski L
J Neurochem · 2026 May · PMID 42130235 · Full text
Elevated levels of the inflammatory cytokine IL-6 and decreased levels of cholesterol in blood and brain tissue have been reported in studies of individuals who attempted or completed suicide. The mechanisms underlying t...
Elevated levels of the inflammatory cytokine IL-6 and decreased levels of cholesterol in blood and brain tissue have been reported in studies of individuals who attempted or completed suicide. The mechanisms underlying these effects remain unclear. In this review, we discuss a potential mechanistic link between these observations involving lipid raft function and serotonergic signaling. Reduced cholesterol availability may affect lipid raft function and could, potentially through reduced levels of the lipid raft protein S100A10 (p11), result in diminished cell-surface expression of the serotonin receptors 5-HT and 5-HT. Both receptors have been implicated in the suppression of impulsive and aggressive behavior. Lipid rafts are also organizing platforms for GABA, glutamate, and serotonin transporters. Reduced serotonin reuptake could contribute to the often-reported decrease in the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in suicidal individuals. Inflammatory cytokines, including IL-6, may further influence serotonergic signaling by increasing expression of the enzyme indoleamine-2,3-dioxygenase (IDO), which enhances tryptophan degradation through the kynurenine pathway. Reduced tryptophan availability may limit serotonin synthesis and thereby decrease activation of the 5-HT and 5-HT receptors. These observations suggest that the combined effects of low cholesterol, elevated IL-6 signaling, and reduced tryptophan availability may increase impulsivity and thereby heighten vulnerability to suicidal behavior. This framework accommodates findings from genetic and biomarker studies in suicidal patients. Owing to its effect on lipid raft organization, the fish-oil component docosahexaenoic acid (DHA) might modulate these processes and potentially reduce suicide risk in individuals with low cholesterol levels.
Anti-Aging Protein Klotho Attenuates Schizophrenia-Associated Cognitive and Synaptic Dysfunctions by Regulating GluN2B-NMDARs in the Hippocampus.
Zhan JQ, Li YH, Jiang FH … +10 more , Wang H, Huang Y, Zhan HY, Xu XM, Liao D, Zhang J, Chen LF, Wei B, Fan H, Yang YJ
J Neurochem · 2026 May · PMID 42117259 · Publisher ↗
Cognitive impairment is a core symptom of schizophrenia and has a significant impact on clinical efficacy and prognosis. However, its underlying pathological mechanism remains unclear and effective treatments are still l...
Cognitive impairment is a core symptom of schizophrenia and has a significant impact on clinical efficacy and prognosis. However, its underlying pathological mechanism remains unclear and effective treatments are still lacking. N-methyl-D-aspartate receptors (NMDARs) hypofunction is the key pathological basis of cognitive impairments in schizophrenia and the anti-aging protein klotho is involved in the regulation of NMDAR function. Our current study aims to investigate the role of klotho in synaptic and cognitive function in a male rat model of schizophrenia, in which rats are briefly exposed to dizocilpine (MK-801) to disrupt NMDAR during early development. We found that MK-801 treatment resulted in hippocampus-dependent synaptic plasticity and cognitive deficits in male rats during adulthood, and the expression of klotho protein in the hippocampus was significantly decreased in these rats. Elevation of hippocampal klotho in MK-801-treated rats via gene overexpression can significantly reverse the synaptic and cognitive dysfunction. At the molecular level, elevation of hippocampal klotho selectively upregulated the total and synaptic expressions of GluN2B-containing NMDARs, significantly increased postsynaptic density protein 95 (PSD-95) level and promoted extracellular signal-regulated kinase (ERK) phosphorylation in the hippocampus of MK-801-treated rats. Furthermore, treatment with a specific GluN2B antagonist Ro 25-6981 significantly abolished the beneficial effects of klotho on hippocampal long-term potentiation (LTP) and cognition in MK-801-treated rats. Collectively, reduced klotho in the hippocampus may contribute to the development of MK-801-induced schizophrenia-like synaptic and cognitive deficits, and elevating klotho is capable of rescuing the synaptic plasticity and cognition by modulating hippocampal GluN2B-containing NMDARs.
Insulin Receptor Isoform Pattern in Aged Normal and Alzheimer's Human Cortex.
Webb-Robinson C, Murray H, Turner CP … +3 more , Palpagama T, Faull RLM, Curtis MA
J Neurochem · 2026 May · PMID 42117240 · Full text
Desensitisation to insulin nearly doubles the risk of developing Alzheimer's disease (AD), a degenerative brain disorder and the leading cause of dementia. Impairment of the insulin signalling pathway is also apparent in...
Desensitisation to insulin nearly doubles the risk of developing Alzheimer's disease (AD), a degenerative brain disorder and the leading cause of dementia. Impairment of the insulin signalling pathway is also apparent in AD brain tissue even in the absence of body-wide insulin resistance. Activation of the insulin receptor (IR) in the brain increases neural resilience by promoting structural and synaptic plasticity, glucose metabolism, and resistance to apoptosis, thereby enhancing cognition and learning. Additionally, the splice variants of IR have differing downstream effects, and their ratio may play a role in insulin resistance. I n this work, the immunolabelling pattern and binding specificity of a range of IR beta subunit (IRβ) antibodies was studied in post-mortem human brain tissue. Immunoreactivity in brain tissue was observed on almost all neurons and some astrocytes, but no other glia. Further, isoforms of IR transcripts both with and without exon 11 (IR-B and IR-A respectively) were identified within neurons and quantified in situ in the aged normal and AD entorhinal cortex (EC) and middle temporal gyrus (MTG) using RNAscope. Our results demonstrate the mRNA for both isoforms were abundant in similar quantities. However, IR-B (Ex11), the more efficient isoform, was predominant in the EC in AD, potentially reflecting a compensatory effect of brain insulin resistance.
Modeling Synaptic Maturation From Growth Cone to Synapse in Human Organoids.
Øhlenschlæger MS, Criscuolo L, Jensen P … +14 more , Lloyd-Davies Sánchez DJ, Sutcliffe M, Bhosale S, Bogetofte H, Tahir M, Jakobsen LA, Pihl M, Brewer J, Schwämmle V, Poulsen FR, Freude K, Lancaster MA, Robinson PJ, Larsen MR
J Neurochem · 2026 May · PMID 42108706 · Full text
Human neural organoids (NOs) provide a powerful platform for investigating synaptic development and dysfunction during early neurodevelopment. However, methodologies for isolating functional synaptic structures from thes...
Human neural organoids (NOs) provide a powerful platform for investigating synaptic development and dysfunction during early neurodevelopment. However, methodologies for isolating functional synaptic structures from these models remain limited. Here, we present a differential centrifugation protocol enabling the enrichment of growth cone particles (GCPs) and immature synaptosomes from air-liquid interface cerebral organoids (ALI-COs) at distinct developmental stages (Day 90 and 150). Notably, the method avoids density gradients, requires minimal starting material while maintaining reproducibility across human and murine tissues. Quantitative proteomic profiling revealed significant enrichment of growth cone markers (e.g., GAP43) and classical synaptosomal proteins (e.g., PCLO, BSN, SYN1). Transmission electron microscopy (TEM) confirmed the presence of membrane-enclosed GCPs with fibrous content and mitochondria in Day 90 isolates, and immature synaptosomes containing synaptic vesicles on day 150. Functional viability of both types of synaptic structures was demonstrated through KCl-induced depolarization, which triggered phosphorylation changes in growth cone proteins (GAP43, MARCKS, MARCKSL1), cytoskeletal regulators (DCLK1, SHTN1, MARK4, MAP1B) and protein kinases (CAMK2G, PRKCE) in Day 90 GCPs, as well as classical synaptic vesicle cycle proteins (SYN1, DNM1, RPH3A) at Day 150. Overall, this study establishes a centrifugation-based protocol for isolating growth cones and immature synapses from human organoids, capturing key stages of synaptic development and enabling scalable, patient-compatible models to study synaptic function and dysfunction in neurodevelopmental and neurodegenerative disorders.
Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.
Sharmin T, Doecke JD, Chatterjee P … +7 more , Pedrini S, Sohrabi HR, Ashton NJ, Zetterberg H, Garg ML, Blennow K, Martins RN
J Neurochem · 2026 May · PMID 42104655 · Full text
Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD trigge...
Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.
Chromaffin Versus Platelet Granules: What We Have Learned From Chromaffin Cells for Human Studies.
Borges R
J Neurochem · 2026 May · PMID 42083311 · Full text
Biological amines-such as dopamine, norepinephrine, epinephrine, octopamine, serotonin, and histamine-are stored at high concentrations within secretory vesicles, also referred to as "granules" in certain cell types, inc...
Biological amines-such as dopamine, norepinephrine, epinephrine, octopamine, serotonin, and histamine-are stored at high concentrations within secretory vesicles, also referred to as "granules" in certain cell types, including mast cells, chromaffin cells, and platelets. Over the past decades, extensive knowledge has been gained regarding the biogenesis, composition, and function of chromaffin granules. This information can now be leveraged to understand amine storage mechanisms in other secretory systems, particularly in human platelets, which are readily accessible. Importantly, dysfunction of secretory vesicles has been implicated in several diseases, and vesicular defects may therefore be detectable in platelets obtained from well-characterized individuals. Such an approach offers significant potential for clinical and translational studies, as personalized functional information can be directly derived from patients. In this brief review, I focus on the vesicular mechanisms involved in biological amine accumulation and discuss the functional consequences of their disruption, with particular emphasis on chromaffin granules and platelet δ-granules.
Hydroxytyrosol Mitigates Anxiety-Like Behaviors After a Traumatic Experience in Aged Mice in Parallel With Increased Neurogenesis in the Ventral and Dorsal Dentate Gyrus, and Preservation of Gut Microbiota Composition.
D'Andrea G, Bertini L, Costanzi M … +12 more , Canini F, Bernini R, Fochetti A, Clemente M, Proietti S, Ceccarelli M, Caruso C, Caruso M, Scavizzi F, Raspa M, Tirone F, Micheli L
J Neurochem · 2026 May · PMID 42059580 · Full text
Hydroxytyrosol (HTyr), a phenolic compound present in olive oil, exhibits antioxidant, anti-inflammatory, and neuroprotective properties, benefiting several age-related diseases. Our previous research demonstrated that o...
Hydroxytyrosol (HTyr), a phenolic compound present in olive oil, exhibits antioxidant, anti-inflammatory, and neuroprotective properties, benefiting several age-related diseases. Our previous research demonstrated that oral HTyr administration counteracts age-associated neurogenesis decline in the dentate gyrus of the hippocampus by promoting the production of stem/progenitor cells and new neurons. Since new neurons generated in the dorsal dentate gyrus support contextual memory discrimination, while those generated in the ventral region modulate anxiety, we investigated whether pure HTyr, synthesized in our laboratories, selectively stimulates neurogenesis in these regions in aging mice and evaluated its effects on contextual memory and stress response. Furthermore, we examined its influence on gut microbiota composition, given the well-established role of the microbiota-gut-brain axis in memory and stress regulation. We found that HTyr induced the production of new neurons and neuroblasts in both dentate gyrus regions, with a prevalent effect in the ventral region. Consistently, we observed that HTyr treatment did not improve the contextual memory discrimination but reduced fear sensitization and anxiety-like behavior after a traumatic experience. Furthermore, we observed a reduction of neuroinflammation in HTyr-treated dentate gyri. In parallel, treatment with HTyr preserved the stability of key microbial families linked to intestinal well-being, counteracting the unhealthy effects of stress on gut microbial structure. Our results suggest that HTyr treatment in aging mice enhances resilience to posttraumatic stress by increasing neurogenesis and modulating the microbiota-gut-brain axis. Future studies should explore its potential as a therapeutic intervention for individuals experiencing posttraumatic stress disorder symptoms.
Urine-Derived iPSC Neurospheres Uncover Proteomic Correlates of Clinical Severity in Dravet Syndrome.
Martins M, Nugue G, Aguiar A … +7 more , Souza LRQ, Abrantes PV, Trajano JR, Stelling M, Junqueira M, Rehen S, Guimarães MZP
J Neurochem · 2026 May · PMID 42051158 · Full text
Dravet syndrome (DS) is a rare and severe childhood-onset developmental epileptic encephalopathy caused primarily by mutations in the sodium channel gene SCN1A. Animal models have undeniably advanced our understanding of...
Dravet syndrome (DS) is a rare and severe childhood-onset developmental epileptic encephalopathy caused primarily by mutations in the sodium channel gene SCN1A. Animal models have undeniably advanced our understanding of DS, but they still do not fully capture its clinical heterogeneity, highlighting the need for complementary human in vitro systems. Here, we generated induced pluripotent stem cells (iPSCs) from urine epithelial cells of three DS patients carrying distinct SCN1A variants and differentiated them into neural stem cells (NSCs) and early-stage neurospheres. Clinical severity was assessed using the DANCE checklist, and molecular phenotypes were characterized through isobaric quantitative proteomics. Comparative analyses identified differences in protein abundance across patient-derived lines, with distinct molecular patterns associated with clinical severity measures. The patient-derived lines exhibited variability in protein groups related to synaptic organization, mitochondrial processes, and RNA processing, reflecting interindividual molecular differences within the cohort. These findings establish patient-derived neurospheres as a scalable human model for investigating molecular variability in DS. This approach provides a framework to explore disease heterogeneity and provides a foundation for future studies linking molecular profiles to clinical variability in DS.
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