Search Results (948)

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

Huntington disease (HD) is a debilitating, genetic disorder with a prevalence of 2.7 per 100,000 people. It is neurodegenerative, leading to cognitive, behavioral, and motor symptoms from neuronal loss within the striatum of the basal ganglia and cortex. Currently, the treatments involve symptomatic management, instead of treating the pathophysiology of the disease. Grape seed extract (GSE) is a complex mixture of polyphenols, proteins, and lipids with antioxidant and anti-inflammatory properties. This literature review examines the possibility of using GSE as a potential adjunctive therapy for HD. Preclinical studies have shown a neuroprotective effect through biologically plausible mechanisms. Clinical research has shown that GSE works on redox and inflammatory pathways related to the pathogenesis of HD. Although there are not many clinical trials on GSE in HD patients directly, the overlap of mechanisms behind both GSE and HD and the favorable side effect profile make GSE a potential adjunctive therapy. Targeted clinical investigation is warranted to determine the full therapeutic potential of GSE. Full article

Background/Objectives: Patient-derived cell lines retaining donor-specific age-related and genomic features are essential for modeling late-onset neurodegenerative disorders like Huntington’s disease (HD). This study aims to establish and comprehensively characterize HDDF2, a novel dermal fibroblast line from an HD patient, to provide a relevant cellular model. Methods: Dermal fibroblasts were isolated and cultured from a 44-year-old male HD patient carrying 46 CAG repeats in the HTT gene. Cells were evaluated for senescence markers (p16, lamin B1, SA-β-Gal activity, proliferation rates) and polyglutamine (polyQ) aggregation. Direct reprogramming protocols were applied to convert these fibroblasts into induced neurons. Results: HDDF2 fibroblasts exhibited a pronounced senescence-associated phenotype, evidenced by increased p16 expression, reduced lamin B1 levels, elevated SA-β-Gal activity, and decreased proliferation. Notably, polyQ deposition was preferentially detected within the senescent subpopulation, displaying distinct localization patterns differentiating senescent from proliferating cells. Despite this, HDDF2 cells retained their capacity for direct reprogramming and were successfully converted into induced neurons. Conclusions: HDDF2 represents a well-characterized, patient-specific cellular model for HD. The observed co-occurrence of polyQ deposition and cellular senescence, combined with successful neuronal conversion, establishes this line as a valuable resource for investigating the relationship between cellular aging and HD pathogenesis. Full article

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), involve the gradual loss of structure or function of neurons in the nervous system and are an increasing threat to the aging population worldwide. Although these disorders have different clinical features which affect cognition, movement and other vital body functions, they share key underlying molecular and cellular processes. This starts with protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, dysregulated protein homeostasis, neuroinflammation, and disrupted cell death pathways. Recent findings have added disease-specific processes, like amyloid-β and tau aggregates in AD, α-synuclein aggregation and mitophagy failure in PD’s, TDP-43-related impaired RNA metabolism in ALS, and mutant huntingtin causing transcription aberrations in HD. Protein interactome network analysis showed mechanistic crosstalk between pathogenic proteins of AD and PD. New evidence highlights how lysosomal dysfunction, endoplasmic reticulum stress, and microglial activation, act as a common axis in neurodegeneration. Advancements in genomics and epigenomics have found shared genetic risk loci and regulatory processes that affect how diseases develop and progress. Simultaneously, new biomarkers like circulating microRNAs, exosome-related pathological proteins, neurofilament light chain, inflammatory cytokines, and microglial activation markers are powering early diagnosis tools and disease variations. New imaging techniques also allow for the identification of protein aggregations before symptoms appear. Overall, these findings are accelerating targeted treatments and personalized medicine aimed at disease progression. This review highlights current insights into the molecular mechanisms of NDs and discusses new biomarkers and treatment targets that help future diagnostic and treatment strategies. Full article

Background/Objective: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive impairment, and psychiatric symptoms. As the disease progresses, weight loss, cachexia, and musculoskeletal atrophy are common, reducing quality of life, decreasing their autonomy in their activities of daily living (ADLs), and increasing morbidity and mortality risk. To describe and compare energy expenditure (EE) during ADLs and resting conditions in individuals with HD and healthy controls, and to examine its associations with quality of life, cognitive status, motor function, and functional capacity. Methods: A cross-sectional observational study was conducted with 16 people with manifest HD and 10 healthy controls. Participants completed five ADLs: resting, dressing, combing hair, feeding, and walking under laboratory conditions. EE during ADLs was measured using a portable indirect calorimetry system. Results: Statistically significant between-group differences in EE were found only during feeding, with individuals with HD showing higher EE than controls (p = 0.021). In the exploratory correlation analysis, cognitive status was significantly associated with EE during dressing (p = 0.033). Conclusions: This exploratory study contributes to the limited evidence on EE during ADLs in adults with HD. The findings suggest that individuals with HD may expend more energy than healthy controls during specific daily activities, particularly feeding. However, these results should be interpreted with caution due to the small sample size and preliminary nature of the study. Larger, multicenter, and longitudinal studies are needed to confirm these findings and determine their clinical relevance. Full article

Dopamine dysregulation is connected to several neurological disorders, including Parkinson’s disease, Huntington’s disease, and addiction. A new, precise, accurate, and specific reversed-phase high-performance liquid chromatographic method was developed for dopamine determination in different biological media (human/mouse plasma and mouse brain homogenate). The chromatographic assay was performed using Avantor ACE^® RP-18 (250 × 4.6 mm, 5 µm) column equipped with a suitable ODS pre-column. The temperature was ambient, and the mobile phase was composed of 10 mM potassium dihydrogen phosphate buffer (pH = 3) with 0.25 g/L sodium octanesulfonate, methanol, and acetonitrile at a volume-to-volume ratio of 75:20:5. Isocratic elution mode, flow rate 1.0 mL/min, and ultraviolet detection (280 nm) were applied. The procedure was validated for linearity, and all calibration curves were linear over the selected range with determination coefficients greater than 0.998. Intraday repeatability, expressed as the coefficient of variation, did not exceed 4.88% for the plasma and 3.32% for the mouse brain homogenate samples across all tested concentration levels. The proposed chromatographic method was evaluated in terms of greenness, whiteness, and blueness using three ecological metrics (the Analytical Greenness software, White Analytical Chemistry model, and Blue Applicability Grade Index). The optimized procedure was proven to be suitable for implementation in the routine analytical practice. Full article

Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle–Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer’s disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson’s disease dementias with visuospatial and attentional alterations; and Huntington’s disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile. Full article

Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin–proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies. Full article

Background: Artificial intelligence in medicine has largely relied on supervised training of disease-specific models, limiting scalability in conditions where labeled data are scarce. Large language models (LLMs), which encode broad medical knowledge through large-scale pretraining, offer an alternative paradigm in which structured physiological measurements can be interpreted directly without task-specific model training. Objective: To evaluate whether smartphone-derived ocular motor biomarkers can be translated into clinically meaningful probabilistic assessments of Huntington’s disease (HD) using general-purpose LLMs operating as inference engines. Methods: In this prospective proof-of-concept study, 26 participants (13 with genetically confirmed HD and 13 age-matched controls) completed a standardized ocular motor assessment using a custom smartphone application. Quantitative eye-movement metrics were validated against expert neurologist ratings. Structured physiological features were then provided to four general-purpose LLMs without task-specific training or diagnostic labels, and the models generated an AI-Assigned HD Probability Score (HAIPS). Discriminative performance and associations with clinical severity measures were evaluated. Results: Smartphone-derived ocular motor metrics showed strong agreement with clinician assessments (Spearman ρ = 0.76–0.95; all p < 0.001), confirming preservation of clinically meaningful physiological signals. LLM-derived HAIPS distinguished HD from controls with high accuracy (AUC 0.879–0.944), with no significant differences across models. Discrimination was statistically equivalent to a supervised logistic regression model trained on the same features. HAIPS correlated strongly with established measures of disease severity, including cognitive (MoCA, ρ = −0.86), functional (TFC, ρ = −0.74), and motor impairment (UHDRS, ρ = 0.85) (all p ≤ 0.003). Conclusions: Structured ocular motor biomarkers acquired using a consumer smartphone can be translated into clinically meaningful probabilistic assessments of HD by general-purpose LLMs without disease-specific model training. These findings support a framework in which physiologically grounded digital biomarkers are coupled with general-purpose inference models, potentially enabling scalable assessment in rare neurological diseases where labeled data are limited. Full article

Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases. Full article

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. Full article

The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington’s disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson’s disease, where epidemiology suggests an important role in dementia/Alzheimer’s disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration. Full article