Search Results (959)

Background/Objectives: The blood–brain barrier (BBB) remains a major obstacle to effective gene therapy for neurological disorders by limiting delivery of viral vectors, nanoparticles, and biologics to the central nervous system. Multiple strategies have been developed to transiently disrupt or bypass the BBB, including focused ultrasound (FUS) with microbubbles, osmotic agents, biochemical modulators, and receptor-mediated transport systems. Among these approaches, FUS-mediated BBB opening has emerged as the most spatially precise and clinically advanced strategy. Methods: This narrative review synthesizes recent preclinical and clinical literature on BBB microdisruption technologies for central nervous system gene therapy, with primary emphasis on FUS combined with microbubbles. We review BBB physiology, gene delivery platforms, the development of FUS technologies, optimization parameters, and translational evidence across neurological diseases from animal models through early-phase human studies. Results: FUS-mediated BBB opening has emerged as the leading method for transient barrier modulation. Preclinical studies in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, glioblastoma, amyotrophic lateral sclerosis, and lysosomal storage disorders demonstrate enhanced gene delivery, increased transgene expression, and improved functional outcomes. Large-animal studies and early clinical trials indicate that BBB opening is reversible, spatially controlled, and generally well tolerated. Clinical investigations have demonstrated successful delivery of therapeutic agents across neurological indications, with preliminary efficacy signals including improved drug penetration, metabolic changes, and potential survival benefits. Optimization of acoustic parameters, microbubble characteristics, and real-time cavitation monitoring remains critical for maximizing safety and therapeutic efficacy. Conclusions: BBB microdisruption, particularly through FUS with microbubbles, represents a transformative platform for central nervous system gene therapy. Continued research is needed to standardize treatment protocols, characterize long-term safety, and facilitate broader clinical translation. Full article

Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood–brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics—integrated diagnostic and therapeutic platforms—focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic “one-pill-for-one-disease” model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies. Full article

The neural circuits of the human brain are highly complex (due to the number of neurons and the diversity of synaptic connections), hindering the analysis of the pathological mechanisms of neurodegenerative diseases. Invertebrates with simple yet well-differentiated nervous systems have a natural advantage over mammalian model organisms in the identification of pathogenic genes and functional studies of neurodegenerative diseases. They can provide unique and profound insights into the pathogenesis of complex human neurodegenerative diseases and the formulation of intervention strategies. This article reviews the conserved mechanisms of three neurodegenerative diseases across species, including protein homeostasis imbalance and aggregation toxicity, mitochondrial dysfunction and metabolic abnormalities, axonal transport defects, and loss of synaptic function. Based on research on three invertebrates in the field of neurodegeneration, namely Caenorhabditis elegans (C. elegans), Drosophila melanogaster (D. melanogaster), and Bombyx mori (B. mori), we cover three major types of neurodegenerative diseases: Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aim is to find important inspirations for the future prevention and treatment of neurodegenerative diseases from the aspects of the material basis and existing treatment strategies. Full article

Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity. Full article

O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions. Full article

Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington’s disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood–brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington’s disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy. Full article

Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice. Full article

Cannabis sativa contains more than 120 phytocannabinoids, with Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the best characterized. This review synthesizes preclinical and clinical evidence on hemp-derived extracts, cannabinoids, and active compounds. THC primarily acts as a partial agonist at cannabinoid receptor type 1 (CB1) and type 2 (CB2), producing psychoactive, appetite-stimulating, antiemetic, and analgesic effects. CBD is non-intoxicating and has a multimodal profile involving CB1 negative allosteric modulation, CB2 inverse agonism or antagonism, inhibition of anandamide inactivation, and activity at 5-HT1A receptors, transient receptor potential channels, GPR55, and peroxisome proliferator-activated receptor gamma. Preclinical models of Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, epilepsy, and pain support anti-inflammatory, antioxidant, anti-excitotoxic, and glial-modulating mechanisms, but clinical translation remains uneven. The strongest evidence supports FDA-approved cannabidiol for Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex, and THC-based agents for refractory chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Moderate-certainty evidence supports nabiximols for multiple sclerosis spasticity and small benefits in selected chronic neuropathic pain populations. Evidence remains insufficient or negative for acute pain, insomnia, most psychiatric disorders, and many promoted indications. Key risks include cannabis use disorder, cognitive and psychiatric effects, cardiovascular events, sedation, high-dose CBD hepatotoxicity, and drug interactions. Rigorous, long-term, product-standardized trials are needed. Full article

Oxidative stress is a key player in the pathogenesis of aging and various neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and multiple sclerosis (MS), among others. Coupled molecules involved in chemical reduction-oxidation (redox) reactions regulate central signaling pathways and ensure the activation of cytoprotective mechanisms as needed. Such redox couples include oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD⁺/NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺/NADPH), and glutathione (GSSG/GSH), respectively. Under pathological conditions, concentrations of NAD⁺, NADPH, and GSH decrease, and an imbalance between the oxidized and reduced forms of these molecules develops. The current review focuses on the mechanisms that underlie these changes and their potential consequences for neurodegenerative processes and aging. The review also evaluates experimental studies on metabolic and genetic abnormalities associated with alterations in NAD⁺, NADPH, and GSH concentrations and highlights current research on strategies to regulate these compounds for neuroprotective purposes. Special attention is paid to understanding the interconnection between disturbed redox homeostasis and mitochondrial dysfunction, as this crosstalk is increasingly recognized as a crucial step in neurodegeneration. Integration of biochemical, genetic, and therapeutic perspectives provides a comprehensive understanding of redox imbalance in the pathogenesis of aging and neurodegenerative disorders. Therefore, these insights may contribute to the development of innovative interventions that target redox homeostasis, with the potential of increasing the human lifespan. Full article

Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single “best” model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research. Full article

Brain plasticity is often described as the capacity of the nervous system to change in response to development, experience, injury, disease, or treatment. That definition is useful, but it can obscure two clinically important points: plasticity is biologically constrained, and change is not always beneficial. This narrative review examines sex-dependent brain plasticity as a context-sensitive process rather than as a simple male–female contrast. We distinguish four operational outcomes of plasticity: (i) reparative plasticity, which restores structure or function; (ii) compensatory plasticity, which preserves performance through alternative or more costly strategies; (iii) insufficient plasticity, in which reorganization is too weak or unstable to sustain function; and (iv) maladaptive plasticity, in which plastic change reinforces dysfunction, pain, excitability, rigidity, or decline. We also define adaptive reserve as the integrated capacity of neural, glial, vascular, immune, metabolic, endocrine, and gene-regulatory systems to support useful reorganization under stress. The review evaluates endocrine, synaptic, neuroimmune, mitochondrial, vascular, stress-related, and epigenetic mechanisms, indicating where evidence for sex-dependent effects is relatively strong and where it remains indirect, inconsistent, or context-dependent. Disease examples include autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, intellectual disability, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, traumatic and ischemic injury, multiple sclerosis, chronic pain, aging, and systemic metabolic or inflammatory disorders. Throughout, biological sex is separated from gender-related social, diagnostic, and health-care determinants. We conclude that therapeutic strategies should not aim simply to enhance plasticity, but to guide it by matching intervention, timing, dose, biological readiness, and monitoring to the patient’s adaptive state. Full article

The kynurenine pathway (KP) constitutes the primary route of tryptophan catabolism, generating a spectrum of neuroactive metabolites that profoundly influence central nervous system function. Dysregulation of the KP is increasingly recognized as a critical pathogenic mechanism underlying diverse neuropathological conditions. This review critically evaluates the most widely cited mammalian cellular models currently utilized to delineate the causal role of KP alterations in neurological disease. Specifically, this article examines primary cell cultures, immortalized and tumor-derived cell lines, stem cell-derived systems, and ex vivo organotypic brain slices and tissues, highlighting their distinct methodological advantages, translational limitations, and specific enzymatic profiles. Across the described cellular systems, a recurring mechanistic theme emerges: quinolinic acid-driven mitochondrial dysfunction, oxidative stress, and NAD+ depletion converge in neurodegenerative conditions such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Conversely, kynurenic acid exhibits disorder-dependent—and at times opposing—roles, attenuating dopaminergic neurotoxicity in Parkinson’s disease models while contributing to synaptic pruning deficits in schizophrenia models. Furthermore, cellular models demonstrate that IDO1/TDO induction and downstream metabolite shifts are frequently cell type- and species-dependent, complicating direct extrapolation to human pathology. Because no single experimental system achieves complete physiological fidelity, elucidating the complex dynamics of the KP and identifying novel therapeutic targets requires the integration of data across complementary platforms. Full article

Neurodegenerative diseases (NDs) such as Alzheimer’s, Parkinson’s, and Huntington’s disease are progressive and currently incurable conditions characterized by the deterioration of neuronal structure and function. Its incidence is increasing, primarily driven by global aging, and it represents a significant public health concern. Traditional therapies offer only symptomatic relief and are unable to halt or reverse the underlying neurodegenerative processes. One of the key challenges in developing effective treatments is the presence of biological barriers, such as the blood–brain barrier (BBB), which limits drug delivery to the central nervous system (CNS), namely the brain. Nanotechnology has emerged as a promising tool to overcome these obstacles. Nanoparticles (NPs), due to their small size, biocompatibility, and versatility, can be engineered to cross the BBB, protect therapeutic agents from degradation, and deliver them precisely to target sites in the brain. This work explores the current advances in lipid and polymeric-based nanoparticle (LNPs and PNPs, respectively) drug delivery systems (DDS) and their application in preclinical studies for the treatment of the NDs previously mentioned. The presented studies suggest that this strategy holds great potential, offering new perspectives and emerging strategies to improve therapeutic outcomes for NDs, and promote neuroprotection of the brain. Full article

Huntington’s disease (HD) has traditionally been conceptualized as a neuron-centric disorder primarily attributed to cell-autonomous toxicity of mutant huntingtin (mHTT) in striatal medium spiny neurons. However, this framework inadequately explains the prolonged presymptomatic phase, selective network vulnerability, early non-motor manifestations, and limited success of neuron-targeted therapeutic interventions. Accumulating evidence from molecular biology, transcriptomics, neuroimaging, and preclinical therapeutics supports a reframing of HD as a disorder of neuroglial systems dysfunction. We synthesize data demonstrating that astrocytes, microglia, and oligodendrocyte lineage cells are not passive bystanders but play direct and interactive roles in HD pathogenesis through defined molecular mechanisms. Expression of mHTT in glial populations impairs synaptic homeostasis, metabolic coupling, immune resolution, and myelin integrity, generating self-amplifying pathological feedback loops that destabilize neural circuits long before overt neuronal death. Critically, we evaluate glial replacement therapy as a potential disease-modifying strategy. Preclinical studies demonstrate that transplantation of healthy human glial progenitor cells substantially ameliorates motor, cognitive, and neuropathological deficits in multiple HD models through oligodendroglial remyelination and lactate-mediated metabolic support, despite persistent neuronal mHTT expression. Effective HD therapy will likely require strategies that jointly target the genetic cause and the dysfunctional neuroglial microenvironment. By integrating systems neuroscience with glial biology and translational strategy, this review defines a neuroglial framework for HD that opens a plausible path toward meaningful disease modification and positions HD as a model disorder for glial-centric interventions in neurodegeneration. Full article

Background: Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), differ in etiology but share several convergent pathological mechanisms. Pterostilbene (PTR) is a natural stilbene with reported antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to prioritize putative PTR-associated targets and biological processes potentially relevant to shared neurodegenerative mechanisms. Methods: An integrative in silico workflow combining network pharmacology, protein–protein interaction (PPI) analysis, GO Biological Process (GO BP) enrichment, molecular docking, and molecular dynamics (MD) simulations was applied. GO BP terms were filtered, focused on neurodegeneration- and neuroprotection-related processes, and subjected to REVIGO-based redundancy reduction. Selected targets were further evaluated by docking and 500 ns MD simulations. Results: A total of 181, 165, 128, and 109 shared PTR–disease targets were identified for AD, PD, HD, and ALS, respectively. Redundancy-reduced GO BP analysis indicated associations with neuroinflammation, oxidative stress and reactive oxygen species-related responses, programmed cell death, MAPK/ERK- and PI3K/AKT-related signaling, ion and calcium transport, and lipid-, steroid-, or hormone-associated regulation. PPI topology prioritized SRC, ESR1, and HSP90AA1 as recurrent hub–bottleneck proteins, whereas MD-based structural interpretation focused on ESR1 and HSP90AA1. MD analyses indicated stable PTR interactions with both proteins, with ESR1 showing the most favorable predicted interaction profile. Conclusions: These findings suggest that PTR may interact with shared neurodegeneration-relevant molecular systems, particularly through ESR1- and HSP90AA1-associated mechanisms. However, the results are exclusively computational and should be interpreted as hypothesis-generating, requiring further experimental validation. Full article