Journal Of Neurochemistry[JOURNAL]
Sun
200 papers
Uncovering Hyperhomocysteinemia: Global Risk Patterns and Molecular Disruption in Brain and Vascular Health.
Ramires Júnior OV, Prauchner GRK, Rieder AS … +3 more , Leite AKO, Farias CP, Wyse ATS
J Neurochem · 2025 Dec · PMID 41427720 · Full text
Hyperhomocysteinemia (HHcy), a condition characterized by elevated plasma levels of the sulfur-containing amino acid homocysteine, has emerged as a multifactorial and systemic risk factor with profound effects on neural...
Hyperhomocysteinemia (HHcy), a condition characterized by elevated plasma levels of the sulfur-containing amino acid homocysteine, has emerged as a multifactorial and systemic risk factor with profound effects on neural and vascular integrity. This review integrates recent findings from epidemiological studies, clinical data, and mechanistic research to provide a comprehensive overview of HHcy's contribution to neurovascular dysfunction. We examine how nutritional deficits, aging, genetic polymorphisms-such as in the methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes-pharmacological agents, and comorbid conditions shape homocysteine homeostasis and susceptibility to pathology. Emphasis is placed on molecular pathways, including oxidative and nitrative stress, inflammasome activation, autophagy, and epigenetic modulation, which link HHcy to cognitive decline, memory impairment, endothelial dysfunction, and increased disease burden in neurodegenerative disorders. By consolidating multidisciplinary evidence, we position HHcy as a pivotal but under-recognized target for intervention in neurochemical and vascular health.
Early Life Mild Adversity Affects in a Sexually Dimorphic Way the Oxytocinergic System Reducing Close Social Interaction in Adult Male Rats.
Raftogianni A, Pavlidi L, Galeou S … +3 more , Kalpachidou T, Stylianopoulou F, Stamatakis A
J Neurochem · 2025 Dec · PMID 41427719 · Full text
The oxytocinergic system is highly responsive to early-life experiences, playing a crucial role in regulating social behaviors. In this study, we examined the effects of a neonatal experience modeling maternal neglect on...
The oxytocinergic system is highly responsive to early-life experiences, playing a crucial role in regulating social behaviors. In this study, we examined the effects of a neonatal experience modeling maternal neglect on the oxytocinergic system in the adult rat brain. To investigate this, rat pups were exposed to a T-maze during Postnatal Days 10-13, where prohibition of contact with the mother-which served as the expected reward-constituted a mildly aversive experience (Denial of Expected Reward, DER). Our findings revealed that adult males subjected to the DER experience exhibited reduced levels of close social interaction, which could be ameliorated by acute intranasal oxytocin administration. Moreover, adult DER males had decreased expression of oxytocin receptors (OTR) in the medial nucleus of the amygdala (MeA) accompanied by alterations in the methylation profile of the OTR gene proximal promoter in MeA, specifically increased methylation levels of cytosines at positions -65, -19 and -11. No such effects were detected in the hippocampus or the medial-orbital prefrontal cortex (MO PFC). Notably, in adult females the DER experience did not affect OTR expression in the brain areas examined (MeA, hippocampus and MO PFC) or their social interaction. These results suggest that the aversive early-life experience of DER has affected the epigenetic regulation of OTR expression in a sexually dimorphic, brain region-specific manner, leading to a reduction in oxytocinergic activity within the adult male amygdala, accompanied by impaired social interactions.
PARP Activity Is Essential for Retinal Photoreceptor Survival in the Human Homologous Rho Mouse Model for Autosomal Dominant Retinitis Pigmentosa.
Zhu Y, Fallatah AHA, Jiao K … +2 more , Seeliger MW, Paquet-Durand F
J Neurochem · 2025 Dec · PMID 41427648 · Full text
Retinitis Pigmentosa (RP) is a group of rare, inherited, neurodegenerative diseases of the retina that primarily affect rod photoreceptors. The initial loss of rods is followed by a secondary cone photoreceptor degenerat...
Retinitis Pigmentosa (RP) is a group of rare, inherited, neurodegenerative diseases of the retina that primarily affect rod photoreceptors. The initial loss of rods is followed by a secondary cone photoreceptor degeneration and eventually legal blindness. Despite several attempts, RP still remains essentially untreatable. In recent years, inhibition of poly (ADP-ribose) polymerase (PARP) has been proposed as a potential therapeutic strategy for autosomal-recessive RP, based on promising work in preclinical animal models. However, the effects of PARP inhibitors in autosomal-dominant RP are still largely unknown. Here, we employed a novel, human-homologous rhodopsin-mutant Rho mouse model for autosomal dominant RP to assess the impact of different PARP inhibitors on the progression of photoreceptor degeneration. The PARP inhibitors used -olaparib, saruparib, INO1001, and nicotinamide-target different PARP isoforms, and their potentially differential effects were evaluated in organotypic retinal explants cultivated under entirely defined conditions. Readouts comprised in situ activity assays for PARP and calpain-type proteases, the TUNEL assay for cell death, as well as immunostaining for activated calpain-2, activated caspase-3, rhodopsin, and cone arrestin-3. Unexpectedly, and in contrast to previous findings in animal models for recessive RP, all of the PARP inhibitors used led to marked and dose-dependent rod photoreceptor toxicity in the Rho dominant RP model. Furthermore, this effect appeared to be independent of rhodopsin expression. On the other hand, cone photoreceptors were apparently unaffected by PARP inhibition. The present study thus demonstrates the importance of PARP activity for rod photoreceptor viability in a dominant rhodopsin mutant, highlights the need for a deeper understanding of the mechanisms underlying photoreceptor degeneration in different RP forms, and cautions against the indiscriminate use of PARP inhibitors for the treatment of RP.
Temporal Dynamics of tsRNA Regulation Mark an Abrupt Transition After Epileptogenesis.
Zaheer S, Baindoor S, Connolly NMC … +8 more , Siebenbrodt K, Bauer S, Rosenow F, Andersen JS, Venø MT, Kjems J, Henshall DC, Prehn JHM
J Neurochem · 2025 Dec · PMID 41392969 · Full text
Epileptogenesis involves widespread molecular remodeling, including transcriptional and post-transcriptional changes that reshape neuronal networks. While microRNAs have been extensively studied in this context, the cont...
Epileptogenesis involves widespread molecular remodeling, including transcriptional and post-transcriptional changes that reshape neuronal networks. While microRNAs have been extensively studied in this context, the contribution of transfer RNA-derived small RNAs (tsRNAs) remains largely unexplored. Understanding how tsRNAs engage in Argonaute 2 (Ago2)-mediated regulation during epileptogenesis could uncover new layers of post-transcriptional control relevant to seizure development and progression. Recent studies increasingly recognize transfer RNA-derived small RNAs or tsRNAs, especially those bound to Argonaute 2 (Ago2), as functional regulators of gene expression. Here, we analyzed Ago2-immunoprecipitated small RNA-Seq data along with matching transcriptomic and proteomic data across seven defined timepoints in a rat model of epilepsy that was induced using perforant pathway stimulation (PPS). The analysis showed dynamic shifts in Ago-2 bound tsRNA expression, with early and intermediate stages showing upregulation of shorter tsRNA fragments, whereas Day of First Seizure (DOFS) and chronic timepoints showed a shift toward 5' tiRNAs, including highly upregulated GlyGCC-derived fragments. Cluster analysis using Weighted Gene Co-Expression Network Analysis (WGCNA) identified modules specific to the DOFS timepoint where tsRNAs clustered together with genes enriched in pathways including neuronal metabolism, mitochondrial function, and synaptic stability. Target prediction analysis using RNAhybrid at DOFS predicted targets in 3' UTR, 5' UTR, and CDS regions showing an association with glycolysis, protein localization, and vesicle trafficking. Subsequent gene-disease association analysis further associated the predicted targets with neurodegenerative conditions including but not limited to Alzheimer's disease, intellectual disability, and epilepsy. This study highlights that tsRNAs potentially play a temporal dynamic regulatory role in epileptogenesis with an evident shift in tsRNA accumulation at DOFS suggesting a potential rewiring of post-transcriptional control at the completion of epileptogenesis. This work also highlights a first integrative approach of tsRNA downstream effects on the transcriptome and proteome in epilepsy and suggests innovative tsRNA-driven mechanisms relevant to disease progression.
Valproic Acid-Induced Autistic-Like Behavior Is Accompanied by Intestinal Damage Driving Changes in Gut Permeability in a Sex-Dependent Way in Rats.
Longo B, Nunes RKS, Cazarin CA … +12 more , Silva TFQE, Sievers J, Nilz ACDS, Venzon L, da Silva LM, Willrich CH, Cury BJ, Costa RA, de Souza MM, Stern CAJ, Zampronio AR, da Silva LM
J Neurochem · 2025 Dec · PMID 41392905 · Full text
A significant proportion of individuals with autism spectrum disorder (ASD) experience gastrointestinal disturbances exacerbating behavioral symptoms. Therefore, this study investigated alterations in the intestinal muco...
A significant proportion of individuals with autism spectrum disorder (ASD) experience gastrointestinal disturbances exacerbating behavioral symptoms. Therefore, this study investigated alterations in the intestinal mucosa that influence intestinal permeability in rats exposed to valproic acid (VPA) in utero, as well as the sexual differences in it. After assessing social behavior, intestinal permeability was assessed using FITC-dextran, and vascular permeability was evaluated through Evans blue dye tests in the intestine and blood-brain barrier (BBB) of male and female offspring. Furthermore, microscopic analyses were performed to assess mucosal architecture and quantify mucin levels, while inflammatory and oxidative parameters, 5-HT and 5-HIAA levels, and serum lipopolysaccharide (LPS) concentrations were measured. Males, but not females, exposed to VPA exhibited reduced social interaction time. Only VPA males showed increased intestinal and vascular permeability, histological changes, elevated mucin levels, and higher serum LPS levels. Male, but not female, rats exposed to VPA displayed increased BBB permeability, and both showed reduced intestinal muscular layer thickness. Additionally, males showed increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and enhanced glutathione S-transferase (GST) and myeloperoxidase (MPO) activities. Conversely, females exhibited no elevation in ROS or MDA intestinal levels. Moreover, a reduction in 5-HT turnover was evidenced in VPA-females compared to VPA-males. These findings support the validity of this model as a tool for investigating the role of intestinal barrier dysfunction in ASD and for identifying novel pharmacological targets in this field, considering the sexual differences in search of the practice of personalized and precision medicine.
The Neurochemical Landscape of Oligodendrocyte Physiology: From Myelination to Metabolic and Synaptic Modulation.
Correale J
J Neurochem · 2025 Dec · PMID 41382341 · Publisher ↗
Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis....
Oligodendrocytes, traditionally recognized for their role in axonal myelination, are increasingly appreciated as metabolically dynamic and functionally diverse cells integral to central nervous system (CNS) homeostasis. This review delineates the evolving neurochemical landscape of oligodendrocyte physiology, emphasizing their roles beyond myelin production. We explore key processes including lipid metabolism, metabolic coupling with neurons, ion buffering, neurotransmitter signaling, and synaptic modulation. Oligodendrocytes preferentially utilize aerobic glycolysis and support axonal energy metabolism via the export of lactate and phosphocreatine, maintaining ATP levels even in the absence of mitochondria within the myelin sheath. Their capacity for regional and transcriptional heterogeneity allows adaptive responses to local microenvironments and neuronal activity. Lipid biosynthesis and storage mechanisms are intricately regulated through mTORC1, SREBPs, and lipophagy, enabling rapid membrane expansion, and structural integrity during myelination. Furthermore, oligodendrocytes modulate the periaxonal milieu via potassium buffering, pH regulation, and osmotic balance, primarily through Kir channels, carbonic anhydrases, and aquaporins. They also express a wide array of neurotransmitter receptors, enabling bidirectional communication with neurons and activity-dependent modulation of maturation and plasticity. Intracellular signaling pathways such as PI3K/Akt/mTOR, MAPK/ERK, and Wnt/β-catenin orchestrate the integration of metabolic and transcriptional programs. Collectively, these findings redefine oligodendrocytes as active participants in CNS physiology, contributing to neuronal health, circuit plasticity, and responses to injury or disease.
Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism.
d'Anglemont de Tassigny X, Jiménez-Medina A, López-López I … +1 more , López-Barneo J
J Neurochem · 2025 Dec · PMID 41382340 · Full text
Glial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striat...
Glial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic adenosine monophosphate (cAMP)-dependent signaling, a compelling strategy for PD treatment is the pharmacological elevation of intracellular cAMP. This approach aims to enhance endogenous GDNF, offering potential neuroprotective benefits. In this study, we show that selective inhibition of phosphodiesterases (PDEs) subtypes, therefore enhancing intracellular cAMP levels, increases Gdnf mRNA expression in striatal slices ex vivo; however, achieving this effect in vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non-selective PDE inhibitor. Ibudilast robustly upregulated striatal Gdnf expression both ex vivo and in vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra, attenuation of TH+ fiber loss in the striatum, and mitigation of striatal dopamine depletion. Given its established clinical use and favorable safety profile, these findings support further investigation of Ibudilast as a potential disease-modifying therapy in PD.
Altered Glut4, IRAP, and Brain Insulin Signaling in a Mouse Model of Epilepsy and Contributions to Glucose Transport in Neurons and Astrocytes.
Xu W, Neal ES, Barlow N … +2 more , Thompson P, Borges K
J Neurochem · 2025 Dec · PMID 41369048 · Publisher ↗
There is evidence that glucose transport is impaired between seizures, which can promote seizure generation. In addition to glucose transporters Glut1 and Glut3, Glut4 is also found in the brain. Glut4 translocation is r...
There is evidence that glucose transport is impaired between seizures, which can promote seizure generation. In addition to glucose transporters Glut1 and Glut3, Glut4 is also found in the brain. Glut4 translocation is regulated by insulin signaling in peripheral tissues and insulin-regulated aminopeptidase (IRAP), but remains poorly understood in the brain. This study aimed to characterize the expression of Glut1, Glut3, Glut4, and key regulators of Glut4 trafficking in the chronic stage of the mouse pilocarpine epilepsy model. Roles of Glut4 and IRAP in glucose uptake were investigated in cultured neurons versus astrocytes. Western blot, RT-qPCR, and immunohistochemistry were used to investigate the expression of Glut1, Glut3, Glut4, IRAP, and insulin signaling genes in the chronic stage of the mouse pilocarpine model in the hippocampus and cortex between seizures. Contributions of Glut4 and IRAP to H-2-deoxyglucose uptake were quantified in primary mouse neurons and astrocytes. In the hippocampus during the chronic stage of the model, Glut1 and IRAP expression was unaltered, Glut3 decreased, but Glut4 2.5-fold increased with Glut4 and IRAP being specifically upregulated in GFAP astrocytes. Insulin signaling appeared altered, with reduced expression of key pathway genes and changed phospho-Akt and -AMPKα levels. Although systemically injected insulin did not activate brain insulin signaling, insulin and neurotransmitters stimulated glucose transport into cultured neurons and astrocytes by 15%-50%. This was largely mediated by Glut4, despite its relatively low expression in these cells. Notably, in neurons but not in astrocytes, IRAP inhibitors further enhanced this stimulated transport by an additional 15% via Glut4-mediated uptake. This is the first report showing increased astrocytic Glut4 expression in a rodent epilepsy model. Along with the finding of significant contributions of Glut4 and IRAP to glucose uptake in neurons, our work points to IRAP inhibitors as new pharmacological approaches improving neuronal energy supply to prevent seizure generation in epilepsy.
Considerations for Spatial Omics, Metabolite Analyses, and Tissue-Harvesting Artifacts.
Hanrieder J, Sun R, Ellis SR … +2 more , Pahnke J, Savas JN
J Neurochem · 2025 Dec · PMID 41347273 · Publisher ↗
Within the emerging field of spatial biology, novel analytical technologies are increasingly demonstrated for mapping neurochemical changes in situ. These tools comprise spatial mass spectrometry (MS imaging, MSI), spati...
Within the emerging field of spatial biology, novel analytical technologies are increasingly demonstrated for mapping neurochemical changes in situ. These tools comprise spatial mass spectrometry (MS imaging, MSI), spatial transcriptomics using in situ sequencing, probe-based spatial omics, as well as laser microdissection and single cell-type isolation interfaced with either mass spectrometry or next generation RNA sequencing (NGS) for single cell-type analysis. These approaches significantly exceed the neurochemical methods that are commonly used with respect to molecular specificity and spatial precision. However, despite all these advancements, close attention has still to be paid to appropriate tissue harvesting and enzyme inactivation methods to avoid degradation of neurochemicals and the generation of artifacts, and because of euthanasia or postmortem ischemia. In this editorial, we aim to present the readership with considerations in lieu of emerging analytical and spatial molecular techniques, as well as highlight the relevance of appropriate tissue preparation. Importantly, we discuss different quenching techniques and their compatibility as well as limitations for novel spatial analyses that require morphologically pristine tissues.
Astrocytic Interleukin-33 Deficiency Reduces Glial Fibrillary Acidic Protein Expression and Exacerbates Microglial Activation and Neuronal Damage in a Chemically Induced Inflamed Frontal Cortex.
Zheng YC, Chen WY, Wang CY … +1 more , Tzeng SF
J Neurochem · 2025 Dec · PMID 41347267 · Publisher ↗
Astrocytes, the most abundant glial cells in the CNS, play a crucial role in supporting neurons and respond to injury or disease through astrogliosis, a process marked by cellular hypertrophy and increased glial fibrilla...
Astrocytes, the most abundant glial cells in the CNS, play a crucial role in supporting neurons and respond to injury or disease through astrogliosis, a process marked by cellular hypertrophy and increased glial fibrillary acidic protein (GFAP) expression. Interleukin-33 (IL-33) was originally identified as an alarmin and is known to be produced by astrocytes and oligodendrocytes in the CNS. Recently, we reported its role in regulating oligodendrocyte differentiation. However, its role in astrocytes remains less defined. In a demyelinating mouse model induced by gliotoxin cuprizone (CPZ), IL-33 was previously shown to be reduced in oligodendrocytes within the corpus callosum. In this study, we found that lipopolysaccharide (LPS) stimulation enhanced nuclear IL-33 expression and GFAP production in cortical astrocytes. Using lentiviral-mediated IL-33 knockdown (IL33KD) and overexpression (IL33oe), we demonstrated that IL-33 positively regulates GFAP expression. Interestingly, we observed an increase in nuclear IL-33-expressing GFAP cortical astrocytes in CPZ-treated mice. In contrast, CPZ-induced GFAP upregulation in cortical astrocytes was abolished in IL-33 knockout (il33) mice. Furthermore, chronic CPZ feeding in il33 mice led to increased microgliosis and neuronal damage within the frontal cortex, as well as abnormal anxiety-like behaviors. Collectively, these results indicate that elevated nuclear IL-33 in astrocytes under inflammatory conditions is critical for GFAP upregulation and astrogliosis. Loss of IL-33 disrupts astrocyte neuroprotective functions and glial reactivity in the frontal cortex, contributing to behavioral abnormalities under a demyelinating insult.
Type 2 Diabetes Mellitus, Cognitive Performance, and Incident Dementia; Identifying Mediating Pathways and Biomarkers From the Plasma Proteome.
Perfetto SE, Ruthirakuhan M, Ryoo SW … +8 more , Wong YY, Xiong LY, Anita NZ, Caveney NA, Edgar LJ, Newman JW, Cogo-Moreira H, Swardfager W
J Neurochem · 2025 Dec · PMID 41342355 · Full text
Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk. Pathophysiological mechanisms are not fully understood. In this prospective study of UK Biobank participants, (...
Type 2 diabetes mellitus (T2DM) is associated with poorer cognitive performance and increased dementia risk. Pathophysiological mechanisms are not fully understood. In this prospective study of UK Biobank participants, (n = 9943 without T2DM, age = 56.3 ± 8.2 years, 55% female, n = 3752 with T2DM, age = 59.1 ± 7.7 years, 41% female), T2DM was associated with poorer attention (Hedges' g = -0.15[-0.17, -0.10]), processing speed (Hedges' g = -0.14[-0.17, -0.09]), and a higher risk of incident dementia over 15 years (HR = 2.13[1.74, 2.61]). Among 2923 proteins measured by Olink proteomics, 1739 were differentially expressed in T2DM. Four-way decomposition models of proteomic markers, and KEGG pathway analyses, were used to identify potential mediating and moderating effects of biological pathways on the association between T2DM and cognitive or dementia outcomes. For dementia, 230 protein mediators implicated inflammatory pathways (complement/coagulation cascades, cytokine-cytokine receptor interactions, and the janus kinase-signal transducer and activator of transcription signaling pathway), and 11 proteins implicated cholesterol/lipid metabolism as moderators (including apolipoprotein E, low-density lipoprotein receptor and prostaglandin reductase 1). Mediators with the highest accuracy to predict incident dementia in T2DM were glial fibrillary acidic protein (AUC = 0.71[0.67, 0.76]) and neurofilament light polypeptide (AUC = 0.71 [0.67, 0.75]). Multivariate proteomic/clinical models (AUC = 0.78 [0.75, 0.81]) improved accuracy beyond clinical risk factors alone (AUC = 0.74 [0.69, 0.78]). Subgroup analyses by sex, apolipoprotein E ε4 carrier status and age showed some features unique within strata. This study suggests potential targets within inflammatory, oxidative, angiogenesis-related, and metabolic pathways to mitigate cognitive decline and dementia risk in T2DM.
Metabolic Remodeling During the Early Phase of Spontaneous Seizure Emergence Highlights Hexosamine Biosynthetic Pathway Dysregulation in Temporal Lobe Epilepsy.
Zhao Z, Zhang YF, Xu LQ … +2 more , Zhong MK, Ma CL
J Neurochem · 2025 Dec · PMID 41328011 · Publisher ↗
Temporal lobe epilepsy (TLE) is a prevalent form of drug-resistant epilepsy characterized by profound biochemical alterations. Emerging evidence suggests that metabolic dysregulation plays a crucial role in the developme...
Temporal lobe epilepsy (TLE) is a prevalent form of drug-resistant epilepsy characterized by profound biochemical alterations. Emerging evidence suggests that metabolic dysregulation plays a crucial role in the development of TLE. In this study, we employed a kainic acid-induced mouse model of TLE to investigate metabolic remodeling and key regulatory pathways at Day 14 post-status epilepticus, a time point within early epilepsy, corresponding to the early phase of spontaneous seizure emergence during epileptogenic progression. Liquid chromatography-mass spectrometry-based proteomics and metabolomics analyses were conducted on hippocampal and serum samples to identify and quantify differentially expressed metabolites and proteins. Joint pathway analysis revealed substantial metabolic reprogramming, with consistent upregulation of the hexosamine biosynthetic pathway (HBP), converging on amino sugar and nucleotide sugar metabolism. Western blotting, immunohistochemistry, and targeted metabolite quantification further validated the elevation of key HBP components in the hippocampus, supporting HBP activation as a hallmark of metabolic remodeling during early seizure emergence. These findings provide novel insight into the metabolic landscape of epileptogenesis and highlight HBP-related alterations as potential contributors to seizure development and promising therapeutic targets.
Clinical Validation of Novel Immunoassays for Plasma Phosphorylated Tau 217, 212, 181, 231, and Brain-Derived Tau Across the Biochemical Spectrum of Alzheimer's Disease.
Dulewicz M, Kac PR, Ortiz FG … +12 more , Karikari TK, Kulczyńska-Przybik A, Mroczko B, Turton M, Harrison P, Maler M, Oberstein T, Kornhuber J, Hanrieder J, Zetterberg H, Blennow K, Lewczuk P
J Neurochem · 2025 Dec · PMID 41321279 · Full text
Plasma biomarkers have emerged as promising less invasive alternatives for Alzheimer's disease (AD) detection. However, the diagnostic performance of phosphorylated tau (p-tau) isoforms remains incompletely validated. In...
Plasma biomarkers have emerged as promising less invasive alternatives for Alzheimer's disease (AD) detection. However, the diagnostic performance of phosphorylated tau (p-tau) isoforms remains incompletely validated. In a cohort of 160 patients from a memory clinic, plasma levels of p-tau217, p-tau212, p-tau181, p-tau231, and BD-tau were measured using Single Molecule Array (Simoa) in-house assays, alongside NFL and GFAP. Subjects were classified using the Erlangen Score into Controls (n = 53), neurochemically possible AD (n = 27), and probable AD (n = 80). Plasma concentrations of all p-tau isoforms were significantly elevated in both Possible AD and Probable AD groups compared to Controls (p < 0.001). Notably, p-tau217 exhibited the highest diagnostic accuracy (AUC = 0.954) and correlated with CSF classical biomarkers. A positive result for p-tau217 increases the probability of AD almost fivefold. Plasma p-tau217 reflects AD neurochemical changes and has high negative predictive value, supporting its use as a screening tool. However, moderate PPV suggests the need for confirmatory testing to ensure an accurate diagnosis.
Patient-Derived Variants Define Constraints for Ligand Binding at the PDZ Domain of CASK.
Tibbe D, Hönck HH, Bhatia N … +6 more , Truong T, Proskauer L, Ortiz-Gonzalez X, Maguire JA, Pak C, Kreienkamp HJ
J Neurochem · 2025 Dec · PMID 41321276 · Full text
Genetic variants in the X-chromosomal gene coding for the calcium-/calmodulin-dependent serine protein kinase (CASK) are associated with a neurodevelopmental disorder. CASK is a member of the membrane-associated guanylat...
Genetic variants in the X-chromosomal gene coding for the calcium-/calmodulin-dependent serine protein kinase (CASK) are associated with a neurodevelopmental disorder. CASK is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. It acts as a scaffold at presynaptic sites, as a regulator of the transport of glutamate receptors, and as a transcriptional regulator. The PDZ domain of CASK has been reported to bind to presynaptic cell adhesion molecules such as Neurexin1-3, CNTNAP2, SynCAM and SALM1. Structural analyses of related MAGUKs indicate that the canonical SH3 and GK domains combine with the PDZ domain to form the so-called PSG supramodule. Conserved aromatic residues (Y723 and W914) flanking the GK domain contribute to the formation of a dimeric structure of two PSG modules, which is required for high-affinity binding to the type 2 PDZ ligand motif of, for example, Neurexin. Here we identify previously uncharacterized patient variants in the SH3 domain of CASK (I672V; P673L), which alter the intermolecular binding pocket for Y723. Both variants interfere with the binding of Neurexin-1β, in a manner similar to the previously reported Y723C variant. Intriguingly, binding to the type 1 PDZ ligand of the cell adhesion molecule SALM1 is not altered. Using a set of highly selective patient variants, we show that the binding of SALM1 to CASK is actually not mediated by the CASK PDZ domain or the PSG supramodule, but depends on other type 1 PDZ domain-containing proteins such as SAP97 and Veli, which associate with CASK through its L27 domains. Our data underline the relevance of an intact PSG tandem of CASK for human health.
Dietary Iron Deficiency in Adult Mice Increases Brain Uptake of High-Affinity, Anti-Transferrin Receptor Antibody RI7217.
Kostrikov S, Johnsen KB, Burkhart A … +3 more , Helgudóttir SS, Andresen TL, Moos T
J Neurochem · 2025 Nov · PMID 41299828 · Publisher ↗
Brain capillary endothelial cells (BCECs) express transferrin receptor 1 (TfR1) to ensure sufficient iron transport into the brain. Our main objective was to examine adult mice subjected to dietary iron deficiency (ID) f...
Brain capillary endothelial cells (BCECs) express transferrin receptor 1 (TfR1) to ensure sufficient iron transport into the brain. Our main objective was to examine adult mice subjected to dietary iron deficiency (ID) for possible changes in the content of TfR1 in BCECs and the influence thereof on the uptake and possible transport across the blood-brain barrier (BBB) of high-affinity, rat anti-mouse transferrin receptor IgG2a antibody (clone RI7217) targeting the TfR1. We subjected adult, female mice to dietary ID for 8 weeks. Iron and copper were measured using inductively coupled plasma mass spectrometry (ICP-MS) in various tissues, including total brain, and fractions of brain tissue separated to contain a capillary enriched fraction ("capillary fraction") and a post-capillary, non-endothelial-containing brain parenchymal fraction ("brain fraction"). Possible effects of ID on the cerebral angioarchitecture were estimated using 3D confocal microscopy of optically cleared brain samples labeled using intravenous injection of wheat germ agglutinin with subsequent machine learning-based segmentation and vascular tracing. TfR1 was quantified using ELISA. RI7217 antibodies were conjugated with 1.4 nm nanogold and brain uptake quantified using ICP-MS. ID significantly reduced the iron content in the capillary fraction, liver, spleen, kidney, heart, and skeletal muscles. ID increased the copper content in the brain. Analysis of cerebral cortical angioarchitecture revealed no changes following dietary ID, except for a minor increase in tortuosity of small-caliber vessels. Following ID, the concentration of TfR1 protein remained unchanged in total brain, and the isolated capillaries and brain fraction. In contrast, the uptake of nanogold-conjugated RI7217 was increased in total brain, the brain fraction, liver, spleen, and isolated retinae. The targeting to TfR1 in ID hence suggested increased brain uptake of RI7217. Hypothetically, elevated transport of RI7217 could occur due to increased trafficking of TfR1-containing vesicles through BCECs in ID.
Local Protein Synthesis at Synapses: A Driver for Synapse Diversification.
Daskin E, Van S, Hafner AS
J Neurochem · 2025 Nov · PMID 41299820 · Full text
Local protein synthesis within neuronal processes seems to be crucial for the rapid and dynamic remodeling of the proteome at synaptic compartments. Indeed, this capability enables neurons to swiftly adapt their synaptic...
Local protein synthesis within neuronal processes seems to be crucial for the rapid and dynamic remodeling of the proteome at synaptic compartments. Indeed, this capability enables neurons to swiftly adapt their synaptic functions in response to activity. In this review, we first explore the diverse mechanisms that allow the targeted transport of mRNAs into both dendrites and axons. Then, we report evidence that local mRNAs are actively recruited for protein synthesis during plasticity. Finally, we highlight how this molecular complexity contributes to the establishment and stabilization of memory traces, or engrams, within neural circuits. We propose that presynaptic protein synthesis is a pivotal factor driving the diversification of presynaptic terminals, a process we foresee as essential for the durable consolidation and specificity of engrams.
Lipidomic Signatures in Microglial Extracellular Vesicles During Acute Inflammation: A Gateway to Neurological Biomarkers.
Ollen-Bittle N, Wang W, Bean KM … +5 more , Zhao S, Buzatto AZ, Dong Y, Li L, Whitehead SN
J Neurochem · 2025 Nov · PMID 41292273 · Publisher ↗
Extracellular vesicles (EVs) are membrane-bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of thei...
Extracellular vesicles (EVs) are membrane-bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of their cell of origin. EVs show promise as neurological disease biomarkers due to their molecular makeup reflecting their parent-cell composition signature and due to their ability to cross the blood-brain barrier. To date, the vast majority of research in this field has explored the protein profiles of EVs; however, lipids play an important role not only in the formation of EVs, but also in mediating cellular function and the pathological progression of many neurodegenerative conditions. Herein, we take a critical first step in determining the potential utility of EV lipids as biomarkers in neurological disease. In vitro we exposed BV-2 microglia to either control media or media containing lipopolysaccharides (LPS), a known pro-inflammatory stimulus, for 24 h then isolated both the cells and their EVs and performed LC-MS/MS. For the first time, we reveal distinct lipidomic changes can differentiate resting versus pro-inflammatory microglia and their EVs, while distinct lipids are preserved between EVs and their parent cell. Moreover, we add to current literature by demonstrating acute pro-inflammatory activation of microglia results in the activation and suppression of distinct lipidomic pathways. Finally, we demonstrate that analysis of lipid-based relationships between parent cells and their EVs may be a useful tool to infer cellular function. This study is the first of its kind to demonstrate that lipidomic analysis can not only differentiate the functional state of cells in vitro but can also differentiate their EVs. We lay the first brick in a foundation to support future research into EV lipids as novel and exciting biomarker candidates in neurological disease.
Development and Validation of an ICP-MS/MS Method for the Multielemental Analysis of Cerebrospinal Fluid, Examination of Alzheimer's Disease Samples.
Pérez-Ramírez R, Cuchillo-Ibáñez I, Sánchez-Romero R … +7 more , Beltrán-Sanahuja A, Escamilla S, Molina-Gasset R, Zetterberg H, Blennow K, Sáez-Valero J, Todolí-Torró JL
J Neurochem · 2025 Nov · PMID 41292253 · Publisher ↗
Multielemental analysis of cerebrospinal fluid (CSF) yields critical insights into the pathophysiology of neurological disorders and holds potential as a diagnostic and predictive tool for Alzheimer's disease (AD). The p...
Multielemental analysis of cerebrospinal fluid (CSF) yields critical insights into the pathophysiology of neurological disorders and holds potential as a diagnostic and predictive tool for Alzheimer's disease (AD). The present work presents the development and validation of an inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) based method for multielemental determination in CSF, including metals and metalloids as analytes. As a proof of concept, the importance of the CSF element determination was evaluated in a cohort of patients with AD (n = 20) and non-AD controls (n = 19) who displayed typical levels of core CSF biomarkers (Aβ42, P-tau, and total-tau). Discrete sample introduction ICP-MS/MS procedure was effective for accurate and precise CSF analysis. The methodology provided better sensitivities and limits of detection than a conventional one based on sample dilution and analysis in continuous sample introduction mode, while only requiring a 20 μL CSF sample volume. A total of 24 elements were encountered and quantified in CSF, with reduced levels of Mn, Cr, Se, Fe, and Zn in the CSF from AD patients and increased levels of Ag and Bi, compared with non-AD patients. Particularly, Mn fully discriminated AD from non-AD subjects, with binary regression analysis indicating that Mn was the most effective element to distinguish between AD and non-AD groups. Furthermore, distinctive correlation profiles were found between AD and non-AD controls for elements with AD core biomarkers and the alternative amyloidogenic sAPPβ fragment. Quantitative determination of metals, metalloids and non-metals displays differences associated with pathological status, serving as additional biomarkers for neurological diseases.
C-Myc Indirectly Controls ATP13A2 Levels via HIF-1α Activation.
Tiryakiler AB, Temizci B, Karabay A
J Neurochem · 2025 Nov · PMID 41292106 · Publisher ↗
c-Myc is an essential transcription factor controlling an extensive range of intracellular processes, and the abnormal activity of c-Myc is associated with many different complex diseases, such as different types of canc...
c-Myc is an essential transcription factor controlling an extensive range of intracellular processes, and the abnormal activity of c-Myc is associated with many different complex diseases, such as different types of cancer and neurodegenerative diseases. Understanding the regulatory functions of c-Myc has been challenging due to its intricate and multifaceted roles in cellular processes. The ATP13A2 (PARK9) gene encodes the ATP13A2 protein, which has important roles in lysosomal functions and metal ion transport. The association of ATP13A2 with Kufor-Rakeb Syndrome (KRS), as well as its role in Parkinson's disease, highlights its significance in maintaining cellular homeostasis. While our previous study indicated that c-Myc might play a role in the regulation of the ATP13A2 gene and its mutation linked to KRS, very little is known about the transcriptional regulation of the ATP13A2 gene. In this study, we identified potential c-Myc transcription factor binding sites on the ATP13A2 promoter and showed in vivo c-Myc binding using ChIP assay. qPCR and luciferase analyses revealed that the ATP13A2 transcription level was decreased upon 36 h of c-Myc overexpression. In contrast, western blot analysis revealed an increased ATP13A2 protein level under the same conditions. We further analyzed this discrepancy in a time-dependent manner, and results indicated that after c-Myc overexpression, ATP13A2 expression was markedly upregulated for the first 24 h, but this impact gradually decreased, returning to baseline levels by 72 h. Both HIF1α and p53 exhibited transient upregulation followed by a time-dependent decrease, suggesting that the initial increase in ATP13A2 may be regulated by c-Myc-driven HIF1α stabilization, which was supported by the elevated ATP13A2 expression and HIF1α stabilization by CoCl treatment. Prussian blue analysis indicated corresponding changes in intracellular iron accumulation with the temporal alterations in ATP13A2 expression. Our findings indicate that c-Myc indirectly causes an increased ATP13A2 expression by increasing HIF1α accumulation.
Extracellular Vesicles as Therapeutic Strategy for Ischemic Stroke.
da Silva EA, Figueiredo JCQ, Rossi EA … +6 more , Cunha RS, Sanches FS, de Lima AVR, Loiola EC, Costa-Ferro ZSM, Souza BSF
J Neurochem · 2025 Nov · PMID 41287994 · Full text
Ischemic stroke remains one of the leading causes of death and long-term disability worldwide, with current treatments limited by narrow therapeutic windows and the risk of hemorrhagic transformation. In this context, ex...
Ischemic stroke remains one of the leading causes of death and long-term disability worldwide, with current treatments limited by narrow therapeutic windows and the risk of hemorrhagic transformation. In this context, extracellular vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate inflammation and support neuroregeneration. This review explores recent advances in the application of EVs in ischemic stroke therapy, highlighting their mechanisms of action, including the delivery of neuroprotective molecules such as microRNAs and proteins that promote angiogenesis, neurogenesis, and anti-apoptotic pathways. We summarize findings from preclinical models demonstrating the regenerative potential of EVs derived from mesenchymal stem cells, microglia, neural progenitor cells, and other cell types, as well as advances in bioengineered EVs for targeted delivery. Despite encouraging results, the clinical translation of EV-based therapies faces challenges, including large-scale production, content variability, and targeted delivery efficiency. Future efforts should focus on optimizing EV characterization and manufacturing processes to ensure therapeutic consistency and safety.
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