Journal of Neurochemistry最新文献

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD-related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane-bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.

Intrathecal immunoglobulin synthesis is a hallmark of neuroinflammatory diseases. Free kappa light chains (FLCK) in cerebrospinal fluid (CSF) have emerged as a sensitive biomarker of B-cell activity in the central nervous system (CNS), yet their relationship to immunoglobulin M (IgM) synthesis and polyspecific antiviral responses remains unclear. We aimed to delineate the diagnostic and immunological significance of FLCK in relation to intrathecal IgM production and the measles–rubella–zoster–herpes (MRZH) antibody reaction across a broad neurological spectrum. We retrospectively analyzed paired CSF and serum samples from 240 patients showing evidence of intrathecal immune activity, defined by oligoclonal bands (OCB), MRZH positivity, or IgM intrathecal fraction (IF) ≥ 10%. Intrathecal synthesis of immunoglobulin classes and FLCK was quantified using Reiber's hyperbolic reference functions. Patients were classified into multiple sclerosis (MS), noninfectious inflammatory neurological disease (NI-IND), infectious neurological disease (IND), neurodegenerative disease (NDD), tumor disease (TUM), and other neurological disease (OND). FLCK intrathecal synthesis (IF ≥ 10%) was detected in 81.7% of patients, including 98% of MS cases. FLCK levels were significantly higher in inflammatory and infectious diseases compared with non-inflammatory conditions (p < 0.001). A subset of OCB-negative but FLCK-positive patients exhibited intrathecal IgM synthesis, suggesting that FLCK capture non-IgG immune responses. In infectious diseases, high FLCK IF correlated with IgM synthesis, whereas in MS and autoimmune disorders, additional immunoglobulin classes likely contributed. FLCK levels also paralleled MRZH reactivity and were highest in patients with multiple viral antibody indices, particularly measles. These findings position FLCK as a quantitative and broadly applicable marker of intrathecal immunoglobulin synthesis across diverse CNS pathologies. FLCK may extend diagnostic sensitivity beyond IgG-based assays and aid in the integrative evaluation of cerebrospinal fluid biomarkers. Prospective studies should evaluate their prognostic value and specificity across neuroinflammatory and infectious diseases.

Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) are a well-established cause of amyotrophic lateral sclerosis (ALS). The mutations promote SOD1 misfolding, resulting in protein aggregation and motor neuron degeneration. SOD1 is normally a structurally stable enzyme, and the mechanisms underlying SOD1 misfolding remain poorly understood. Approximately one third of SOD1 in cerebrospinal fluid (CSF) exhibits an N-terminal truncation, the biological significance of which remains unclear. This is remarkable given the dramatic effects ALS-linked C-terminal truncations have on the enzyme. In this study, we identified the truncation site and investigated its impact on SOD1 stability and enzymatic activity. Edman degradation revealed the cleavage site between Asn-26 and Gly-27, generating a 26-residue peptide that was confirmed by mass spectrometry. We analyzed postmortem tissues from different parts of the central nervous system (CNS), including the choroid plexus, and found only trace amounts of N-terminally truncated SOD1. Biochemical characterization of the SOD1 in CSF was done by size exclusion chromatography, ion exchange chromatography, and mass spectrometry. Our findings demonstrate that SOD1 in CSF retains full enzymatic activity, that the N-terminally truncated variant is mainly present in heterodimers with native SOD1 subunits, and that the dimer remains folded and active, with both fragments of the truncated SOD1 fixed after proteolysis. Truncated SOD1 was absent in human plasma. In mice, only transgenically expressed human SOD1 underwent truncation in CSF, whereas endogenous murine SOD1 remained intact. Lastly, the N-terminal truncation does not induce misfolding, unlike the destabilizing effects observed with C-terminal truncations. The location where the truncation takes place and the underlying mechanism could not be identified. Whether the N-truncated SOD1 variant contributes to ALS pathogenesis remains to be determined.

Fetal alcohol spectrum disorders (FASD) result from exposure to alcohol (ethanol) during embryonic development. These diseases cause lifelong struggle for the affected patients. Due to the complex nature of how alcohol affects embryonic development, understanding of underlying mechanisms is lacking and treatment options are limited. Reliable diagnostic markers are also unavailable. As a start to bridge this hiatus, animal models have been proposed. One of the most recent ones among these animal models is the zebrafish. In this review, I focus on our own efforts that attempted to model the milder and most prevalent end of the spectrum of this disorder using zebrafish. We discovered that a short period (2 h-long) exposure of the zebrafish embryo to low doses of alcohol (up to 1% vol/vol external bath) at 24th hour post-fertilization led to a lifelong and dose-dependent impairment of social behavior (shoaling) in zebrafish, associated with an apparently selective disruption of dopaminergic neurotransmitter system responses. Here I review these findings and, for example, discuss how analysis of the neurochemistry of the zebrafish brain may aid our understanding of the mechanisms underlying embryonic alcohol-induced abnormalities. I theorize about how a non-selective and pharmacologically complex drug like alcohol may lead to the apparently selective impairment in shoaling and dopaminergic responses in zebrafish. Last, I briefly delineate future plans that may address questions including what specific brain areas, synaptic and molecular mechanisms may underlie the behavioral and neurochemical effects of embryonic alcohol exposure we have observed in zebrafish.

Exposure of the embryonic central nervous system (CNS) to drugs of abuse, such as ethanol, induces severe and persistent damage to neural cells, contributing to the development of fetal alcohol spectrum disorders (FASD). Previously, using a mouse model of FASD, we showed that prenatal alcohol exposure (PAE) directly impairs blood–brain barrier (BBB) development by inducing excessive angiogenesis, altering TJ protein and glucose transporter expression, and modifying the endothelial secretome in the neonatal cerebral cortex. Here, we investigated whether ethanol-induced effects on endothelial cells involve epigenetic reprogramming, specifically through alterations in DNA methylation profiles. Using human brain microcapillary endothelial cells (HBMECs) treated with ethanol, we observed reduced 5-methylcytosine (5mC) labeling intensity and DNA methyltransferase (DNMT) activity, accompanied by changes in the levels of DNMT1, DNMT3a, DNMT3b, methyl-CpG binding protein 2 (MeCP2), and vascular endothelial zinc finger 1 (VEZF1). These effects were associated with altered methylation levels at the promoters of BBB-related genes, including GLUT1 and CLDN5. Notably, ethanol-induced hypomethylation persisted over a prolonged period, even after ethanol withdrawal in HBMEC cultures. Treatment with S-adenosylmethionine (SAM) prevented ethanol-induced hypomethylation in vitro. In vivo, PAE resulted in increased cortical vascular permeability along with persistent vascularization deficits. Together, our findings suggest that ethanol induces long-lasting changes in endothelial cells that may compromise cerebral vasculature formation and function, with modulation of DNA methylation representing a potential molecular mechanism underlying these effects.

Glutathione is a major component of the cellular antioxidant system, providing a means of controlling redox homeostasis and affording protection against oxidative damage. Proton magnetic resonance spectroscopy (MRS) offers insights into brain metabolism by enabling the noninvasive quantification of metabolites. Previous studies have demonstrated that the neurotransmitters glutamate and GABA detected by MRS show activity-dependent concentration changes and correlate with cognitive performance. Yet how MRS detected antioxidant capacity, particularly glutathione levels, relates to cognition remains unclear. In this issue, Lee et al. report that higher cortical glutathione levels are associated with better cognitive outcomes in older adults. These findings might contribute to understanding whether glutathione levels index resilience or degeneration. However, observations reported across the literature remain inconsistent, and the observed discrepancies underscore the need for further research using harmonized MRS acquisitions, deeper metabolic and cognitive phenotyping, and longitudinal study designs to clarify the role of cortical glutathione in cognitive trajectories.

Microglia are the primary innate immune cells of the central nervous system and act as dynamic regulators of neural development, homeostasis, and response to injury. This review summarizes key discussions from the Glial Club South Cone Meeting 2025, focusing on (i) mechanisms and regulation of microglial phagocytosis and its dual role in tissue repair and neurodegeneration, (ii) the emerging immunometabolic and neuroprotective functions of the lipid-sensing receptor CD300f in aging and Alzheimer's disease models, and (iii) the context-dependent roles of autophagy in microglial activation, inflammation control and proteostasis. We highlight how phagocytic signaling (IFN, IL-6, “eat-me,” “don't-eat-me” cues), immune receptors and epigenetic regulation shape microglial states and function. Translational implications are discussed, including strategies to preserve beneficial microglial functions while limiting detrimental phagoptotic and pro-inflammatory responses. Identifying receptor-specific ligands, clarifying causal roles of phagocytosis in neurodegeneration, and dissecting autophagy-dependent quality-control pathways emerge as priority areas for future research.

Adult central nervous system (CNS) neurons exhibit limited intrinsic regenerative capacity, contributing to poor recovery after injury. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, yet their therapeutic potential in CNS repair remains incompletely understood. Here, we investigated whether adeno-associated virus (AAV) vector-mediated overexpression of miR-146a enhances neurite and axon regeneration in primary cortical neurons from Wistar rats. We found that AAV.miR-146a significantly increased neurite outgrowth, branching, and long-distance neurite regeneration following scratch injury. Using a microfluidic platform that allows us to selectively lesion axons, we further demonstrated that AAV.miR-146a robustly promotes axonal regrowth. Bioinformatic analyses revealed enrichment of miR-146a target genes involved in transcriptional regulation and synaptic function, with the inflammatory adaptor TRAF6 emerging as a key predicted target. Consistent with these predictions, AAV.miR-146a markedly reduced TRAF6 expression. Together, our results identify miR-146a as a promising therapeutic candidate for enhancing CNS axonal repair and highlight TRAF6 signaling as a potential mechanistic link to its regenerative effects.