Search Results (3,044)

Neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Lewy Body Disease (LBD), and related dementias, represent a global health challenge, particularly in aging populations. The simultaneous occurrence of neurodegenerative diseases in an aging population suggests a potential link between causative proteins. Such neurodegenerative proteins, including amyloid-β (Aβ), τ-protein (tau), α-synuclein, TAR DNA-binding protein 43 (TDP-43), and Fused in Sarcoma (FUS), share key characteristics of intrinsically disordered proteins (IDPs), which can explain promiscuous physical interactions, cross-seeding, co-occurrence, pathological synergy, and shared upstream and downstream mechanisms. This review synthesizes current evidence on (1) shared biophysical features of neurodegeneration-associated proteins, (2) mechanisms driving mixed neuropathology, (3) therapeutic implications of disorder-driven interactions, and (4) key unresolved questions shaping future research. By framing neurodegeneration as a network of interacting, disorder-driven proteinopathies rather than isolated entities, this perspective highlights the need for integrative, systems-level approaches to better understand disease heterogeneity and to identify novel targets for intervention. Full article

Hybrid renewable energy systems, which combine photovoltaic panels, wind turbines, batteries, generators, and grid connections, require careful sizing to balance economic performance, renewable integration, and supply reliability. In this context, this study proposes a deep reinforcement learning (DRL)-based sensitivity analysis framework in which the admissible energy contributions from the diesel generator and the grid are treated as explicit design-control parameters. The objective is to simultaneously minimize the levelized cost of energy, minimize the loss of power supply probability, and maximize the renewable energy fraction. A sensitivity analysis was conducted across different HRES configurations, load profiles, and tau/gamma values. The performance of the DRL approach was compared with that of multi-objective particle swarm optimization and the non-dominated sorting genetic algorithm II under the same study setting. The results indicate that DRL can identify competitive trade-offs, especially under standard load conditions, while also providing insight into how admissible backup-energy constraints reshape techno-economic and reliability compromises. The best trade-offs were observed around intermediate tau and gamma values, suggesting that moderate backup-energy margins are more favorable than extreme values. These findings should be interpreted within the scope of a simulation-based study and provide comparative design-oriented evidence rather than universally transferable design rules. Full article

This narrative review proposes the ‘Brain Health Triad’ as a novel integrative framework for neurorehabilitation and cognitive enhancement, built upon three interdependent biological pillars: neurostimulation, neurotrophy, and neuroprotection. We illustrate how the synergistic interplay between a ‘core triad’ composed of Hericium erinaceus, Bacopa monnieri, and L-Theanine targets these pillars with high specificity. Hericium erinaceus fosters neurotrophy by inducing Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF) synthesis through erinacines and hericenones; Bacopa monnieri complements this by enhancing neurostimulation and synaptic plasticity via bacosides; and L-Theanine regulates neurotransmitter balance and alpha-wave activity to stabilize the neural signaling environment. This core architecture is further reinforced by adjunctive nootropic clusters—including withanolides, ginkgolides, citicoline, cordycepin, macamides, and fulvic acid—which provide essential support for mitochondrial resilience and the mitigation of amyloid-β and tau toxicities. By synthesizing molecular evidence from the BDNF/TrkB/CREB signaling axis and the Nrf2/NF-κB homeostatic switch, we demonstrate that this multi-target strategy offers a more robust path to neuronal resilience than traditional single-target approaches. We conclude that this integrated model provides a solid framework for future clinical applications in the management of age-related cognitive decline and neurodegenerative diseases. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

Alzheimer’s disease (AD) is the leading cause of dementia, responsible for approximately 60–70% of cases globally. AD is a gradually progressive neurodegenerative disorder that is characterized by widespread deposition of β-amyloid (Aβ) plaques, followed by aggregation of tau protein in the neocortex, neurodegeneration, and cognitive decline. Within these complex pathological interactions, Aβ and tau proteins, together with astrogliosis, neuroinflammation, and other factors, play a key role in the development of clinical AD. Accumulating evidence indicates that the formation of protein oligomers, followed by their aggregation into pathological fibrils, constitutes an early and critical step in the pathogenesis of the disease. Specific pathological proteins are often treated as biomarkers of particular diseases because their presence, concentration, or altered structure reflects an underlying disease process. It is well established that the Aβ and tau proteins are the key hallmarks of AD, and their mutual interaction may significantly influence the pathology of the disease. Early diagnosis is crucial for maximizing the therapeutic benefits of currently available symptomatic treatments, which can alleviate symptoms and modestly delay clinical deterioration in patients with AD. This review highlights the mechanisms involved in protein-dependent neurodegeneration and describes both traditional and novel approaches for the cure of AD. The most important aspect of this publication is the integration of the two key proteins: Aβ and tau, and the resulting shift toward a new therapeutic approach. Full article

DP-128 is a multitarget benzonaphthyridine-6-chlorotacrine hybrid molecule with potent in vitro anticholinesterase and Aβ42 and tau anti-aggregating activity. While often used as a reference protein aggregation inhibitor, its further development as an anti-Alzheimer agent is limited by significant cytotoxicity, suboptimal aqueous solubility and microsomal stability. Since these drawbacks might arise from its rather high lipophilicity, in this work we have developed a series of more polar analogues, designed by structural modifications at the benzonaphthyridine or 6-chlorotacrine moieties or within the eight-atom linker. Half of the new analogues are indeed slightly more soluble and clearly less cytotoxic than DP-128, display single-digit acetylcholinesterase inhibitory activity, and retain the Aβ42 and tau anti-aggregating potency of the lead, as well as favourable brain permeation and high plasma stability. While further optimization of microsomal stability is necessary for a potential therapeutic use of this class of compounds, hybrids 16 and 17, with similar or even higher Aβ42 and tau anti-aggregating activity and lower cytotoxicity than DP-128, might represent novel pharmacological tools for protein aggregation studies. Full article

Transonic buffet is a critical self-sustained shock/boundary-layer instability limiting the flight envelope of modern transport aircraft. This study investigates the interaction between shock buffet and forced wing motion on the Airbus XRF-1 wind tunnel model, using unsteady Reynolds-Averaged Navier–Stokes (URANS) simulations with the DLR TAU code. The investigation is carried out in deep buffet condition ($\mathrm{Ma}=0.84$, $\alpha =4.5^{\circ }$, $\mathrm{Re}=25\times {10}^6$) and validated against wind tunnel data at the same flow condition. The buffet flow is superimposed with forced wing motions derived from a symmetric wing eigenmode at $\mathrm{Sr}=0.164$. Two different amplitudes scaled with the half-span s are considered: $A_{tip}=0.0025·s$ and $0.01·s$. The baseline no-forcing URANS captures the buffet flow quite well with only small deviations in the standard deviation of the surface pressure coefficient $c_{p,rms}$. A special variant of the Discrete Fourier Transformation for the whole wing upper surface $c_p$ distribution revealed that the typical buffet frequencies are also matched. The analysis of the forced simulations revealed a strong influence of the local wing motion on the increase of $c_{p,rms}$. The spectral content showed a shift and damping or amplification of different buffet modes, which is relevant for the interaction of motion induced and buffed induced aerodynamic forces. Full article

Alzheimer’s disease (AD) is primarily recognized for progressive cognitive decline driven by beta-amyloid accumulation and tau pathology. However, many individuals with AD also experience chronic pain and depressive symptoms, which significantly impair daily functioning and quality of life and increase caregiver burden. These non-cognitive features are frequently underrecognized, despite evidence suggesting they share overlapping biological pathways with neurodegeneration. Emerging data highlight the role of neuroinflammation, oxidative stress, hypothalamic–pituitary–adrenal axis dysregulation, and endocannabinoid system alterations in linking AD pathology to disturbances in pain processing and mood regulation. Persistent microglial activation, cytokine imbalance, redox disruption, and chronic stress signaling may simultaneously promote neuronal vulnerability while shaping affective and nociceptive responses. This review synthesizes current preclinical and clinical evidence on the interplay between pain, depression, and AD, emphasizing their shared pathophysiological mechanisms and clinical relevance. Recognizing these symptoms as integral components of disease progression, rather than isolated comorbidities, can inform the development of integrated, multidimensional therapeutic strategies in AD care. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Beyond genetic and proteostatic mechanisms, infection- and dysbiosis-based models of AD have gained renewed attention, including the antimicrobial protection hypothesis, in which Aβ may participate in innate immune defense. Here, we reanalyzed ribosomal depleted (Ribo-Zero) RNA-seq data from dorsolateral prefrontal cortex (DLPFC) samples from the Mount Sinai Brain Bank cohort (GSE53697) to screen for non-human transcripts. Reads underwent quality control and adapter trimming, taxonomic classification with Kraken2, abundance re-estimation with Bracken, and differential abundance testing with edgeR. Across 17 samples (9 advanced AD and 8 controls), we detected low-biomass microbial signals, with Acinetobacter radioresistens showing enrichment in the AD group (FDR = 0.018). Several additional taxa showed suggestive group differences but did not remain significant after multiple testing correction, including Lactobacillus iners (FDR = 0.051). We also performed an exploratory in silico analysis of an A. radioresistens biofilm-associated protein homolog, identifying predicted amyloidogenic motifs and surface-exposed regions that may be relevant to cross-seeding hypotheses, although no mechanistic inference can be drawn without experimental validation. Given the technical challenges of inferring microbial signals from post-mortem brain RNA-seq data, including contamination risk, low microbial biomass, and overwhelming host background, these findings should be interpreted as hypothesis-generating and warrant orthogonal validation in larger, microbiome-aware cohorts. Full article

Children with Autism Spectrum Disorder (ASD) frequently exhibit marked impairments in nonverbal communication, particularly in eye contact, which serves as a foundational element for social interaction and relational development. This study evaluated the effectiveness of an early intervention program utilizing interactive games supported by Augmented Reality (AR) technology to enhance eye contact behaviors, specifically initiation and maintenance, in children with autism. Using a multiple baseline across participants single-case experimental design, four boys (aged 5–7 years) diagnosed with ASD participated in an 8-week intervention at a specialized center in Saudi Arabia. The intervention featured tablet-based, gamified AR tasks incorporating real-time visual feedback, graduated difficulty levels, and reinforcement mechanisms designed to elicit social gaze and sustained eye contact. Eye contact duration and frequency were measured during structured social interactions via systematic direct observation. The results demonstrated significant improvements across all participants, with the mean duration of eye contact increasing from a baseline of 2.0 s to 5.8 s post-intervention. Visual analysis revealed robust treatment effects, further supported by substantial Tau-U effect sizes (range = 0.89–0.96; M = 0.93). Follow-up data collected three weeks post-intervention confirmed the maintenance of gains for three of the four participants. These findings suggest that AR-based interventions provide an effective and culturally responsive approach for enhancing specific nonverbal communication behaviors among children with autism in Middle Eastern contexts. Implications for clinical practice and directions for future research are discussed. Full article

The increasing prevalence of obesity and Alzheimer’s disease (AD) in the aging population underscores an urgent need to understand the common cellular and metabolic mechanisms they share. Accumulated evidence suggests that overlapping metabolic disturbances contribute to the pathogenesis of these two conditions. In this review, we highlight key underlying interconnecting metabolic pathways: (1) adipose-brain crosstalk mediated by adipokines and adipose tissue-derived extracellular vesicles that can modulate neuronal function and amyloid pathology, (2) dysregulated lipid metabolism affecting cholesterol, sphingolipids, and phospholipids and thereby promoting inflammation, amyloid precursor protein processing, and tau hyperphosphorylation, (3) impaired glycolysis and insulin resistance, which accelerate both obesity and neurodegenerative processes, (4) mitochondrial dysfunction marked by disrupted tricarboxylic acid cycle enzymes and electron transport chain complexes, leading to elevated reactive oxygen species and driving both obesity and AD pathology, and (5) gut microbiota dysbiosis, which can trigger inflammation as well as amyloid and tau aggregation. Together, these mechanisms show that metabolic alterations appear early, preceding clinical disease, and that understanding these underlying connections can provide strategies to protect metabolic health and prevent disease progression. Full article

Background: Polygenic risk scores for Alzheimer’s disease (AD), organized by gene networks shared between the blood and brain, may provide insights into underlying disease mechanisms common to both tissues. Methods: We derived a blood–brain network-based polygenic risk score (nbPRS) from AD-associated genetic variants for three blood-brain networks, selected by the preservation of blood and brain gene co-expression networks, and AD association. Participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n = 1109), Framingham Heart Study (FHS, n = 8310), the Religious Orders Study Memory Aging Project (ROSMAP, n = 1215), and Mount Sinai Brain Bank (MSBB, n = 323) were stratified into low- and high-nbPRS subgroups, then profiled using longitudinal and cross-sectional data. We compared the conversion from normal cognition to AD between nbPRS subgroups. Genes differentially expressed among low- and high-nbPRS individuals were profiled with classical neuropathological markers and we investigated potential biologically relevant pathways for the genes significantly expressed in high-risk individuals. Results: Individuals with high nbPRS in three AD-associated networks (M2, M6, M14) demonstrated significant impairment in executive function and memory performance, whereas high-risk individuals in networks M2 and M14 had significantly reduced hippocampal volume. We observed high-risk individuals in M2 and M14 developed AD at twice the rate of low-risk individuals in these networks. HLA genes were differentially expressed with transcriptome-wide significance among low- and high-nbPRS individuals in M14 and associated with neuroinflammatory and tau pathology. Conclusions: Polygenic risk scores derived from blood and brain networks can differentiate individuals with a high risk of AD conversion. Full article

Neurodegenerative diseases arise when normally functional aggregation-prone proteins transition into stable cross-β amyloid fibrils. Although these fibrils share a conserved architecture, the pathways that lead to fibrillation vary across proteins and cellular environments. Liquid–liquid phase separation is now recognized as a central organizer of intracellular biochemistry that modulates protein aggregation. Physiological condensation can buffer aggregation by maintaining macromolecular solubility and providing partner interactions that compete against pathological protein–protein interactions. However, condensates can transform and age into gel-like states that can favor the emergence of β-rich oligomers and solid-state fibrils. Across six disease-linked proteins that include Tau, ⍺-synuclein, amyloid-β, TDP-43, FUS, and hnRNPA1, we compare how sequence-encoded interaction motifs, cellular cofactors, and interfacial microenvironments shape the balance between physiological condensates and pathological amyloids. Here, we highlight the unifying drivers of aggregation and intervention points that preserve native function while limiting toxic amyloid formation. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, and mitochondrial dysfunction. Emerging evidence indicates that the gut microbiota plays a critical role in modulating neuroinflammatory, and metabolic pathways involved in AD pathogenesis through the microbiota-gut-brain axis. Objective: This systematic review aims to comprehensively evaluate the role of the microbiota-gut-brain axis in Alzheimer’s disease, with a particular focus on its mechanistic links to oxidative stress, mitochondrial dysfunction, and amyloid pathology, as well as its therapeutic potential. Methodology: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases, focusing on studies evaluating gut microbiota composition, metabolomic changes, oxidative stress markers, mitochondrial activity, and therapeutic interventions in AD models and patients. Results: Altered gut microbial composition in AD is associated with increased pro-inflammatory taxa (Escherichia-Shigella, Bacteroides) and depletion of short-chain fatty acid (SCFA) producing bacteria (Faecalibacterium, Roseburia). Dysbiosis contributes to systemic inflammation, disrupted intestinal permeability, and microglial activation, leading to oxidative damage and mitochondrial impairment in neurons. Preclinical and clinical studies indicate that probiotics, prebiotics, and fecal microbiota transplantation can restore redox balance, reduce neuroinflammation, and improve cognitive outcomes. Multi-omics and AI-based models are emerging as tools for identifying microbiome-derived biomarkers for early AD detection. Conclusion: The gut microbiota-mitochondria-oxidative stress axis represents a promising therapeutic target in Alzheimer’s disease. Future research should focus on longitudinal human studies, standardized microbial profiling, and personalized microbiome-based interventions to translate these mechanistic insights into clinical benefit. Full article

Alzheimer’s disease is a devastating progressive neurodegenerative disorder characterized by extracellular amyloid-beta plaques and intracellular tau tangles. Despite recent advancements in amyloid-beta-targeting immunotherapies, achieving safe and definitive disease control remains a profound clinical challenge. The CRISPR/Cas9 system has emerged as a powerful technology for precision neurogenetics, offering significant potential to address the fundamental questions behind Alzheimer’s disease. This comprehensive review delineates the trajectory of CRISPR applications in Alzheimer’s disease research and therapeutics. First, we explore the integration of CRISPR in engineering high-fidelity in vitro models, such as isogenic induced pluripotent stem cells and three-dimensional cerebral organoids, alongside advanced in vivo mammalian models. Second, we examine how these platforms facilitate unbiased high-throughput genetic screening to uncover molecular underpinnings regulating tau, lipid metabolism, and neuroinflammation. Third, we critically evaluate precision editing strategies targeting core risk genes (APP, MAPT, APOE, and TREM2), explicitly highlighting the severe physiopathological trade-offs between therapeutic efficacy and loss-of-function toxicity. Finally, we address the ultimate translational bottlenecks impeding clinical application. By dissecting the packaging limits of adeno-associated viral vectors and the physical barricade of the blood–brain barrier, we underscore the necessity of transitioning toward next-generation base editors and non-viral lipid nanoparticles to realize safe and efficacious in vivo clinical gene therapies against Alzheimer’s disease. Full article