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Talanta Jun 2024Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has...
Dysregulation of peptidyl arginine deiminase 4 (PAD4) is involved in a variety of diseases including rheumatoid arthritis (RA) and Alzheimer's disease (AD), and it has emerged as potential and promising therapeutic target. However, no PAD4 inhibitor is ready for clinical use. Immobilized enzyme screening technology has gained increasing attention due to its low cost, reusability, easy separation from the reaction mixture, and resistance to changes in environmental conditions. In this study, PAD4 was immobilized on the magnetic nanoparticles (MNP) to prolong its activity stability, and a simple and rapid screening strategy of traditional Chinese medicine inhibitors based on immobilized PAD4 was established. The PAD4 enzyme was immobilized on magnetic nanoparticles (MNP) via Schiff base reaction using glutaraldehyde (GA) as crosslinking agent. Compared with free PAD4, the resulting MNP@GA@PAD4 exhibited an enhanced tolerance to temperature and storage stability, and its reusability was greatly improved with 66 % of initial enzyme activity after being recycled 10 times. The inhibitory activity of the immobilized PAD4 was assessed using two known PAD4 inhibitors GSK484 and BB-Cl-amidine. The semi-maximum inhibitory concentrations (IC) of GSK484 and BB-Cl-amidine for MNP@GA@PAD4 were 1.00 and 0.97 μM, respectively, for free PAD4 were 0.64 and 0.85 μM, respectively. Finally, the MNP@GA@PAD4 was employed to rapid screen of natural PAD4 inhibitors from forty traditional Chinese medicines (TCMs). Under the same conditions, the controlled experiment was conducted with free PAD4. The screening results of TCMs inhibitors on MNP@GA@PAD4 and free PAD4 were similar, the alcohol extracts of Cinnamomi Cortex and Caryophylli Flos had significant inhibitory effects on PAD4 enzyme activity. The IC values of Cinnamomi Cortex extract for MNP@GA@PAD4 and free PAD4 were determined as 27 and 48 μg/mL, respectively. The IC values of Caryophylli Flos extracts for MNP@GA@PAD4 and free PAD4 were determined as 48 and 32 μg/mL, respectively. For the first time, this study proposed a method to immobilize PAD4 on magnetic materials, and developed a rapid, reusable and feasible strategy to screening natural PAD4 inhibitors from TCMs.
PubMed: 38955099
DOI: 10.1016/j.talanta.2024.126492 -
Computer Methods and Programs in... Jun 2024Alzheimer's disease dementia (ADD) is well known to induce alterations in both structural and functional brain connectivity. However, reported changes in connectivity...
BACKGROUND AND OBJECTIVE
Alzheimer's disease dementia (ADD) is well known to induce alterations in both structural and functional brain connectivity. However, reported changes in connectivity are mostly limited to global/local network features, which have poor specificity for diagnostic purposes. Following recent advances in machine learning, deep neural networks, particularly Graph Neural Network (GNN) based approaches, have found applications in brain research as well. The majority of existing applications of GNNs employ a single network (uni-modal or structure/function unified), despite the widely accepted view that there is a nontrivial interdependence between the brain's structural connectivity and the neural activity patterns, which is hypothesized to be disrupted in ADD. This disruption is quantified as a discrepancy score by the proposed "structure-function discrepancy learning network" (sfDLN) and its distribution is studied over the spectrum of clinical cognitive decline. The measured discrepancy score is utilized as a diagnostic biomarker and is compared with state-of-the-art diagnostic classifiers.
METHODS
sfDLN is a GNN with a siamese architecture built on the hypothesis that the mismatch between structural and functional connectivity patterns increases over the cognitive decline spectrum, starting from subjective cognitive impairment (SCI), passing through a mid-stage mild cognitive impairment (MCI), and ending up with ADD. The structural brain connectome (sNET) built using diffusion MRI-based tractography and the novel, sparse (lean) functional brain connectome (ℓNET) built using fMRI are input to sfDLN. The siamese sfDLN is trained to extract connectome representations and a discrepancy (dissimilarity) score that complies with the proposed hypothesis and is blindly tested on an MCI group.
RESULTS
The sfDLN generated structure-function discrepancy scores show high disparity between ADD and SCI subjects. Leave-one-out experiments of SCI-ADD classification over a cohort of 42 subjects reach 88% accuracy, surpassing state-of-the-art GNN-based classifiers in the literature. Furthermore, a blind assessment over a cohort of 46 MCI subjects confirmed that it captures the intermediary character of the MCI group. GNNExplainer module employed to investigate the anatomical determinants of the observed discrepancy confirms that sfDLN attends to cortical regions neurologically relevant to ADD.
CONCLUSION
In support of our hypothesis, the harmony between the structural and functional organization of the brain degrades with increasing cognitive decline. This discrepancy, shown to be rooted in brain regions neurologically relevant to ADD, can be quantified by sfDLN and outperforms state-of-the-art GNN-based ADD classification methods when used as a biomarker.
PubMed: 38954916
DOI: 10.1016/j.cmpb.2024.108290 -
Scientific Reports Jul 2024Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization...
Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval.
PubMed: 38956440
DOI: 10.1038/s41598-024-65364-y -
ACS Applied Materials & Interfaces Jul 2024Alzheimer's disease (AD) has a complex etiology and diverse pathological processes. The therapeutic effect of single-target drugs is limited, so simultaneous...
Alzheimer's disease (AD) has a complex etiology and diverse pathological processes. The therapeutic effect of single-target drugs is limited, so simultaneous intervention of multiple targets is gradually becoming a new research trend. Critical stages in AD progression involve amyloid-β (Aβ) self-aggregation, metal-ion-triggered fibril formation, and elevated reactive oxygen species (ROS). Herein, red blood cell membranes (RBC) are used as templates for the in situ growth of cerium oxide (CeO) nanocrystals. Then, carbon quantum dots (CQDs) are encapsulated to form nanocomposites (CQD-Ce-RBC). This strategy is combined with photothermal therapy (PTT) for AD therapy. The application of RBC enhances the materials' biocompatibility and improves immune evasion. RBC-grown CeO, the first application in the field of AD, demonstrates outstanding antioxidant properties. CQD acts as a chelating agent for copper ions, which prevents the aggregation of Aβ. In addition, the thermal effect induced by near-infrared laser-induced CQD can break down Aβ fibers and improve the permeability of the blood-brain barrier. In vivo experiments on APP/PS1 mice demonstrate that CQD-Ce-RBC combined with PTT effectively clears cerebral amyloid deposits and significantly enhances learning and cognitive abilities, thereby retarding disease progression. This innovative multipathway approach under light-induced conditions holds promise for AD treatment.
PubMed: 38954799
DOI: 10.1021/acsami.4c02088 -
Issues in Mental Health Nursing Jul 2024Electrophysiological biomarkers are being examined as potential diagnostic measures of cognitive impairment and its manifestations for psychiatric nurses' use in the... (Review)
Review
Electrophysiological biomarkers are being examined as potential diagnostic measures of cognitive impairment and its manifestations for psychiatric nurses' use in the care of Alzheimer's disease (AD). However, there is no integrative review describing the themes from the current research about electrophysiological biomarkers and the developing relationship among the themes. Characterizing this developing relationship is imperative for any possible integration of biomarkers into the care of AD by psychiatric nurses. The purpose of this integrative review is to identify themes from the current research about electrophysiological biomarkers of AD and the developing relationship among the themes, the conceivable relational premise for psychiatric nurses to integrate electrophysiological biomarkers into the screening, assessment, diagnosis, and treatment of AD for the care of persons with AD. A literature search was executed with PUBMED (accessing Medline and Elsevier) and CINAHL databases that focused on studies about electrophysiological biomarkers of AD from 2015 to 2022. Twenty-seven peer-reviewed studies met this review's inclusion criteria. Five themes emerged: (1) assessing/screening, (2) assessment differential, (3) diagnosing, (4) diagnostic accuracy, and (5) treating. These themes related sequentially and linearly, establishing a developing relationship about the risk, the onset, and the progression of AD. Electrophysiological biomarkers associated to cognitive impairment in AD, supporting the accepted understanding of the symptoms of AD. Changes in behavior and functioning were not examined, limiting the possible integration of electrophysiological biomarkers. Further investigations are warranted with an expansion of the clinical symptoms and diverse study populations.
PubMed: 38954497
DOI: 10.1080/01612840.2024.2352011 -
Natural Products and Bioprospecting Jul 2024Alzheimer's disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula...
Alzheimer's disease (AD) is a complex neurodegenerative condition. 5α-epoxyalantolactone (5α-EAL), a eudesmane-type sesquiterpene isolated from the herb of Inula macrophylla, has various pharmacological effects. This work supposed to investigate the improved impact of 5α-EAL on cognitive impairment. 5α-EAL inhibited the generation of nitric oxide (NO) in BV-2 cells stimulated with lipopolysaccharide (LPS) with an EC of 6.2 μM. 5α-EAL significantly reduced the production of prostaglandin E2 (PGE) and tumor necrosis factor-α (TNF-α), while also inhibiting the production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proteins. The ability of 5α-EAL to penetrate the blood-brain barrier (BBB) was confirmed via a parallel artificial membrane permeation assay. Scopolamine (SCOP)-induced AD mice model was employed to assess the improved impacts of 5α-EAL on cognitive impairment in vivo. After the mice were pretreated with 5α-EAL (10 and 30 mg/kg per day, i.p.) for 21 days, the behavioral experiments indicated that the administration of the 5α-EAL could alleviate the cognitive and memory impairments. 5α-EAL significantly reduced the AChE activity in the brain of SCOP-induced AD mice. In summary, these findings highlight the beneficial effects of the natural product 5α-EAL as a potential bioactive compound for attenuating cognitive deficits in AD due to its pharmacological profile.
PubMed: 38954263
DOI: 10.1007/s13659-024-00462-y -
AAPS PharmSciTech Jul 2024Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c...
Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aβ) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aβ intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aβ. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aβ in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aβ aggregate acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aβ toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.
Topics: Animals; Amyloid beta-Peptides; Mice; Silybin; Mice, Inbred BALB C; Peptide Fragments; Neuroprotective Agents; Male; Brain; Particle Size; Nanoparticles; Reactive Oxygen Species; Disease Models, Animal; Alzheimer Disease; Acetylcholinesterase
PubMed: 38954224
DOI: 10.1208/s12249-024-02859-x -
European Journal of Nuclear Medicine... Jul 2024There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here,...
PURPOSE
There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils.
METHODS
SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aβ), K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies.
RESULTS
We optimized the protocol for the immobilization of Aβ, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aβ in arcAβ mice, and AT-8/AT-100-positivity in pR5 mice.
CONCLUSION
SPR measurements of small molecules binding to Aβ, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.
PubMed: 38953933
DOI: 10.1007/s00259-024-06806-7 -
Aging Cell Jul 2024Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are...
Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.
PubMed: 38953594
DOI: 10.1111/acel.14264 -
General Physiology and Biophysics Jul 2024Alzheimer's disease is currently not curable. Almost all attempts to identify disease-modifying drugs failed and the causes of disease etiology are not well understood....
Alzheimer's disease is currently not curable. Almost all attempts to identify disease-modifying drugs failed and the causes of disease etiology are not well understood. Neurofibrillary tangles composed of pathological tau protein belong to the main hallmarks of this disease. Identification of novel physiological and pathological tau interacting proteins may lead to a better understanding of Alzheimer's disease pathology and tau physiology and therefore we performed a screening of the brain library by a yeast two-hybrid system intending to identify new tau interaction partners. We identified CHORDC1 (cysteine and histidine-rich domain-containing protein 1) as a novel tau interaction partner by this approach. The CHORDC1-tau interaction was validated by co-immunoprecipitation from rat brain tissues and by in vitro co-localization in the cellular model expressing full-length human tau protein. We believe that our results can be useful for researchers studying tau protein in health and disease.
Topics: tau Proteins; Rats; Animals; Humans; Protein Binding; Brain; Protein Interaction Mapping; Two-Hybrid System Techniques
PubMed: 38953578
DOI: 10.4149/gpb_2024019