Neurodegenerative Diseases Research Articles

The role of mitochondrial remodeling in neurodegenerative diseases.

Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

Oxidative stress of mitophagy in neurodegenerative diseases: Mechanism and potential therapeutic targets.

Neurodegenerative diseases are now significant chronic progressive neurological conditions that affect individuals' physical health. Oxidative stress is crucial in the development of these diseases. Among the various neurodegenerative diseases, mitochondrial damage has become a major factor in oxidative stress and disease advancement. During this process, oxidative stress and mitophagy plays an important role. In this paper, we introduced the role of mitophagy and oxidative stress in detail, and expounded the relationship between them. In addition, we summarized the pathogenesis of some neurodegenerative diseases and the mechanism of three antioxidants. The former includes AD, PD, HD and ALS, while the latter includes carnosine, adiponectin and resveratrol. Provide goals and directions for further research and treatment of neurodegenerative diseases. This review summarizes the impact of oxidative stress on neurodegenerative diseases by regulating mitophagy, provides a deeper understanding of their pathological mechanisms, and suggests potential new therapeutic targets.

The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.

Comprehensive In Silico Analysis of Uncaria Tomentosa Extract: Chemical Profiling, Antioxidant Assessment, and CLASP Protein Interaction for Drug Design in Neurodegenerative Diseases.

Uncaria tomentosa is a traditional medicinal herb renowned for its anti-inflammatory, antioxidant, and immune-enhancing properties. In the realm of neurodegenerative diseases (NDDS), CLASP proteins, responsible for regulating microtubule dynamics in neurons, have emerged as critical players. Dysregulation of CLASP proteins is associated with NDDS, such as Alzheimer's, Parkinson's, and Huntington's diseases. Consequently, comprehending the role of CLASP proteins in NDDS holds promise for the development of innovative therapeutic interventions. The objectives of the research were to identify phytoconstituents in the hydroalcoholic extract of Uncaria tomentosa (HEUT), to evaluate its antioxidant potential through in vitro free radical scavenging assays and to explore its potential interaction with CLASP using in silico molecular docking studies. HPLC and LC-MS techniques were used to identify and quantify phytochemicals in HEUT. The antioxidant potential was assessed through DPPH, ferric reducing antioxidant power (FRAP), nitric oxide (NO) and superoxide (SO) free radical scavenging methods. Interactions between conventional quinovic acid, chlorogenic acid, epicatechin, corynoxeine, rhynchophylline and syringic acid and CLASP were studied through in silico molecular docking using Auto Dock 4.2. The HEUT extract demonstrated the highest concentration of quinovic acid derivatives. HEUT exhibited strong free radical-scavenging activity with IC50 values of 0.113 μg/ml (DPPH) and 9.51 μM (FRAP). It also suppressed NO production by 47.1 ± 0.37% at 40 μg/ml and inhibited 77.3 ± 0.69% of SO generation. Additionally, molecular docking revealed the potential interaction of quinovic acid with CLASP for NDDS. The strong antioxidant potential of HEUT and the interaction of quinovic acid with CLASP protein suggest a promising role in treating NDDS linked to CLASP protein dysregulation.

Selecting a smartwatch for trials involving older adults with neurodegenerative diseases: A researcher's framework to avoid hidden pitfalls.

Increased prevalence of neurodegenerative diseases complicates care needs for older adults. Sensing technologies, such as smartwatches, are one available solution which can help address the challenges of aging. Knowledge of the possibilities and pitfalls of these sensing technologies is of key importance to researchers when choosing a device for a trial and considering the sustainability of these technologies in real-world settings. This study aims to uncover hidden truths related to the suitability of smartwatches for use in clinical trials which include older adults with neurodegenerative diseases, including end-of-life and palliative care studies. We perform an analysis of smartwatch features vs. user and researcher needs and provide an overview of hidden expenses which should be considered by the research team. Investigative research on 11 smartwatches is presented, selected based on previous use in clinical studies and recommendations from fellow researchers. We found that expenses, battery life, choice of research vs. commercial grade devices, data management, study methodology, and participant demographics are principal factors in selecting a smartwatch for a clinical trial involving older adults with neurodegenerative diseases. A revised framework based on our findings, and concepts from Connely (2021), Mattison (2023), and Espay (2019) et al.'s previous work, is presented as a tool for researchers in evaluation of smartwatches and future sensing technologies. Careful consideration must be given to the fitness of technologies for future research, especially considering that this is a rapidly changing field. The process of selection of a smartwatch for a clinical trial should be thoughtful, scrutinous, and include interdisciplinary collaboration.

Roles of SIRT3 in cardiovascular and neurodegenerative diseases.

Sirtuin-3 (SIRT3) in mitochondria has nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase activity. As such, SIRT3 is crucial in cardiovascular and neurodegenerative diseases. Advanced proteomics and transcriptomics studies have revealed that SIRT3 expression becomes altered when the heart or brain is affected by external stimuli or disease, such as diabetic cardiomyopathy, atherosclerosis, myocardial infarction, Alzheimer's disease, Huntington's disease, and Parkinson's disease. More specifically, SIRT3 participates in the development of these disorders through its deacetylase activity and in combination with downstream signaling pathways. The paper reviews SIRT3's expression changes, roles, and mechanisms associated with the development of cardiovascular and neurodegenerative diseases. Additionally, strategies targeting SIRT3 to treat or regulate cardiovascular and neurodegenerative disease development are discussed.

New perspectives on the glymphatic system and the relationship between glymphatic system and neurodegenerative diseases.

Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial fluid (ISF), facilitates the movement of metabolic substances within the brain, serving functions akin to those of the peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on the removal of pathological substances in ND. This article elucidates recent discoveries regarding the glymphatic system and updates relevant concepts within its model. It discusses the potential roles of the glymphatic system in ND, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA), and proposes the glymphatic system as a novel therapeutic target for these conditions.

The Activation of Microglia by the Complement System in Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs) are a group of neurological disorders characterized by the progressive loss of neuronal structure and function, leading to cognitive and behavioral impairments. Despite significant research advancements, there is currently no definitive cure for NDDs. With global aging on the rise, the burden of these diseases is becoming increasingly severe, highlighting the urgency of understanding their pathogenesis and developing effective therapeutic strategies. Microglia, specialized macrophages in the central nervous system, play a dual role in maintaining neural homeostasis. They are involved in clearing cellular debris and apoptotic cells, but in their activated state, they release inflammatory factors that contribute significantly to neuroinflammation. The complement system (CS), a critical component of the innate immune system, assists in clearing damaged cells and proteins. However, excessive or uncontrolled activation of the CS can lead to chronic neuroinflammation, exacerbating neuronal damage. This review aims to explore the roles of microglia and the CS in the progression of NDDs, with a specific focus on the mechanisms through which the CS activates microglia by modulating mitochondrial function. Understanding these interactions may provide insights into potential therapeutic targets for mitigating neuroinflammation and slowing neurodegeneration.

Understanding glucose metabolism and insulin action at the blood-brain barrier: Implications for brain health and neurodegenerative diseases.

The blood-brain barrier (BBB) is a highly selective, semipermeable barrier critical for maintaining brain homeostasis. The BBB regulates the transport of essential nutrients, hormones, and signaling molecules between the bloodstream and the central nervous system (CNS), while simultaneously protecting the brain from potentially harmful substances and pathogens. This selective permeability ensures that the brain is nourished and shielded from toxins. An exception to this are brain regions, such as the hypothalamus and circumventricular organs, which are irrigated by fenestrated capillaries, allowing rapid and direct response to various blood components. We overview the metabolic functions of the BBB, with an emphasis on the impact of altered glucose metabolism and insulin signaling on BBB in the pathogenesis of neurodegenerative diseases. Notably, endothelial cells constituting the BBB exhibit distinct metabolic characteristics, primarily generating ATP through aerobic glycolysis. This occurs despite their direct exposure to the abundant oxygen in the bloodstream, which typically supports oxidative phosphorylation. The effects of insulin on astrocytes, which form the glial limitans component of the BBB, show a marked sexual dimorphism. BBB nutrient sensing in the hypothalamus, along with insulin signaling, regulates systemic metabolism. Insulin modifies BBB permeability by regulating the expression of tight junction proteins, angiogenesis, and vascular remodeling, as well as modulating blood flow in the brain. The disruptions in glucose and insulin signaling are particularly evident in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where BBB breakdown accelerates cognitive decline. This review highlights the critical role of normal glucose metabolism and insulin signaling in maintaining BBB functionality and investigates how disruptions in these pathways contribute to the onset and progression of neurodegenerative diseases.

Environmental Mycotoxins: A Potential Etiological Factor for Neurodegenerative Diseases?

Mycotoxins are potential environmental risk factors for neurodegenerative diseases. These toxins penetrate the central nervous system via a compromised blood-brain barrier, which may cause oxidative stress and neuroinflammation, these can also contribute to amyloid-beta (Aβ) plaque accumulation, Tau protein hyperphosphorylation, and neurofibrillary tangle formation. Mycotoxins also activate microglia, cause neuronal apoptosis, and disrupt central nervous system function. This study examines the evidence linking mycotoxin exposure to neurodegenerative disorders like Alzheimer's and Parkinson's diseases. We explore mechanisms such as oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, neuroinflammation, and direct neurotoxic effects. Epidemiological studies show regional variations in mycotoxin prevalence and corresponding neurodegenerative disease incidences, supporting this association. We also review current approaches to mitigate mycotoxin exposure and discuss the challenges and opportunities in developing strategies to prevent or slow neurodegenerative disease progression. This work highlights the need for increased awareness and research on mycotoxins as modifiable risk factors in neurological health.

Biofilm-modified Prussian blue improves memory function in late-stage Alzheimer's disease mice with triple therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that is significantly characterized by cognitive and memory impairments, which worsen significantly with age. In the late stages of AD, metal ion disorders and an imbalance of reactive oxygen species (ROS) levels occur in the brain microenvironment, which causes abnormal aggregation of β-amyloid (Aβ), leading to a significant worsening of the AD symptoms. Therefore, we designed a composite nanomaterial of macrophage membranes-encapsulated Prussian blue nanoparticles (PB NPs/MM). Prussian blue nanoparticles (PB NPs) are capable of chelating Cu2+ and reducing ROS. Macrophage membranes (MM) have advantages over liposomal and erythrocyte membrane carriers, including inflammatory targeting capabilities and more effective immune evasion. Concurrently, the excellent photothermal ability of PB NPs can briefly open the blood-brain barrier (BBB) under near-infrared laser irradiation, which improves the transport efficiency of PB NPs/MM across the BBB and ablates Aβ deposition, thus achieving optimal therapeutic efficacy. In vitro experiments demonstrated that PB NPs/MM is a multifunctional nanosystem, which can effectively inhibit Cu2+-induced Aβ monomers aggregation, photothermally depolymerize Aβ fibrils, and attenuate oxidative stress through the combined treatment of chelating metals, photothermal therapy and scavenging ROS. In behavioral experiments, it also significantly improved the cognitive and learning deficits in late-stage APP/PS1 mice, thereby providing new ideas for the treatment of late-stage AD and other neurodegenerative diseases.

Revolutionising Neurological Therapeutics: Investigating Drug Repurposing Strategies.

Repurposing drugs (DR) has become a viable approach to hasten the search for cures for neurodegenerative diseases (NDs). This review examines different off-target and on-target drug discovery techniques and how they might be used to find possible treatments for non-diagnostic depressions. Off-target strategies look at the known or unknown side effects of currently approved drugs for repositioning, whereas on-target strategies connect disease pathways to targets that can be treated with drugs. The review highlights the potential of experimental and computational methodologies, such as machine learning, proteomic techniques, network and genomics-based approaches, and in silico screening, in uncovering new drug-disease correlations. It also looks at difficulties and failed attempts at drug repurposing for NDs, highlighting the necessity of exact and standardised procedures to increase success rates. This review's objectives are to address the purpose of drug repurposing in human disorders, particularly neurological diseases, and to provide an overview of repurposing candidates that are presently undergoing clinical trials for neurological conditions, along with any possible causes and early findings. We then include a list of drug repurposing strategies, restrictions, and difficulties for upcoming research.

Research on the protective effect of Rhizoma of Anemarrhena asphodeloides on TMT induced AD mice model based on network pharmacology combined with in vitro and in vivo experimental validation.

Alzheimer's disease (AD) is a neurodegenerative disease, and neuroprotection is an important approach to improving AD outcomes. Rhizoma of Anemarrhena asphodeloides (RAA) is a commonly used Traditional Chinese Medicine (TCM) with demonstrated neuroprotective effects, but its anti-AD mechanism requires further exploration. To elucidate the neuroprotective mechanism of RAA on TMT-induced AD mice. The AD mice model was established via intraperitoneal injection of TMT. The effect of RAA on ameliorating learning and memory was assessed using the Morris Water Maze (MWM) and Y-maze tests. Haematoxylin-Eosin (HE), Nissl, and TUNEL staining were used to observe the neuroprotective effect of RAA. The components in serum containing RAA (RAA-S) were detected using UPLC-Q-Orbitrap MS. Potential targets were predicted through network pharmacology and molecular docking. Serum levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPx) were measured with ELISA kits. The HT22 hippocampal neuronal cell line injured by l-glutamate (L-Glu) was used to further elucidate the mechanism of RAA. ROS levels in HT22cells were detected with the 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and flow cytometry. Apoptosis in HT22cells was measured by flow cytometry. The proteins MAP2, GAP-43, Nrf2, Keap1, HO-1, Bax, and Bcl-2 were detected by Western blotting. Immunofluorescence staining was employed to observe Nrf2 nuclear translocation. RAA significantly increased the residence time of mice in the W zone and enhanced the correct alternation rate in TMT-treated mice. RAA preserved the integrity and orderly arrangement of nerve cells. A total of 12 components were detected in RAA-S. AKT1, PPARG, CASP3, STAT3, HSP90AA1, and NFE2L2 (Nrf2) were involved in the RAA-S target pathway network. Molecular docking revealed that Nrf2 exhibited the highest average binding energy with all components in RAA-S. In vivo, RAA elevated MAP2, GAP-43, Nrf2, and HO-1 levels, along with GPx, GSH, and SOD activity, which had been reduced by TMT. Additionally, RAA reduced serum levels of MDA and ROS, which had been elevated by TMT. In vitro, RAA-S reduced HT22cell apoptosis and ROS accumulation caused by TMT. Furthermore, RAA-S promoted the expression of N-Nrf2 and HO-1 in L-Glu-injured HT22cells. RAA attenuated oxidative stress induced by TMT and L-Glu in AD model mice. The underlying mechanism was associated with the activation of the Nrf2/Keap1-HO-1 pathway.

Advanced lipidomics using UHPLC-ESI-QTOF-MS/MS reveals novel lipids in hibernating syrian hamsters.

Mammalian hibernation offers a unique model for exploring neuroprotective mechanisms relevant to neurodegenerative diseases. In this study, we employed untargeted lipidomics with iterative tandem mass spectrometry (MS/MS) to profile the brain lipidome of Syrian hamsters across different hibernation stages: late torpor, arousal, and euthermia (control). Previously, a lipid species identified as methyl-PA(16:0/0:0) showed a significant increase during torpor, but its precise structure was unresolved due to technological constraints. Leveraging iterative MS/MS and advanced lipid annotation tools (LipidAnnotator and MS-DIAL), we accurately annotated 377 lipid species, including the re-identification of methyl-PA(16:0/0:0) as methylated lysophosphatidic acid (PMeOH 16:0/0:0). This reannotation led to the discovery of two additional lipids during torpor: PMeOH 18:0/0:0 and PMeOH 18:1/0:0. Verification involved manual inspection of MS/MS spectra and Kendrick Mass Defect plots. The lipid alterations observed during torpor suggest biochemical adaptations to maintain membrane fluidity and protect against oxidative stress under hypothermic conditions. Elevated levels of PMeOH lipids and their lyso-forms may play roles in cell survival signalling. Additionally, a decrease in phosphatidic acid species and an increase in diacylglycerol species imply a metabolic shift favouring diacylglycerol production, potentially activating protein kinase C signalling pathways. The increased levels of monogalactosyl diglyceride lipids during torpor suggest a role in neuroprotection by enhancing oligodendrocyte function and myelination. Our comprehensive lipidomic profiling provides detailed insights into lipid dynamics associated with hibernation and underscores the potential of advanced MS/MS methodologies in lipidomics for developing therapeutic strategies against neurodegenerative diseases.

Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.

Concentric Ring Trajectory Sampling With k-Space Reordering Enables Assessment of Tissue-Specific T1 and T2 Relaxation for 2H-Labeled Substrates in the Human Brain at 7 T.

Deuterium metabolic imaging (DMI) is an emerging Magnetic Resonance technique providing valuable insight into the dynamics of cellular glucose (Glc) metabolism of the human brain invivo using deuterium-labeled (2H) glucose as non-invasive tracer. Reliable concentration estimation of 2H-Glc and downstream synthesized neurotransmitters glutamate + glutamine (Glx) requires accurate knowledge of relaxation times, but so far tissue-specific T1 and T2 relaxation times (e.g., in gray and white matter) have not been determined. Such measurements are time-consuming and particularly challenging in the presence of dynamically changing metabolite levels (e.g. 2H Glc and 2H Glx). This study aimed to assess T1 and T2 relaxation times of deuterated resonances, i.e., water, Glc and Glx in human gray and white matter using inversion recovery and Hahn spin-echo 2H MRSI (magnetic resonance spectroscopic imaging), respectively, with non-Cartesian concentric ring trajectory readout (CRT) including specific k-space reordering at 7 T. The sequence was validated using phantom measurements and all results were compared to unlocalized acquisitions. Thirteen healthy volunteers participated in the study, with 10 of them scanned ~90 min after oral administration of 0.8 g/kg [6,6'-2H]-glucose. Significantly different T1 and T2 relaxation was observed between GM and WM for 2H water (T1 GM/WM/unlocalized = 358 ± 21/328 ± 12/335 m ± 6 ms, p = 0.01) and 2H Glx (T2 GM/WM/unlocalized = 37 ± 2/35 ± 2/33 ± 3 ms, p = 0.02), respectively, consistent with unlocalized acquisitions. No significant regional differences were found for 2H water (T2 GM/WM/unlocalized = 36 ± 2/34 ± 2/31 ± 2 ms, p = 0.08), 2H Glc (T1 GM/WM/unlocalized = 70 ± 5/73 ± 4/80 ± 5 ms, p = 0.13; T2 GM/WM/unlocalized = 36 ± 1/34 ± 2/34 ± 2 ms, p = 0.24) and Glx (T1 GM/WM/unlocalized = 172 ± 15/172 ± 12/165 ± 11 ms, p = 1.00). Knowledge of tissue-specific relaxation times can enhance the accuracy of concentration estimation and metabolic flux rates in future studies, potentially improving our understanding of various brain diseases such as cancer, neurodegenerative diseases or diabetes, which are often linked to impaired glucose metabolism.

Copper exposure induces neurotoxicity through ferroptosis in C. elegans.

Copper, as a vital trace element and ubiquitous environmental pollutant, exhibits a positive correlation with the neurodegenerative diseases. Recent studies have highlighted ferroptosis's significance in heavy metal-induced neurodegenerative diseases, yet its role in copper-related neurotoxicity remains unclear. This study aimed to investigate the role of ferroptosis in copper-induced neurotoxicity. Previously, we established that copper induced motor behaviors inhibition and neuronal degeneration through oxidative stress in Caenorhabditis elegans (C. elegans). This study revealed that the behavior inhibition (head thrash, body bends, pumping frequency and defecation interval) and neuronal degeneration (GABAergic neurons and dopaminergic neurons) in copper-treated nematodes were reversed by the ferroptosis inhibitor Fer-1. Additionally, copper treatment increased the Fe2+ level and MDA content, and decreased GSH content, suggesting copper activated the ferroptosis in C. elegans. Furthermore, studies found that copper exposure altered the expression of ferroptosis-related genes gpx-1, ftn-1, and acs-17 in C. elegans. The results showed RNAi of gpx-1 and RNAi of ftn-1 significantly promoted Cu-induced neurotoxicity, while the RNAi of acs-17 appeared to rescue the Cu-induced ferroptosis and neurotoxicity. In conclusion, Cu might induce behavior inhibition and neuronal degeneration through ferroptosis in C. elegans. The findings of this study provided new insights in the mechanisms underlying Cu-induced neurotoxicity.

In vivo imaging markers of glymphatic dysfunction in amyotrophic lateral sclerosis: Analysis of ALPS index and choroid plexus volume.

The glymphatic system, essential for brain waste clearance, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Emerging imaging markers, such as the analysis along the perivascular space (ALPS) index and choroid plexus volume (CPV), may provide insights into glymphatic function, but their relevance to ALS remains unclear. To assess glymphatic dysfunction in ALS patients using the ALPS index and CPV. In this prospective single-center study, we analyzed 51 ALS patients and 51 age- and sex-matched healthy controls (HC). The ALPS index was calculated using diffusion tensor imaging, and 3D T1-weighted MRI was used for automated estimation of CPV and its fraction (CPV/total intracranial volume). Diagnostic performance was assessed using area under the receiver operating curve (AUC). Correlations between imaging markers and clinical parameters were also examined. ALS patients had a significantly lower ALPS index (ALS: 1.45±0.15; HC: 1.55±0.16; p=0.002) and higher CPV fraction (ALS: 0.12±0.04%; HC: 0.10±0.02%; p<0.001). The ALPS index and CPV fraction had AUCs of 0.70 and 0.72, respectively. A significant inverse correlation was observed between the ALPS index and CPV fraction (r=-0.31, p=0.002). Both markers correlated with aging but not with clinical disability or progression rate. This study identifies glymphatic dysfunction in ALS, as evidenced by changes in the ALPS index and CPV. Larger studies are warranted to validate these findings and assess their potential as biomarkers for ALS.

Actigraphy validation in behavioral variant frontotemporal dementia.

Actigraphy is increasingly being used to assess sleep in patients with neurodegenerative diseases. However, information on its accuracy relative to polysomnography (PSG) in this clinical population remains scarce. This study investigates the performance of actigraphy compared to PSG in patients with behavioral variant frontotemporal dementia (bvFTD), which is the leading form of early-onset dementia. Eighteen patients with bvFTD (10 males, mean age 70.50±8.48 years) underwent overnight, in-home PSG while concurrently wearing an actigraph on their non-dominant wrist. Actigraphy performance was assessed through discrepancy analysis, Bland-Altman plots, and epoch-by-epoch analysis (EBE). Analyses were conducted separately for the Cole-Kripke and UCSD scoring algorithms. Discrepancy analysis highlighted that the Cole-Kripke and UCSD algorithms overestimate total sleep time (by 43 and 60min, respectively) and sleep efficiency (by 7.13% and 10.33%, respectively). The Cole-Kripke algorithm also overestimates sleep onset latency (by 7.75min). Wake after sleep onset (WASO) showed a negative proportional bias for both algorithms, indicating that actigraphy underestimates WASO for subjects with longer PSG-measured WASO. In the EBE analysis, the Cole-Kripke algorithm shows an accuracy of 84% (sensitivity 93%, specificity 62%) and the UCSD algorithm an accuracy of 85% (sensitivity 96%, specificity 57%). In patients with bvFTD, actigraphy significantly overestimates total sleep time, sleep latency, and sleep efficiency, while underestimating WASO. Clinicians and researchers using actigraphy to study sleep in bvFTD must carefully consider these measurement biases and correct for them based on the results of previous comparison studies.

Potential molecular mechanisms of tobacco smoke exposure in Alzheimer's disease.

Smoking is detrimental to health, with tobacco use being a critical factor in the development of various neurodegenerative diseases, including Alzheimer's disease (AD), which progressively impairs brain function and poses a significant threat to public health. This study aims to examine the potential genetic alterations induced by smoking that are associated with AD and to investigate the underlying regulatory mechanisms. The research will provide theoretical foundations for targeted prevention and treatment strategies for AD. This study analyzed datasets from the Gene Expression Omnibus (GEO) and the Comparative Toxicogenomics Database (CTD) to identify genes affected by tobacco smoke exposure and those altered in patients with AD relative to normal controls. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using OmicShare tools to screen for key pathways. Key genes were identified by constructing protein-protein interaction networks (PPI) in the STRING database with the aid of CytoHubba. Additionally, the binding activity of the proteins encoded by these key genes to nicotine, the main component of tobacco, was analyzed using molecular docking techniques. Finally, the analytical results were verified using Quantitative Real-Time Polymerase Chain Reaction. The CTD identified 12,164 CE-related genes affected by tobacco smoke exposure. A comparison of these datasets yielded 94 common genes that were both influenced by tobacco and differentially expressed across all brain regions. The GO and KEGG pathway enrichment analyses showed that these common differentially expressed genes (DEGs) were predominantly enriched in the Wnt/β-catenin and PI3K-AKT signaling pathways. The DEGs' PPI network, constructed using the STRING database, highlighted key genes such as HSP90AB1, SOS2, MAGI1, and YWHAZ. Molecular docking studies demonstrated that nicotine binds effectively to the protein structures of these key genes, primarily through amino acid residues such as Ser and Glu. Experimental validation showed that HSP90AB1 and YWHAZ exhibited notable expression discrepancies under varying concentrations of cigarette smoke extract (CSE) treatments, particularly demonstrating a pronounced down-regulation trend at elevated concentrations. The study indicates that tobacco may impact the function of transmembrane transporter proteins and contribute to the development of AD by affecting key genes such as HSP90AB1 and YWHAZ, as well as signaling pathways like PI3K-AKT.