Human milk omega-3 PUFA and infant neurodevelopment: Evidence and insights from indian mothers.

Alzheimer's disease (AD) is a leading cause of death among the elderly, with no existing treatment. The development of therapies is further hindered by a limited understanding of the molecular pathogenesis and the absence of reliable early-detection biomarkers. Neuroimaging and lipidomic studies reveal structural and biochemical alterations in both gray and white matter in AD patients, including disruptions in membrane organization and neuronal signaling pathways. In the present work, we employed lipidomics-guided modeling of membranes in gray and white matter regions under healthy and diseased (AD) conditions, and used all-atom molecular dynamics (MD) simulations to examine how AD-associated alterations in lipid composition influence the structure, spatial organization, and micro-heterogeneity of neuronal plasma membranes. The data suggest that Alzheimer's disease-associated lipid alterations in gray matter (GM) and white matter (WM) impact membrane thickness and microdomain distribution, highlighting the critical role of lipid composition in maintaining neuronal membrane homeostasis and function. Higher-order cholesterol-ceramide-sphingomyelin-enriched domains are more abundant in the neuronal membranes of the GM region under diseased conditions. Under AD-mimicking conditions, lipidomic analyses demonstrate that neuronal membranes in GM experience more substantial compositional and structural remodeling than those in WM. Our results show significant changes in membrane microdomain distribution across the lipid bilayers, and, interestingly, these changes are more pronounced in the gray matter than in the white matter. This study establishes a framework for modeling the tissue-specific lipidomics data to understand how disease-driven compositional changes affect the structure, organization, and dynamics of biological membranes.

Signaling of glycoRNAs to Siglec-11 protects neurons by suppressing NF-κB.

Embryonic lead (Pb) contact impairs lipid, oxidative, and behavioral markers in zebrafish across multiple generations.

Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid-beta (Aβ) aggregates, in the form of fibrils and plaques. While it has largely been stated that Aβ oligomers are the main toxic species, significant evidence indicates that fibrils may also be relevant to AD pathogenesis. Notably, evidence indicates that while fibrils, through direct interaction with neuronal membranes, contribute to synaptic dysfunction and cellular damage, no direct evidence between fibrils and their impact on neuronal functions, including plasticity, was investigated. This study inquired into the impact of Aβ fibrils complex on neuronal function and membrane integrity, shedding light on their contribution to synaptic defects. Aβ fibrils were generated from Aβ1-42 oligomers, and their effects were evaluated on synaptic plasticity in ex vivo hippocampal slices from both female and male mice. Compared to Aβ1-42 oligomers, fibrils induced more severe damage in synaptic plasticity, emphasizing their potent neurotoxicity effect underlying cognitive decline. Additionally, using a liposomal model to examine fibril-membrane interactions, it was observed that Aβ fibrils are able to affect membrane fluidity compared to the Aβ1-42 oligomeric species, indicating that the size and aggregation state of Aβ fibrils are crucial for their toxicity. These findings challenge the view that oligomers are the primary toxic species in AD, showing that Aβ fibrils also play an active role in cellular dysfunction, promoting a synaptic dysfunction correlated to the cognitive impairment observed in AD.

Structural and functional compromise of the cellular membrane is a central mechanism in the pathogenesis of numerous diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. However, existing techniques for assessing membrane integrity often lack the ability to provide dynamic, whole-cell measurements and are limited to localized damage detection or population-level analysis. There is a growing need for methods capable of monitoring membrane integrity over time at the single-cell level and across the entire membrane surface. In this study, we present a microfluidic platform for real-time, label-free assessment of membrane integrity by analyzing dielectric properties. We apply this system to investigate how different aggregated forms of α-Synuclein (aSyn), a protein that plays a central role in the pathogenesis of Parkinson’s disease and disrupts neuronal membranes. Our platform integrates electrokinetic microdevices with 3D microelectrodes and imaging, enabling continuous analysis of up to 30 live neuronal cells per hour in flow. By measuring electrorotation responses, we quantify changes in plasma membrane capacitance in response to monomeric, oligomeric, and fibrillar aSyn. This approach allows direct, time-resolved comparison of membrane-disruptive effects across different aSyn conformations with single-cell resolution and whole-membrane sensitivity.

Blocking estrogen synthesis via aromatase inhibition helps prevent the recurrence of estrogen-receptor positive breast cancer but also results in cognitive, sleep and thermoregulatory disturbances. These side-effects diminish quality of life and contribute to treatment nonadherence in a large proportion of patients. DHED is a brain-selective prodrug that, in rodent models, converts to 17β-estradiol (E2) selectively in the brain without affecting the periphery. We investigated whether DHED could prevent side effects associated with the aromatase inhibitor letrozole in a primate model of aging. Chronic oral treatment with DHED in letrozole-treated male and female marmosets led to a robust increase in E2 levels across brain regions without affecting estrogen levels at the periphery. In addition, DHED treatment (1) improved memory at short delays and prevented letrozole-induced cognitive slowing in a hippocampal-dependent memory task; (2) normalized hippocampal neuronal membrane potential and excitability and (3) reduced sleep fragmentation. However, DHED treatment had opposite effects on thermoregulation in males and females, necessitating additional research in this area. Overall, the results suggest that DHED, which lacks estrogenic effects in peripheral tissues, could be a safe and effective novel hormonal therapy for improving quality of life in breast cancer patients treated with aromatase inhibitors.Significance statement Women with estrogen receptor positive (ER+) breast cancers take aromatase inhibitors to lower estrogens and reduce cancer recurrence. As a result, they often experience symptoms of estrogen deficiency that compromise treatment adherence. Here, we show that a brain-selective estrogen therapy administered orally via the prodrug DHED substantially increases estrogen levels in the marmoset brain without affecting the periphery and normalizes impairments in working memory, hippocampal neuronal excitability and sleep induced by aromatase inhibition. These findings in a translational primate model represent a significant advance for women's health by positioning DHED as a non-invasive, safe and efficient novel hormone therapy to improve quality of life of women with ER+ breast cancers.

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG trinucleotide in the exon 1 of the huntingtin gmodellerene. This abnormal expansion produces a mutant huntingtin (mHTT) protein with extended polyglutamine (polyQ) tracts. Although the molecular mechanisms underlying HD onset and progression remain poorly understood, aberrant folding, aggregation, and membrane interactions of mHTT are considered central to disease pathogenesis. In this study, we used molecular dynamics (MD) simulations to investigate the structural properties, dimerization propensity, and membrane lipid interaction of mHTT carrying 70 polyQ repeats (mHTT-Q70). Our analyses revealed that mHTT-Q70 retains partially structured α-helical conformations with increased flexibility within the polyQ domain, thus being predisposed to misfolding. Coarse-grained MD simulations further revealed a strong tendency of mHTT-Q70 to dimerize, indicating that early oligomerization may represent a critical step in protein aggregation. Interestingly, we show that membrane cholesterol content dose-dependently promotes dimeric mHTT-Q70—but not monomeric mHTT-Q70—association with neuronal membrane models, which was observed for 70% of simulation time at 40% cholesterol content. Such a cholesterol-dependent membrane binding of dimeric mHTT-Q70 suggests that membrane lipid composition may represent a critical checkpoint in the early stages of mHTT-Q70 aggregation, and of cytotoxicity thereof. Moreover, distinct neuronal membrane lipids like phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine differently contributed to mHTT-Q70 binding, highlighting the complexity of such a lipid-dependent modulation. Taken together, these findings underscore the dynamic interplay between polyQ-driven misfolding, dimerization, and membrane lipids in HD pathogenesis, suggesting that modulation of membrane composition, and in particular of cholesterol levels, may be a novel action point to design therapeutic drugs for HD.

Neuronal function relies on precise compartmentalization into dendritic, somatic, axonal, and synaptic domains that require specialized cellular architectures. Axons, in particular, can extend over extraordinary distances while preserving stable membrane composition, mechanical integrity, and reliable excitability. A submembranous scaffold composed of spectrin, ankyrin, actin, and associated proteins provides a conserved platform for coupling membrane proteins to cytoskeletal support and organizing membrane domains. In axons, this scaffold assembles into a membrane-associated periodic skeleton (MPS) with near-regular spacing that supports mechanical load, patterns membrane components, and contributes to compartmental boundaries. Comparative genetics indicates that core principles of spectrin-ankyrin organization are ancient, whereas vertebrate evolution expanded spectrin and ankyrin families and enabled specialized excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. Pathogenic variants in spectrin and ankyrin genes disrupt neuronal development and excitability and cause a growing spectrum of neurodevelopmental and neurodegenerative disorders, underscoring scaffold integrity as a key determinant of circuit stability. Here, we examine how conserved spectrin-ankyrin scaffold principles were adapted to neuronal cell-type diversity and domain specialization, with emphasis on axons, synapses, and disease, and we discuss how the membrane-associated periodic skeleton may function not only as a stabilizing framework but also as a nanoscale organizer of neuronal membrane architecture.

Neuronal cilia have emerged as crucial signaling hubs, yet their molecular composition and integration with synaptic communication remain poorly understood. Using a newly developed Arl13b-TurboID mouse model, we achieved robust cilia-specific biotinylation and proteomic profiling across diverse tissues and cell types. Comparative proteomics revealed notable tissue-specific specialization, with neuronal cilia uniquely enriched in synaptic proteins, adhesion molecules, and neurotransmitter receptors. Unexpectedly, several signaling and adhesion molecules localize to neuronal cilia in discrete nanodomains maintained by active retrieval mechanisms. In the mouse cortex, expansion microscopy revealed that the NMDA receptor subunit GluN1 is organized in nanodomains on neuronal ciliary membranes, which are precisely positioned to sample neurotransmitter efflux from neighboring glutamatergic synapses. These findings establish neuronal cilia as specialized extrasynaptic signaling platforms, with nanoscale organization enabling them to integrate local synaptic cues and modulate neuronal connectivity.

Genetically encoded voltage indicators (GEVIs) enable minimally invasive, cell‑type‑specific optical measurements of neuronal membrane potential with millisecond temporal resolution. Red‑shifted GEVIs are especially advantageous because they permit spectral multiplexing with complementary sensors and enable all‑optical circuit interrogation in combination with blue‑light‑activated opsins. Despite these advantages, existing red GEVIs remain poorly suited for in vivo use due to limited performance under two‑photon (2P) excitation, the predominant modality for deep‑tissue imaging. Here, we introduce VADER1, a red GEVI that overcomes this limitation and enables reliable spike detection in vivo under 2P illumination. Under 2P excitation, VADER1 supports extended voltage imaging with both random‑access and resonant‑scanning microscopy, enables recordings from neurons as deep as cortical layer 5, and allows dual-color imaging with calcium indicators. By filling a critical spectral gap, VADER1 enables integrated optical measurements of fast electrical activity alongside other neural signals and establishes a foundation for two‑photon all‑optical electrophysiology.

Diabetic neuropathy represents one of the most prevalent complications associated with diabetes mellitus. The pathophysiology of this condition is closely linked to oxidative stress and abnormalities in fatty acid metabolism, leading to compromised nerve perfusion. These factors are significant contributors to the pathogenesis of peripheral neuropathy in diabetic patients. Evening primrose oil is a rich source of essential fatty acids, notably gamma-linolenic acid (GLA) and linoleic acid. These fatty acids are critical components of myelin sheaths and neuronal cell membranes, playing a vital role in maintaining the structural integrity and functionality of the nervous system. Limited research exists regarding the impact of evening primrose oil on peripheral nerve function in human subjects. The present study aims to examine the Effect of Linoderm ointment, containing Evening Primrose Oil, Phonophoresis on patients with type 2 diabetes with neuropathy. In a single blind experimental study, 20 patients with diabetic neuropathy, including 39 feet, were examined. Patients were assigned to three groups and were treated during 6 sessions for 2 weeks. In the first group (Group A), ultrasound therapy was administered with a neutral and ineffective ointment (ultrasound gel). The second group (Group B) received ultrasound treatment plus Linoderm ointment (3g of Linoderm lotion from Barij Essans Company, containing 89% gamma-linolenic acid). The third group (Group C) was treated with Linoderm ointment, and the ultrasound device was turned off. All patients were assessed using the Visual Analogue Scale (VAS), the Michigan Neuropathy Screening Instrument, the Monofilament Test, and Nerve Conduction Studies at three points: before treatment, immediately following the last treatment session, and one-month post-treatment completion. Group C demonstrated the most consistent and statistically significant improvements within subjects over time, in all comparisons, indicating both immediate and sustained benefits from before treatment to one month after (p < 0.05). Group B showed moderate improvements, particularly in NCVp, NCVt, Monofilament, Michigan and visual analogue scale (VAS) scores (all p < 0.05 for Before-After and Before-One Month After comparisons), but many After-One Month After differences were nonsignificant (p > 0.05), suggesting that early gains were only partially maintained. Group A exhibited the weakest response, with limited short-term improvements in NCVp, NCVt, and VAS scores (Before-After p < 0.05) but little sustained change thereafter. A significant improvement in the Michigan score was observed in group A between the pre-treatment period and one month post-treatment. In Group A, monofilament test scores showed no statistically significant differences between any time points There were no significant differences between groups in terms of NCVp, NCVt, Michigan scores,, and VAS scores immediately after intervention and during follow- up except for monofilament score. The results of the present study indicate that using the topical Linoderm significantly enhances the characteristics of Nerve Conduction Velocity (NCV) and alleviates pain associated with diabetic neuropathy in these patients.

Transmembrane ionic flow through artificial ion channels is integral to the development of biohybrid electronics, such as neural interface technologies. However, achieving accurate and stable intracellular access through these synthetic analogues has remained a challenge. Here we use DNA origami tiles (0.8 nm diameter), anchored into live neuronal membranes, both with and without cholesterol tags, to demonstrate highly stable ion transport (net ~2 nS), channel-like stochasticity and intracellular drug delivery without disrupting neuronal physiology. These results are supported by molecular dynamics simulations. Using a suite of patch-clamp techniques, including two-photon-targeted variants, we obtain repeatable intracellular and quasi-intracellular voltage measurements across DNA tiles, eliminating the need for membrane break-in even from thin dendritic structures (~1 µm), which are inaccessible with standard electrodes. This advancement establishes an 'outside looking in' method to probe intracellular voltage dynamics using DNA nanostructure-based transmembrane access.

Perinatal LC-ω-3-PUFA supplementation offsets prenatal THC-induced cognitive deficit via sex-specific modulation of hippocampal neuroplasticity.

Acyl-CoA synthetase long-chain family member 6 (ACSL6) is a member of the long-chain acyl-CoA synthetase (ACSLs) family that is particularly expressed in nervous system. It mainly catalyzes the activation reaction of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA), providing substrates for the synthesis and remodeling of neuronal membrane lipids. Recent studies have shown that ACSL6 plays a decisive role in DHA enrichment, synaptic plasticity and antioxidant defense in the brain. Its dysfunction can lead to changes in membrane lipid composition, weakened synaptic signals and excessive activation of neuroinflammation, thereby causing neurological deficits like cognitive and motor disorders. This review comprehensively summarizes the molecular structure characteristics and catalytic mechanism of ACSL6, and analyzes the roles of its different domains in substrate recognition and reaction regulation. ACSL6 participates in lipid metabolism by converting DHA into DHA-CoA, forming a local DHA metabolic pathway and providing continuous energy supply for the structural stability and signal transmission of nerve membranes. The localization characteristics of ACSL6 enable the spatial directional distribution of DHA in the synaptic membrane and endoplasmic reticulum regions, which is a key link in maintaining brain lipid homeostasis. In addition, ACSL6 is involved in the defense mechanisms of the nervous system by regulating oxidative stress responses, ferroptosis and inflammatory pathways. Its dysregulation has been confirmed to be associated with various neurodegenerative diseases. A thorough clarification of the molecular mechanism of ACSL6 may provide a new theoretical basis and highlight potential avenues for future therapeutic exploration regarding the imbalance of lipid homeostasis in neurons and related diseases.

Circadian behaviors are controlled by dedicated brain pacemaker neurons, whose activity oscillate during the day and the night. The Drosophila brain contains ca. 240 such neurons. Their molecular clock is synchronized, but the phase of their rhythmic neural activity differs dramatically between functional groups. This explains how specific circadian neurons can for example promote morning or evening locomotor activity. To understand in depth how the circadian network functions, we surveyed its membrane proteome in the morning and evening, using in situ protein labeling and mass spectrometry. In addition to detecting known regulators of circadian behavior, we identified novel membrane or membrane-associated proteins present in circadian neurons. Through genetic screens, we found that many of these proteins regulate circadian behavior. In particular, Piezo regulates morning activity specifically under short photoperiod, and its loss compromises the structural plasticity of the clock neurons controlling locomotion at dawn. Our work thus illustrates the power of proteome-guided genetic screens to understand the mechanisms underlying circadian behavior.

Background and ObjectivesAnti-IgLON5 disease is a progressive neurologic disorder characterized by sleep disturbances, gait instability, involuntary movements, and bulbar dysfunction. In long-standing cases, autopsy studies reveal a brainstem-predominant neuronal tauopathy. The disease is defined by antibodies against the neuronal adhesion molecule IgLON5 (IgLON5-abs), which reduce IgLON5 membrane clusters and disrupt the cytoskeleton in vitro. Our aim was to investigate whether these pathogenic effects occur in vivo through passive antibody transfer.MethodsA passive transfer model was established by infusing CSF from patients with anti-IgLON5 disease or controls into the lateral ventricles of adult mice for 14 days via osmotic pumps. Motor and behavioral performance was evaluated using tests of coordination, sociability, anxiety-like behavior, and spatial memory. Mice were sacrificed at days 7, 18, and 30 for analysis of brain-bound human antibodies and quantification of total and synaptic IgLON5 clusters by confocal microscopy. Additional analyses included immunohistochemistry for phosphorylated tau, gliosis, and microglial activation.ResultsMice receiving anti-IgLON5 CSF exhibited impaired motor coordination in the beam-walking and rotarod performance. Behavioral alterations included reduced social interaction, increased anxiety-like behavior, weight loss, and increased liquid intake. Human IgG deposition was predominantly localized in the hippocampus and periventricular regions, coinciding with a reduction in total and synaptic IgLON5 clusters whereas levels of the postsynaptic marker PSD95 remained unchanged. The reduction in IgLON5 clusters persisted through day 30. Microglial activation was consistently observed in affected regions, but tau pathology and gliosis were absent.DiscussionThis passive transfer model demonstrates that IgLON5 antibodies reduce neuronal membrane IgLON5 clusters, accompanied by microglial activation and motor and behavioral alterations. These results support a pathogenic role of IgLON5 antibodies in anti-IgLON5 disease.

Associations between perfluoroalkyl substances and multiple sclerosis in U.S. cohorts compared with NMOSD, MOGAD, and healthy controls

We present a free and open-source, semi-automated, topologically robust pipeline for fitting cable models to 3D surface mesh morphology data of neuronal membranes, particularly suited to structures with complex shapes and topological holes. The motivation for this work is the discovery of morphologically complex neural spines on the auditory space-specific neurons of the barn owl (Tyto alba, Tyto furcata), dubbed “toric spines”, notable for their high curvature, branching density, and holes/loops. Multicompartmental simulation software requires morphology to be represented as cable models (e.g., SWC format), yet existing software tools for fitting cable models to complex 3D surface meshes have not produced satisfactory results for toric spines, and loops are generally unsupported. We present the Mesh and Skeleton Cable Fitting (MASCAF) pipeline and software, which fits a cable model (e.g., SWC format) to a surface mesh using mean-curvature flow skeletonization. In this paper, we demonstrate howMASCAFis applied to fit cable models, how loops can be reconstructed in simulations with theArborandNEURONsimulation software, and how the results can be validated using geometry and simulator-based methods. While non-tree morphologies such as toric spines are neuroanatomically special, our software pipeline provides a cable-model fitting approach for surface mesh data that is topologically robust, deterministic, open-source, and applicable to general morphologies, thereby closing a crucial gap between neuronal imaging and high-resolution simulation.

Disrupted calcium (Ca2+) homeostasis is a hallmark of neurodegenerative diseases, yet the mechanisms driving excessive Ca2+ entry at the neuronal plasma membrane remain poorly understood. Here, we show that α-synuclein pre-formed fibrils trigger a reorganization of voltage-gated calcium (CaV) channels in cultured mouse cortical neurons, increasing their clustering at the soma and dendrites. We find that α-synuclein fibrils promote cyclin-dependent kinase 5–mediated phosphorylation of KV2.1 at serine 603, enhancing its scaffolding capacity for CaV channels. Disrupting CaV–KV2.1 coupling with a competitive peptide or pharmacological CDK5 inhibition restores channel proximity to control levels. Functionally, the enhanced CaV clustering amplifies depolarization-evoked Ca2+ influx and drives aberrant excitation–transcription coupling, as reflected by elevated expression of the immediate early gene c-Fos. All effects were rescued by disrupting CaV–KV2.1 interactions or inhibiting CaV channel activity. These findings identify nanoscale CaV channel remodeling as a mechanistic link between α-synuclein pathology and Ca2+-dependent transcriptional dysregulation, positioning Parkinson’s disease as a nanostructural channelopathy.