International Journal of Molecular Sciences

Research

22 pages, 6114 KB

Open AccessArticle

Human and Mouse Alpha-Synuclein Fibrillation: Impact on h-FTAA Binding and Advancing Strain-Specific Biomarkers in PD Animal Models

by Priyanka Swaminathan, Vasileios Theologidis, Hjalte Gram, Debdeep Chatterjee, Per Hammarström, Nathalie Van Den Berge and Mikael Lindgren

Int. J. Mol. Sci. 2026, 27(9), 3807; https://doi.org/10.3390/ijms27093807 - 24 Apr 2026

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Abstract

Disease-specific alpha-synuclein (αsyn) strains have been linked to different synucleinopathies. Current αsyn biomarkers are limited to binary detection of pathogenic αsyn in peripheral tissue biopsies or fluids, limiting differential diagnosis. Hence, there is an urgent need for methods that allow strain-specific detection and [...] Read more.

Disease-specific alpha-synuclein (αsyn) strains have been linked to different synucleinopathies. Current αsyn biomarkers are limited to binary detection of pathogenic αsyn in peripheral tissue biopsies or fluids, limiting differential diagnosis. Hence, there is an urgent need for methods that allow strain-specific detection and characterization of αsyn strain architecture. Notably, luminescent conjugated oligothiophenes (LCOs) have been successfully used to detect distinct protein strain conformers in prion diseases and Alzheimer’s disease, highlighting their utility in differentiating disease-specific amyloid structures. Species-dependent differences in αsyn structure are increasingly recognized as one of the critical aspects that shape how fibrils form, propagate and interact with molecular LCO probes. Here, we evaluate the potential of the LCO h-FTAA to differentiate species-specific αsyn strains and conduct a translational investigation using peripheral cardiac tissue of a gut-first synucleinopathy rodent model. Our in vitro data demonstrate strain-specific probe–fibril interactions, reflecting a differential strain architecture and cellular micro-environment. While h-FTAA binds with comparable efficiency to mouse (mo-) and human (hu-) pre-formed fibrils (PFFs), h-FTAA exhibits markedly lower quantum yield when bound to moPFFs versus huPFFs. Spectral imaging revealed h-FTAA-moPFF binding produces blue-shifted maxima (505–550 nm), contrasting with the red-shifted maxima (545–580 nm) of huPFFs. Fluorescence lifetime imaging microscopy confirmed h-FTAA’s intrinsic sensitivity to species-dependent variations through distinct temporal fluorescence signatures (moPFFs: ~0.60–1.5 ns vs. huPFFs: ~0.65–1.0 ns). Our translational investigation showed h-FTAA binding to peripheral cardiac pathology exhibits comparable red-shifted emission, but distinct fluorescence lifetimes of h-FTAA-bound aggregates in moPFF-injected (~1.0–1.4 ns) versus huPFF-injected (~0.69–0.8 ns) rats. Interestingly, we observed distinct blue-shifted emission profiles in a few selected regions of the heart of moPFF-injected rodents, further characterized by extra-long fluorescence decay shifts (~1.5–1.9 ns), reflecting differences in both aggregate conformation and maturity in moPFF-induced compared with huPFF-induced rats. Taken together, our findings underscore the potential of LCO ligands, like h-FTAA, to enable more precise disease staging and diagnosis through peripheral biopsies, complementing existing αsyn biomarker methods. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

14 pages, 4921 KB

Open AccessArticle

by Olga Junemann, Dmitry Otlyga, Inna Bukreeva and Sergey Saveliev

Int. J. Mol. Sci. 2026, 27(7), 3093; https://doi.org/10.3390/ijms27073093 - 28 Mar 2026

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Abstract

The human pineal gland (PG) undergoes structural and cellular changes during the aging process, yet the underlying patterns and mechanisms remain insufficiently understood. In this study, we analyzed the lobular architecture and astrocytic network of the PG and identified two distinct pathways associated [...] Read more.

The human pineal gland (PG) undergoes structural and cellular changes during the aging process, yet the underlying patterns and mechanisms remain insufficiently understood. In this study, we analyzed the lobular architecture and astrocytic network of the PG and identified two distinct pathways associated with normal aging. The first is characterized by an increase in astrocyte number within the pineal parenchyma, suggesting a compensatory role in supporting pinealocyte function. The second pathway involves disruption of the lobular structure, leading to a decline in the functional integrity of the gland. While pathological conditions such as neurodegenerative and psychiatric disorders may accelerate pineal degeneration and reduce melatonin production, our results suggest that normal aging is the principal factor driving this involutional process. These findings contribute to a deeper understanding of the morphological aging pathways of the pineal gland and their potential functional implications. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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20 pages, 7006 KB

Open AccessArticle

Possible Role of Dopamine in the Enhancement of Intrahippocampal Arc Protein Expression Induced by Post-Learning Noradrenergic Stimulation of the Basolateral Amygdala

by Bogomil Peshev, Dimitrinka Atanasova, Pavel Rashev, Lidia Kortenska, Milena Mourdjeva, Despina Pupaki, Nikolaos Efstratiou, Nikolay Dimitrov and Jana Tchekalarova

Int. J. Mol. Sci. 2026, 27(3), 1273; https://doi.org/10.3390/ijms27031273 - 27 Jan 2026

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Abstract

Extensive research in laboratory rodents has shown that novelty exposure enhances the consolidation of memories for preceding or following low-arousal events by elevating dopamine release in the dorsal hippocampus (dHipp). Additionally, numerous studies have demonstrated that post-encoding noradrenergic activation of the basolateral amygdala [...] Read more.

Extensive research in laboratory rodents has shown that novelty exposure enhances the consolidation of memories for preceding or following low-arousal events by elevating dopamine release in the dorsal hippocampus (dHipp). Additionally, numerous studies have demonstrated that post-encoding noradrenergic activation of the basolateral amygdala (BLA) can also enhance memory consolidation in dHipp. Since the BLA is most active during emotionally arousing or stress-related situations, it was suggested that this nuclear complex mediates the effects of emotional salience on memory consolidation. However, it is presently unknown whether the reinforcement of memory storage in dHipp induced by novel and arousing environmental conditions results from the interaction between these two modulatory systems. To test the hypothesis of a functional interaction between dopaminergic and noradrenergic systems, this study assessed their combined effects on a low-arousal object-location (OL) task. Rats received post-training intra-BLA infusions of vehicle or clenbuterol (Clen), a selective β-adrenoceptor agonist. Novelty-induced dopamine release in the dHipp was enhanced by omitting habituation prior to training, and the contribution of dopamine signaling was further evaluated using pre-infusion administration of the D1/D5 receptor antagonist SCH 23390. The distribution of two important proteins for memory processing, namely the activity-regulated cytoskeleton-associated protein (Arc) and the phosphorylated form of the transcription factor, cAMP-response element-binding protein (pCREB) in the dHipp, was explored in a subset of rats perfused 60 min after the training phase. Stimulation of the BLA significantly increased the number of Arc- and pCREB-positive cells in several dHipp areas. The preceding application of SCH 23390, however, substantially decreased these effects in the same areas, i.e., the dentate gyrus (DG), CA2, and CA1 subregions for pCREB, and the CA3b, CA3c, CA2, and CA1 subregions for Arc. This interaction is considered essential for the initial stages of memory consolidation. The obtained results indicate the presence of a region-specific interaction between BLA modulatory inputs and intrahippocampal dopaminergic transmission, the mechanisms of which remain to be elucidated. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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35 pages, 3522 KB

Open AccessArticle

The Mechanism of LTX^N4C-Induced Ca²⁺ Influx Involves Latrophilin-Mediated Activation of Ca_v2.x Channels

by Jennifer K. Blackburn, John-Paul Silva, Evelina Petitto, Dietmar Cholewa, Elizaveta Fasler-Kan, Kirill E. Volynski and Yuri A. Ushkaryov

Int. J. Mol. Sci. 2025, 26(22), 11200; https://doi.org/10.3390/ijms262211200 - 19 Nov 2025

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Abstract

Store-operated Ca²⁺ entry (SOCE) is a key regulator of cytosolic Ca²⁺ (Ca²⁺_cyt). Presynaptic SOCE can be activated by ligands like α-latrotoxin, which acts through the presynaptic G-protein-coupled receptor latrophilin-1 (LPHN1), inducing Ca²⁺ influx and neurotransmitter release. To [...] Read more.

Store-operated Ca²⁺ entry (SOCE) is a key regulator of cytosolic Ca²⁺ (Ca²⁺_cyt). Presynaptic SOCE can be activated by ligands like α-latrotoxin, which acts through the presynaptic G-protein-coupled receptor latrophilin-1 (LPHN1), inducing Ca²⁺ influx and neurotransmitter release. To understand how SOCE-associated proteins contribute to LPHN1 signaling in neurons, we used mouse neuroblastoma NB2a cells as a genetically tractable neuronal model. The cells were stably transfected with exogenous LPHN1 or its non-signaling mutant and stimulated with the non-pore-forming α-latrotoxin mutant LTX^N4C, a known trigger of neurotransmitter release. LPHN1 expression increased the proportion of neuron-like cells and upregulated the voltage-gated Ca²⁺ channels Ca_v1.2 and Ca_v2.1. LPHN1 stimulation by LTX^N4C induced a small Ca²⁺ release sensitive to thapsigargin, and a strong, gradual influx of Ca²⁺, which was insensitive to thapsigargin. Single-cell imaging revealed that this influx consisted of desynchronized high-amplitude Ca²⁺ oscillations in individual cells. This response was reduced by Orai2 knockdown and completely blocked by the Ca_v2.1/2.2 inhibitor ω-conotoxin MVIIC. We conclude that LPHN1 activation by LTX^N4C primes Ca²⁺ stores and induces the opening of Ca_v2.1/2.2 channels. These channels mediate an initial Ca²⁺ influx that triggers Ca²⁺-induced Ca²⁺ release and SOCE. This mechanism, elucidated in model cells, can explain how LTX^N4C stimulates neurotransmitter release. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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24 pages, 5090 KB

Open AccessArticle

PAC1 Receptor Knockout Mice Reveal Critical Links Between ER Stress, Myelin Homeostasis, and Neurodegeneration

by Minduli Withana, Laura Bradfield, Margo I. Jansen, Giuseppe Musumeci, James A. Waschek and Alessandro Castorina

Int. J. Mol. Sci. 2025, 26(17), 8668; https://doi.org/10.3390/ijms26178668 - 5 Sep 2025

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Abstract

The pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1) plays a pivotal role in central nervous system development and homeostasis. Comparisons of PAC1 knockout (PAC1^−/−), heterozygous (PAC1^+/−) and wild-type (PAC1^+/+) mice demonstrate that PAC1 deficiency severely impairs pre-weaning [...] Read more.

The pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1) plays a pivotal role in central nervous system development and homeostasis. Comparisons of PAC1 knockout (PAC1^−/−), heterozygous (PAC1^+/−) and wild-type (PAC1^+/+) mice demonstrate that PAC1 deficiency severely impairs pre-weaning survival and results in marked developmental deficits, including reduced postnatal weight and altered locomotor behavior. PAC1^−/− mice exhibited hyperlocomotion, reduced anxiety-like behavior, and transient deficits in motor coordination. Gene expression analyses revealed widespread dysregulation of oligodendrocyte-associated markers, with significant myelin reduction and decreased mature oligodendrocyte density in the corpus callosum. ER stress was evidenced in both white matter and motor cortex, as indicated by altered expression of UPR-related genes and increased phosphorylated (p)IRE1⁺ neurons. Retinal morphology was compromised in PAC1^−/− animals, with reduced overall retinal and ganglion cell layer thickness. Notably, no gross morphological or molecular abnormalities were detected in the spinal cord regarding myelin content or MBP expression; however, synaptic marker expression was selectively reduced in the ventral horn of PAC1-deficient mice. Together, these findings highlight a critical role for PAC1 in oligodendrocyte maturation, retinal development, and synaptogenesis, providing new insights with relevance in multiple sclerosis and other neurodevelopmental and neurodegenerative conditions. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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18 pages, 1615 KB

Open AccessArticle

Spectroscopic Profile of Metabolome Dynamics During Rat Cortical Neuronal Differentiation

by Idália Almeida, Filipa Martins, Brian J. Goodfellow, Alexandra Nunes and Sandra Rebelo

Int. J. Mol. Sci. 2025, 26(16), 8027; https://doi.org/10.3390/ijms26168027 - 20 Aug 2025

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Abstract

Neuronal differentiation is a highly dynamic process marked by coordinated biochemical, structural, and metabolic changes. Rat primary cortical neurons are the preferred cell model to study this process as they can maintain their functional attributes, including functional synapses, and simulate the behavior of [...] Read more.

Neuronal differentiation is a highly dynamic process marked by coordinated biochemical, structural, and metabolic changes. Rat primary cortical neurons are the preferred cell model to study this process as they can maintain their functional attributes, including functional synapses, and simulate the behavior of neuronal cells in vivo. In this study, we employed Fourier transform infrared (FTIR) spectroscopy to monitor the molecular transformations that occur during the differentiation of rat cortical neurons. Partial least squares regression (PLS-R) analysis from the 1800–1500 cm⁻¹ region further allows the identification of the spectroscopic profile of early and late differentiation stages, highlighting the technique’s ability to detect subtle molecular changes. Further peak intensity analysis revealed significant changes in the cells’ metabolome during differentiation; it was possible to observe remodeling of protein secondary structures and an increase in protein phosphorylation levels, which can imply activation of signaling pathways essential for neuronal differentiation and maturation. Concomitantly, lipid-associated spectral regions demonstrated increased levels of total lipids, lipid esters, and longer acyl chains and decreased unsaturation levels, alterations that can be linked to membrane expansion throughout neuronal differentiation. These findings underscore FTIR spectroscopy as a valuable tool for studying neuronal differentiation, offering insights into the conformational and metabolic shifts underlying the formation of mature neuronal phenotypes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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13 pages, 1848 KB

Open AccessArticle

Expression of Dynorphin and Kappa-Opioid Receptors in the Bed Nucleus of the Stria Terminalis: Focus on Adolescent Development

by Albert R. Gradev, Pavel I. Rashev, Dimitrinka Y. Atanasova, Angel D. Dandov and Nikolai E. Lazarov

Int. J. Mol. Sci. 2025, 26(16), 7955; https://doi.org/10.3390/ijms26167955 - 18 Aug 2025

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Abstract

The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in drug addiction and anxiety. Dynorphin and kappa-opioid receptors (DYN/KOR) comprise a crucial neural system involved in modulating stress-induced drug and alcohol [...] Read more.

The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in drug addiction and anxiety. Dynorphin and kappa-opioid receptors (DYN/KOR) comprise a crucial neural system involved in modulating stress-induced drug and alcohol addiction. Previous studies have highlighted the BNST as a brain region with a strong DYN/KOR expression. However, no research has been conducted on the adolescent plasticity of this system. In the present study, we used 20- and 60-day-old Wistar rats to reveal the adolescent dynamics and possible sex differences of the DYN/KOR system in certain BNST nuclei associated with addiction behavior. We found a low expression of DYN in neuronal perikarya and a significant increase in DYN-containing nerve fibers in the lateral posterior and lateral dorsal nuclei of the rat BNST. In addition, an enhanced expression of KORs was observed in the examined BNST subnuclei with some sex differences favoring females, thus highlighting the importance of considering critical developmental differences between sexes in research. The dynamics of the DYN/KOR system observed in this study may help to explain the increased vulnerability of adolescents for developing drug and alcohol addiction. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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17 pages, 3248 KB

Open AccessArticle

Interneuron-Driven Ictogenesis in the 4-Aminopyridine Model: Depolarization Block and Potassium Accumulation Initiate Seizure-like Activity

by Elena Yu. Proskurina, Julia L. Ergina and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2025, 26(14), 6812; https://doi.org/10.3390/ijms26146812 - 16 Jul 2025

Cited by 1 | Viewed by 1363

Abstract

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine [...] Read more.

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K⁺] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K⁺]_o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K⁺-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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Review

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30 pages, 2034 KB

Open AccessReview

The Axon as a Self-Modifying Computational System: Autonomous Inference, Adaptive Propagation, and AI-Enabled Mechanistic Insight

by Matei Șerban, Corneliu Toader and Răzvan-Adrian Covache-Busuioc

Int. J. Mol. Sci. 2026, 27(4), 1826; https://doi.org/10.3390/ijms27041826 - 14 Feb 2026

Cited by 1 | Viewed by 739

Abstract

Research has demonstrated that axonal signaling processes are influenced by both static structural factors and dynamic metabolic and electro-dynamic processes. Imaging, computational modeling and research in molecular neuroscience have demonstrated that multiple processes contribute to axonal signal processing, including periodic rearrangement of cytoskeletal [...] Read more.

Research has demonstrated that axonal signaling processes are influenced by both static structural factors and dynamic metabolic and electro-dynamic processes. Imaging, computational modeling and research in molecular neuroscience have demonstrated that multiple processes contribute to axonal signal processing, including periodic rearrangement of cytoskeletal structures and membrane structures, and redistribution of ion channel clusters and organelles (such as mitochondria), which occur rapidly and transiently to modify excitability. The dynamics of energy production and distribution also vary between regions of the axon and at different time points during signal generation and transmission. Additionally, myelin-associated glia may temporarily modulate their metabolic and structural contributions to axonal conduction. Advanced AI-based techniques for mapping and simulating ultrastructure and the use of closed-loop perturbation experiments demonstrate that axons can generate multiple distinct electromechanical states, and therefore potentially influence both the timing of signals generated by the axon, the routing of signals to branches of the axon, and the robustness of signal propagation. While the existence of these adaptive microstates appears well established, there are many aspects of their influence on circuit level function that are poorly understood. In summary, these data support the concept that axonal conduction represents a continuum of reversible and state-dependent configurations generated by integrated interactions among molecular, structural and energetic processes. Therefore, this review will attempt to synthesize the available literature into a unified conceptual framework and identify areas of uncertainty that may direct future research into the adaptive processes underlying axonal computation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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23 pages, 1130 KB

Open AccessReview

Apolipoprotein E4 in Alzheimer’s Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment

by Nour F. Al-Ghraiybah, Amer E. Alkhalifa, Yutaka Itokazu, Taylor O. Farr, Naima C. Perez, Hande Ali and Amal Kaddoumi

Int. J. Mol. Sci. 2026, 27(2), 1004; https://doi.org/10.3390/ijms27021004 - 19 Jan 2026

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Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD [...] Read more.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Among the genetic risk factors linked to AD, the Apolipoprotein E4 (ApoE4) remains the strongest. It is well known that carrying the ApoE4 isoform is associated with advanced AD pathology, blood–brain barrier (BBB) disruption, and changes in lipid metabolism. In this review, we provide an overview of the role of centrally and peripherally produced ApoE in AD. After this introduction, we focus on new findings regarding ApoE4’s effects on AD pathology and BBB function. We then discuss ApoE’s role in lipid metabolism in AD, highlighting examples of lipid changes caused by carrying the ApoE4 isoform. Next, the review explores the implications of ApoE4 isoforms for current treatments—whether they involve anti-amyloid therapy or other pharmacological agents used for AD—emphasizing the importance of personalized medicine approaches for patients with this high-risk allele. This review aims to provide an updated overview of ApoE4’s effects on AD pathology and treatment. By integrating recent discoveries, it underscores the critical need to consider ApoE4 status in both research and clinical settings to enhance therapeutic strategies and outcomes for individuals with AD. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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15 pages, 476 KB

Open AccessReview

Incretin Mimetics as Potential Therapeutics for Concussion and Traumatic Brain Injury: A Narrative Review

by Samuel Sipos, Mirjana Jerkic, Ori D. Rotstein and Tom A. Schweizer

Int. J. Mol. Sci. 2026, 27(1), 45; https://doi.org/10.3390/ijms27010045 - 20 Dec 2025

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Abstract

Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood–brain [...] Read more.

Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood–brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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13 pages, 588 KB

Open AccessReview

Efficacy and Tolerability of Bupropion in Major Depressive Disorder with Comorbid Anxiety Symptoms: A Systematic Review

by Mario Pinzi, Alessandro Cuomo, Despoina Koukouna, Giacomo Gualtieri, Caterina Pierini, Maria Beatrice Rescalli, Simone Pardossi, Benjamin Patrizio and Andrea Fagiolini

Int. J. Mol. Sci. 2025, 26(24), 11767; https://doi.org/10.3390/ijms262411767 - 5 Dec 2025

Cited by 2 | Viewed by 4478

Abstract

Anxiety symptoms are highly prevalent in major depressive disorder (MDD) and are associated with greater severity, functional impairment, and poorer treatment outcomes. Bupropion is widely used in clinical practice and is generally considered to have a favorable tolerability profile, but its effects on [...] Read more.

Anxiety symptoms are highly prevalent in major depressive disorder (MDD) and are associated with greater severity, functional impairment, and poorer treatment outcomes. Bupropion is widely used in clinical practice and is generally considered to have a favorable tolerability profile, but its effects on comorbid anxiety remain uncertain. We conducted a PRISMA-guided systematic review of randomized controlled trials, pooled analyses, and open-label comparative studies evaluating bupropion in adults with MDD and clinically significant anxiety symptoms. Searches of PubMed, Scopus and Web of Science were performed through August 2025. Outcomes included validated measures of anxiety and depressive symptoms and reported tolerability. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence was evaluated using GRADE. Six studies (n ≈ 3700) met inclusion criteria. Anxiety was a predefined secondary outcome in some trials and a post hoc or exploratory measure in others. Across designs, bupropion was generally associated with improvements in anxiety and depressive symptoms on secondary or exploratory anxiety measures. In pooled patient-level analyses, SSRIs showed a modest advantage over bupropion in patients with high baseline anxiety, whereas individual randomized and open-label studies found no significant between-group differences. None of the included studies reported a clear signal of anxiety worsening with bupropion on the anxiety measures used. Tolerability findings indicated a lower risk of sexual dysfunction with bupropion compared with SSRIs, while insomnia occurred more frequently but was generally manageable. Low-certainty evidence suggests that bupropion may provide clinically relevant improvement in anxiety symptoms in adults with MDD, with generally comparable efficacy to SSRIs in most presentations but a modest SSRI advantage in highly anxious subgroups. Interpretation should consider that anxiety outcomes were often secondary or exploratory and that several studies were at risk of bias. Well-designed randomized trials with anxiety as a primary endpoint are needed. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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26 pages, 1700 KB

Open AccessReview

Multisystemic Impact of RNF213 Arg4810Lys: A Comprehensive Review of Moyamoya Disease and Associated Vasculopathies

by Eva Bagyinszky, YoungSoon Yang and Seong Soo A. An

Int. J. Mol. Sci. 2025, 26(16), 7864; https://doi.org/10.3390/ijms26167864 - 14 Aug 2025

Cited by 5 | Viewed by 3841

Abstract

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome [...] Read more.

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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38 pages, 1540 KB

Open AccessReview

Understanding the Pre-Clinical Stages of Parkinson’s Disease: Where Are We in Clinical and Research Settings?

by Camilla Dalla Verde, Sri Jayanti, Korri El Khobar, John A. Stanford, Claudio Tiribelli and Silvia Gazzin

Int. J. Mol. Sci. 2025, 26(14), 6881; https://doi.org/10.3390/ijms26146881 - 17 Jul 2025

Cited by 2 | Viewed by 4198

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. PD is characterized by motor and non-motor symptoms, but the diagnosis primarily relies on the clinical assessment of postural and movement abnormalities, supported by imaging and genetic testing. It is [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. PD is characterized by motor and non-motor symptoms, but the diagnosis primarily relies on the clinical assessment of postural and movement abnormalities, supported by imaging and genetic testing. It is widely accepted that the disease process begins decades before the onset of overt symptoms. Emerging evidence suggests that neuroinflammation plays a central role in the pathogenesis of PD, particularly during the pre-clinical phase. Activated microglia, increased levels of pro-inflammatory cytokines, and persistent oxidative stress have all been associated with the gradual loss of dopaminergic neurons. Although earlier detection and diagnosis remain elusive, achieving these goals is crucial for advancing prevention and disease-modifying strategies. Clinical studies are ongoing. To fill the gap, research models that recapitulate the chronic disease progression of PD are crucial to test preventive and disease-modifying strategies. This review briefly summarizes clinical knowledge on PD as a starting point for improving research models. Furthermore, we will critically evaluate how the existing models have been utilized and highlight opportunities to overcome their limitations and enhance the translational relevance to clinical application. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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100 pages, 15718 KB

Open AccessPerspective

Therapeutic Options for Alzheimer’s Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm

by Vladimir Volloch and Sophia Rits-Volloch

Int. J. Mol. Sci. 2026, 27(3), 1486; https://doi.org/10.3390/ijms27031486 - 2 Feb 2026

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Abstract

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer’s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies [...] Read more.

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer’s disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2α kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal Aβ (iAβ) accumulated to a PKR- and/or HRI-activating concentration and designated, in terms of the ACH2.0, as a “conventional stressor”. The ensuing disease is referred to, accordingly, as “conventional AD”. Any stressor other than iAβ, which is capable of activating one or more eIF2α kinases in neuronal cells, is designated as an “unconventional stressor”. At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as “unconventional AD”, at levels of iAβ below those required for activation of PKR and/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human AβPP mRNA is eligible for this process, and its asymmetric amplification yields 5′-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in AβPP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of AβPP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the AβPP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iAβ and C99, anti-antisense oligonucleotides (AASO) for AβPP RNA, and the restructuring of the 5′ terminus of AβPP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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